J Mol Neurosci DOI 10.1007/s12031-014-0252-4

Abstracts The 22 Annual Meeting of the Israel Society for Neuroscience (ISFN) & The 2nd Bi national Italy-Israel Neuroscience Meeting Hilton Queen of Sheba Eilat, December 14–17, 2013 nd

Journal of Molecular Neuroscience

The abstracts are presented according to alphabetical order based on the last name of the presenting author (underlined name)

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Israel Society for Neuroscience (ISFN) Committee Esther Shohami – President, ISFN The Hebrew University of Jerusalem Gabi Amitai – Past President, ISFN Israel Institute for Biological Research, Ness Ziona Rony Azouz Ben-Gurion University Alexander Binshtok The Hebrew University of Jerusalem Hagit Eldar-Finkelman Tel Aviv University Itamar Kahn Technion Haifa Rami Yaka The Hebrew University of Jerusalem Dan Frenkel – Treasurer Tel Aviv University Liat Nissanov – Administrative Assistant Herzlia

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Abstracts Journal of Molecular Neuroscience 2013 nd The 22 Annual Meeting of the Israel Society for Neuroscience (ISFN) & The 2nd Bi national Italy-Israel Neuroscience Meeting Hilton Queen of Sheba Eilat, December 14–17, 2013 The Israel Society for Neuroscience gratefully acknowledges the generous support of Abital Pharma Pipelines Ltd., Yokneam Adams Super Center for Brain Studies, Tel-Aviv University Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem School of Pharmacy, The Hebrew University of Jerusalem Goldschleger Conference Foundation, Weizmann Institute of Science Sagol School of Neuroscience, Tel-Aviv University Scientific Committee, the SINS 2012 Congress, Catania, Italy Sieratzki Family, London, UK Tel Aviv University The Dr. Miriam Sheldon G. Adelson Medical Ressearch Foundation (AMRF) The Leslie and Susan Gonda Multidisciplinary Brain Research Center, Bar Ilan University The Ministry of Science and Technology (MOST), Israel The National Institute for Psychobiology in Israel, Jerusalem The Nella & Leon Benoziyo Center for Neurological Diseases, Weizmann Institute of Science The Nella & Leon Benoziyo Center for Neurosciences, Weizmann Institute of Science Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer Sheva Alomone Labs, Jerusalem, Israel Alpha Omega Engineering, Nazareth, Israel Eisenberg Brothers Ltd. Air Port City, Israel Luigs & Neumann GmbH, Ratingen, Germany Mercury Ltd, Rosh Haayin, Israel NBT - New Biotechnology Ltd., Jerusalem, Israel Teva Pharmaceutical Industries Ltd., Petah Tikva, Israel TSE Systems, Bad Homburg , Germany

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A novel inhibitor of Caspase-6 provides protection against mutant huntingtin toxicity Aharony I. 1*, Ehrnhoefer D. 2, Shruster A. 1, Franciosi S. 2, Hayden M.R. 2,3, Offen D. 1 1 Human Molecular Genetics and Biochemistry, Felsenstein medical research center, Tel-Aviv Univ. 2 Centre for Molecular Medicine and Therapeutics, Univ. of British Columbia 3Teva Pharmaceutical Industries Ltd. Background: Huntington's disease (HD) is a devastating inherited neurodegenerative disease involving progressive motor, cognitive, and psychiatric symptoms. HD pathogenesis is strongly associated with caspase-6, which is activated early in the disease process, and inversely correlates with age of onset of HD patients. Furthermore, genetic prevention of caspase-6 cleavage of mutant huntingtin protects a mouse model of HD from neurodegeneration. Therefore, inhibiting caspase-6 activity was suggested as a therapeutic approach for HD. In aim to competitively inhibit caspase-6 activity we designed a peptide based on huntingtin's caspase-6 cleavage site, fused to a cell penetration peptide sequence. Results: The peptide, designated as ED11, significantly reduced caspase-6 activity in a cell free assay. In accordance with these findings, ED11 significantly decreased human mutant huntingtin direct proteolysis by caspase-6. Furthermore, ED11 efficacy in-vitro was demonstrated by its ability to protect PC12 cells from mutant huntingtin's toxicity. To evaluate ED11 efficacy in-vivo, we used the BACHD mouse model, which expresses human mutated huntingtin. BloodBrain-Barrier penetration was verified using fluorescent labeling and in-vivo tracking. ED11 was given continuously for four months by an implanted sub-cutaneous mini-pump, at a dose of 4mg/kg/day. We found that the ED11-treated mice demonstrated markedly preserved motor performance in the Rotarod test. In addition, depression-related immobility in the forced swim test was significantly reduced in the ED11treated BACHD mice. Moreover, anxiety-related behavior was reduced in the ED11-treated mice, as was demonstrated in the dark-light box and the elevated plus maze tests. Conclusions: ED11, a specific and potent caspase-6 inhibitor, provides neuroprotection in cell culture and in a mouse model of HD. This study may lay the foundations for a peptide based therapy in HD. Allostatic changes of the GABAergic system after traumatic experience in adulthood following exposure to 'Juvenile stress': Behavioral classification reveals differential expression patterns Albrecht A. 1,2*, Ardi Z. 1,3,2, Saha R. 1, Richter-Levin G. 1,3,2,4 1 Neurobiology and Ethology Dept. Univ. of Haifa, Israel 2 The Institute for the Study of Affective Neuroscience (ISAN) 3 The Brain and Behavior Research Center, Israel 4Psychology Dept., Univ. of Haifa, Israel

While most individuals are able to cope with traumatic experiences, a minority fails to recover and exhibits prolonged maladaptive behavioral and physiological alterations. Such a posttraumatic stress is characterized by persistently increased anxiety, hypervigilance as well as intrusive recollections of the traumatic experience that are often triggered by reminders of the initial trauma. Early-life stress is a predominant risk factor for developing PTSD symptoms. For understanding the neurobiological mechanisms of PTSD risk and resilience, a rat model was developed that combines juvenile stress and underwater trauma. Presentation of reminders of underwater trauma results in long-lasting alterations of activity and anxiety-like behavior that are further exacerbated by previous experiences of juvenile stress. A detailed classification of behavioral profiles revealed different behavioral phenotypes of affected animals (see poster by Ardi et al.). In these animals we now analyzed protein expression levels of GABAergic factors in limbic brain areas. Four weeks after underwater trauma altered expression was observed predominantly in animals with a history of juvenile stress. In the basolateral amygdala the expression of the GABA A receptor subunits alpha 1 and 2 as well as the GABA-synthetizing enzyme GAD65 was increased, while expression patterns were more distinct in subregions of the dorsal and ventral hippocampus. Based on the behavioral classification, expression patterns were compared in animals stated as affected or non-affected. Detailed analysis revealed that after combined juvenile stress and underwater trauma expression of the GABA A receptor alpha 1 subunit is highly increased in unaffected animals. This suggests that the alpha 1 subunit of the GABA A receptor can serve as a resilience factor, with increased expression after highly stressful events preventing the behavioral consequences of the stress exposure observed in the affected animals. This work was supported by A DOD award number W81XWH-11-2-0111 to GRL The role of Ventral Hippocampus GAD 65 in anxiolytic behavior Algon R. 1,2, Anunu R. 1,2, Muller B. 3, Stork O. 3, RichterLevin G. 1,2* 1 Sagol Dept. of Neurobiology and Ethology.Univ. of Haifa, Haifa, Israel 2 The Institute for the Study of Affective Neuroscience (ISAN). 3 Otto-von-Guericke Univ., Magdeburg, Germany Recent studies emphasize the importance of GABA and its Co-family factors in mediating affective disorders. In these stress related disorders, impaired learning abilities compromise the organism's ability to cope with stress. Previous study, conducted in O.Stork's lab revealed impaired learning abilities and increased anxiety levels in GAD65 KO mice. Another study, from our lab, found decreased levels of GAD 65 mRNA in the Ventral hippocampus (VH) after stress exposure. In the

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current study we aimed to compare the potential specificity of the role of GAD 65 in anxiety and in learning under stress, by comparing modulation of its expression in the VH compared to the dorsal hippocampus (DH). We used a lentivirus vector to down regulate GAD 65 directly in the ventral or dorsal hippocampus of adult SD rats (VH GAD65 Vs DH GAD65). The experiment groups were compared to control groups, which were injected with a control virus. The Elevated Plus Maze (EPM) test was performed in order to test changes in anxiety behavior. Learning ability and stress coping behavior were measured in the two-way shuttle test (TWS). VH GAD65 rats spent more time in the open arms and exhibited higher mobility rates, indicative of lower levels of anxiety. DH GAD65 rats did not display any changes in levels of anxiety relative to control. As for the learning abilities tested in the TWS, while Rats injected with the control virus showed high rates of performance, the VH GAD65 virus injected rats were impaired. DH GAD65 KO rats did not display any indication of learning. These results suggest that GAD65 down regulation in the VH leads to increased anxiety effects in rats and to a mild impairment in learning under stress. However, GAD65 down regulation in the DH, while does not alter anxiety levels, induces severe impairment in the ability to cope under stress. The results suggest that GAD65 expression contributes to the more emotional role of the VH and to the more cognitive role of the DH. Intermittent explosive disorder: characterizing the phenotype through brain-behavior modeling Alia-Klein N. 1*, Moeller SJ. 1, Frobose MI. 2, PrestonCampbell R. 1, Konnova AB. 3, Misyrlis M.4, Parvaz MA. 1, Goldstein RZ. 1 1 Dept. of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY 10 2 Radboud Univ. Nijmegen, Donders Institute for Brain, Cognition and Behaviour, Centre for Cognit 3 Dept. of Psychology, Stony Brook Univ., Stony Brook, NY 11794 4 Dept. of Computer Science, Stony Brook Univ., Stony Brook, NY 11794 Intermittent explosive disorder (IED) is quite prevalent and can complicate course of illness and recovery across many psychiatric disorders. Although explosive anger takes a heavy toll on patients and their victims, this problem is severely understudied. Here we present a series of fMRI paradigms interrogating basic brain and behavior mechanisms of IED. Compared to controls, results from the color-word Stroop task revealed higher (less optimized) error-related activity in IED in two core task regions relevant to conflict monitoring, error processing and cognitive control (anterior cingulate and dorsolateral PFC). Results from threat Stroop revealed higher activation to threat words in thalamus and parahippocampus and lower activation in dorsomedial PFC in IED . From the passively viewed emotional pictures, two-way interactions

between group x valence emerged in the right pallidum/ thalamus and midcingulate. Group x arousal were found in bilateral inferior frontal gyrus, right medial PFC, and pallidum (For all, p-uncorrected < 0.005). These interactions show abnormalities in PFC regulation and limbic reactivity in IED in both intensely pleasant or negative stimuli. Notably, across participants and tasks, trait anger correlated with activations in most of these regions of difference: pallidum/thalamic (r = -0.485, p < 0.05) midcingulate (r = 0.505, p < 0.05) and dorsolateral PFC (r=0.41, p < 0.005). The emerging brain behavior patterns in IED suggest a deficit in executive function commonly observed in disorders of self-control, while pointing to subcortical (instead of prefrontal) management of threat and emotional stimuli of intense valence and arousal. It appears that underlying these abnormalities in IED are their individual differences in trait anger. Treatment strategies might be focused on strengthening cortical control while reappraising hyper-responsivity to emotionally arousing cues. Supported by NIMH R01MH090134 and NIDA R21DA034954 Small Molecule Scavengers for mitigating nerve agents poisoning: in vitro and in vivo efficacy Amitai G 1*, Chapman S 1, Gez R 1, Raveh L 1, Bar-Ner N 1, Ashkenazi N 1 1 Div. of Medicinal Chemistry, IIBR, PO Box 19 Ness Ziona 74100, Israel The need for more effective medical countermeasures toward toxic organophosphorus (OP) nerve agents was accentuated by the recent tragic events in Syria. In contrast toenzyme bioscavengers that may create immunogenic response and excessivepayload due to their large molecular size (MW 4080KD), we have developed new small molecules scavengers (SMS, MW 300-600D) for active detoxification of nerveagents. The molecular design was based on combining two functions in onemolecule i.e. direct degradation of OPs and reactivation of OP-inhibited AChE. Degradation of OPs was achieved by substituted benzhydroxamic (BHA) and pyridinehydroxamic acid (PHA) derivatives. Certain BHAs and PHAs were coupled via various linkers to pyridine oximes providing hybrid compounds. Thus, 12 new bifunctional SMS were synthesized. Two hybrid compounds 2-PAM-Pr-4PHA (PAPP) and 2-PAM-Me-BHA (PAMB) displayed rapid detoxification toward sarin, cyclosarin and soman as well as reactivation toward OP-AChE in vitro. PAPP displayed a 10-fold faster kinetics than 2-PAM toward cyclosarin-inhibited AChE. Both hybrid compounds exhibited high decontamination activity (88-98%) toward VX on pig-ear skin in vitro. PAPP and PAMB are relatively non-toxic compounds LD50, im >568, 508 μmole/kg in rats and 144, 203 μmole/kg in guinea pigs, respectively. Pharmacodynamics (PD) of PAPP and PAMB in rats in pre- and post-exposure to 0.8xLD50sarin demonstrateda

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dose-dependent faster ChE regeneration than either 2PAM (in conjunction withatropine) or atropine alone. Antidotal efficacy of PAPP and PAMB administered as pre-treatment toward sarin poisoning in rats yielded Protection Ratios (PR =LD50 with treatment/LD50 without) of 11.6 and 11.5, respectively, compared to 5.5 with 2PAM (all treatments were in conjunction with atropine). Our in vivo safety, PD and antidotal PR data toward sarin indicate that these two hybrid compounds are promising novel scavengers of OP nerve agents. Supported by DTRA HDTRA1-C-12-0008 Spatial structure of spiking correlations in the barrel cortex of anesthetized rats Reyes-Puerta V.1, Amitai Y.2*, Shani, I.2, Sun JJ.1, Luhmann HJ.1, Shamir M.2, 3 1 Institute of Physiology, Univ. Medical Center, Johannes Gutenberg Univ., D-55128 Mainz, Germany. 2 Dept. of Physiology and Cell Biology, Ben-Gurion Univ. of the Negev, BeerSheva 84105, Israel. 3 Dept. of Physics, Ben-Gurion Univ. of the Negev, Beer-Sheva 84105, Israel. The properties of correlations between neuronal firing in the neocortex are important for cortical processing and encoding. It has been generally assumed, by virtue of the columnar organization of the neocortex, that the firing of neurons residing in a vertical domain is highly correlated. On the other hand, firing correlations between neurons are assumed to be weaker and to decline with horizontal distance. Technical difficulties in sampling multiple neurons with sufficient spatial resolution or information on precise location have precluded the critical evaluation of these notions. Multiple (up to 74) neurons were recorded simultaneously during spontaneous activity in the barrel cortex of anesthetized rats by silicon probes containing 8 shanks, each one hosting 16 electrodes. The laminar organization was determined by computing the current source densities from the local field potentials, and the location of the probe shanks with respect to the barrels was confirmed histologically. The time-spiking correlations were stable over periods of tens of minutes. Using eigen decomposition, we found that the correlations are composed of a small number of 2-3 significant principle components. The first principle component reflects a uniform collective mode of fluctuations, wherein all neurons increase (or decrease) their firing rate simultaneously. On the other hand, the second and third components demonstrate a spatial structure. Markedly, the second component displays a laminar structure, wherein layer 6 neurons fluctuate in opposite direction to neurons of layers 5 and 4. Moreover, we find that within each experiment, the distribution of the horizontal (within same lamina) correlation coefficients is practically identical to the distribution of vertical (within same column) correlation coefficients for horizontal distances of up to 700μm. Taken together, these data establish the laminar position of a neuron as a significant determinant of its spike-timing correlations.

Grant of the Deutsche Forschungsgemeinschaft to H.J.L. (BaCoFun, DFG FOR 1341). Differential effects of training regimen on the learning of speech and non-speech discrimination Amitay S 1, Banai K 2* 1 MRC Institute of Hearing Research, United Kingdom 2 Dept. of Communication Sciences and Disorders, Univ. of Haifa Background: While perceptual learning of speech was shown to generalise more widely when trained using a variable regimen, this was not the case for the perceptual learning of acoustic feature discrimination. Nevertheless, the two types of stimuli were rarely assessed using comparable training schedules. Results: Listeners concurrently trained on discrimination of either four synthetic syllable contrasts or four tone durations. During training, stimuli were presented either in a blocked (160 trials each stimulus, ran consecutively) or a roving (all four stimuli randomly interleaved within each 160-trial block) training schedule. All listeners trained for a total of 640 trials per session for 9 sessions, interspersed over 1-2 months. All completed a pre- and post-test that included testing on all stimuli, presented either in blocks or roved for separate groups. Regardless of training schedule, speech-trained listeners showed significant improvement on speech stimuli compared to duration-trained listeners, who showed no learning effects whatsoever. Learning on the speech stimuli did not generalise to the acoustic stimuli. Although roving impeded naïve discrimination performance, training with either blocked or roved speech stimuli resulted in similar posttraining thresholds for both blocked and roved speech stimuli. It is unclear why no learning was observed for the blocked duration training. Conclusions: Roving and blocked training regimens were equally efficient (or inefficient) for perceptual learning. Whereas speech learning appears robust, durationdiscrimination learning seems highly sensitive to the particulars of the training schedule. The National Institute of Psychobiology in Israel and the Medical Research Council, UK. NCX activity in astrocytes, microglia and oligodendrocytes during brain ischemia Boscia F 1,2, Casamassa A 1,2, Pannaccione A 1,2, Secondo A 1,2, D'Avanzo C 1,2, Formisano L1,2, Guida N 1,2, Scorziello a 1,2, Di Renzo G 1,2, Annunziato L. 1,2* 1 Federico II Univ. of Naples, School of Medicine 2 Dept. of Neuroscience The Na+/Ca2+ exchanger (NCX), a key mediator for [Na+]i and [Ca2+]i homeostasis, has been proposed as a potential therapeutic target in different disorders of the CNS, including stroke, de-myelinating conditions such as Multiple Sclerosis,

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and spinal cord injury. It is now clear that changes in [Ca2+]i have a critical role in inducing and maintaining microglia and oligodendrocytes responses to the brain injury. Our studies revealed that 3 and 7 days after MCA occlusion,NCX1 signal increases in the round-shaped microglia invading the infarct core. NCX1 activity and expression were significantly enhanced both in cultured microglia from the core and in BV2 microglia exposed to OGD. Conversely, the protein expression of NCX2 and NCX3, significantly decreased. Expression and functional studies suggest that NCX3 represents the main isoform expressed in mature oligodendrocytes and, consequently, the main contributor to NCX currents recorded in these cells. The importance of calcium signaling mediated by NCX3 exchanger during oligodendrocyte development and myelin formation was supported by several findings: (1)the knocking-down of NCX3 expression and activity by siRNA strategy in OPC cultures prevented the up-regulation of the myelin markers; (2)NCX3 overexpression induced the up-regulation of the myelin markers; (3)NCX3 KO mice exhibited hypomyelination that is accompanied by an augmented OPC cell number and a reduction of spinal cord size. Our results suggest that calcium signaling mediated by NCX1 and NCX3 might play a relevant role in modulating microglia and oligodendrocyte responses to the brain injury. References: Annunziato L, Boscia F, Pignataro G. J Cereb Blood Flow Metab. 33:969-82. 2013. Boscia F, D'Avanzo C, Pannaccione A, Secondo A, Casamassa A, Formisano L, Guida N, Sokolow S, Herchuelz A, Annunziato L. Cell Death Differ. 19:562-72. 2012. Boscia F, Gala R, Pannaccione A, Secondo A, Scorziello A, Di Renzo G, Annunziato L. Stroke. 40:3608-17. 2009 The eye as a novel model system for studying Alzheimer's disease genetic risk factor Antes R. 1*, Salomon-Zimri S. 1, Solomon A. 2, Weinberger D. 3, Ofri R. 4, Michaelson DM 1 1 The Dept. of Neurobiology, The Sagol School of Neuroscience, Tel Aviv Univ. 2Goldschleger Eye Research Institute, Chaim Sheba Medical Center, Tel Hashomer, Israel 3Dept. of Ophthalmology, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel 4 Koret School of Veterinary Medicine, Faculty of Agriculture, Hebrew Univ., Rehovot, Israel Background: Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD) is involved in neuronal and vascular impairments in both the brain and the eye. The objective of this study is to establish the mouse eye as a model for studying the neuronal and vascular pathological effects of apoE4 and to understand whether there is a common mechanism underlying them. We have used the retina of 4 months old naïve apoE3 and apoE4-targeted replacement mice as a model for studying the neuronal effects of apoE4,

and the RPE/choroid of laser treated apoE3 and apoE4targeted replacement mice as a model for studying the vascular pathology. Results: Immunohistochemistry and western blot analysis of 4 months old naive apoE3 and apoE4 mice revealed lower synaptic density in the retina of the apoE4 mice. This was associated with a decrease in excitatory synapses and impaired retinal function as measured by electroretinography (ERG). Studies of the effects of apoE4 on the vascular system utilizing the laser induced choroidal neovascularization (CNV) paradigm showed that apoE4 mice are hyper-sensitive to the laser insult. Accordingly, the density of the pathological blood vessels in apoE4 was significantly higher. The level of Vascular endothelial growth factor (VEGF), a well known neurotrophic and angiogenic growth factor, were shown to be lower in the impaired retinas of the naïve apoE4 and higher in the hyper-vascular choroid of the laser treated apoE4 mice. Conclusions: These findings show that the eye is an excellent model system for investigating the neurovascular system. Using this system we were able to show that VEGF is playing a role in mediating both the neuronal and vascular pathologies of apoE4 in the eye, seting the stage for a novel therapeutic target for counteracting the effects of apoE4 by anti-VEGF treatment. 'Juvenile stress' exacerbates the impact of an exposure to an odor reminder of a traumatic experience in adulthood Ardi Z. 1,2,3*, Richter-Levin A. 2,4, Richter-Levin G. 1,2,3,5 1 Neurobiology and Etiology Dept., Univ. of Haifa, Israel 2 The Brain and Behavior ResearchCenter, Israel 3 The Institute for the Study of Affective Neuroscience (ISAN) 4 he Institute for the Study of Affective Neuroscience (ISAN) 5 Psychology Dept., Univ. of Haifa, Israel While most individuals are able to cope with trauma, a minority fail to recover and exhibit prolonged and maladaptive behavioral and physiological responses to the traumatic experience. Many times, these are manifested as symptoms of PTSD. Among the many proposed risk factors, early-life stress is predominantly associated with higher prevalence of both mood and anxiety disorders, particularly depression and PTSD (Heim & Nemeroff, 2001). Dealing with PTSD, a core symptom is intrusive recollections of the traumatic experience. These episodes of re-experiencing are often triggered by reminders (e.g. places, sights, sounds and other sensations) of the traumatic event (Kardiner, 1941; Marx and Soler-Baillo, 2005). Therefore, the aims of the study is was aimed to examine the long term ability of an odor reminder to act as an effective reminder of the traumatic experience (UWT) and to evaluate the ability of an exposure to 'juvenile stress' to act as a predisposing factor that will exacerbate the impact of such

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a reminder exposure in adulthood. Results suggests that stress in juvenility exacerbates the effects of an exposure to the UWT in adulthood and an exposure to a reminder of the UWT on the background of a previous exposure to stress in juvenility exacerbates these effects even further In addition, classifying the behavioral profiles of affected animals revealed different behavioral phenotypes within each of the populations.

The effects of parental exposure to escitalopram or to a novel herbal treatment on the expression of serotonin transporter in the brain of offspring mice Armoza S. 1*, Atrakchi D. 2, Doron R. 2,3, Rehavi M. 1 1 Dept. of physiology & Pharmacology, Sackler Faculty of Medicine , Tel-Aviv Univ. 2Dept. of Behavioral Science, The Academic Col. of Tel-Aviv Yaffo 3 Dept. of Education and Psychology, The Open Univ.

Early iron deficiency predicts right frontal EEG asymmetry in infancy Armony-Sivan R. 1,2*, Shao J. 3, Xu L. 3, Li M. 3, Clark K. 2, Richards B. 2, Lozoff B. 2 1 Dept. of Psychology, Ashkelon Academic College, Ashkelon, Israel 2 Center for Human Growth and Development, Univ. of Michigan, Ann Arbor, MI, USA 3 Dept. of Child Health Care, Children's Hospital Zhejiang Univ., Hangzhou, China

In recent years, anxiety disorders have reached epidemic proportion worldwide. These disorders are common among pregnant women and may be harmful not only to the mother but also to the fetus. The serotonergic system is known to modulate mood, emotion, sleep and appetite. Altered activity of brain serotonergic system has been implicated in a wide range of behavioral disorders, including anxiety. Serotonin transporter mediates serotonin levels in the synapse, and its inhibition by selective serotonin reuptake inhibitors (SSRIs) serves as the first line treatment for anxiety disorders. Treatment with SSRIs during pregnancy might lead to development abnormalities of the offspring. Therefore, the aim of the present study was to evaluate the effects of maternal exposure to escitalopram, commonly used SSRI, compared with a novel herbal treatment developed in our laboratory, during pregnancy on the expression of serotonin transporter in offspring mice. On the eighth day of their pregnancy, female mice were randomly divided into four treatment groups: (a) herbal treatment (30mg/kg per day) (b) escitalopram (15mg/kg per day) (c) vehicle (d) control (did not receive any treatment). On post natal day 30, offspring's anxiety-like behaviors and physiological changes, were evaluated. We found that offspring of mice treated with escitalopram, herbal treatment or vehicle during pregnancy demonstrated lower levels of serotonin transporter in the hypothalamus and pre-frontal cortex than controls. In addition, the herbal treatment showed the least anxiety behavior in the elevated plus maze, and that the escitalopram was the least active in the open field test. These results suggest that further studies are needed in order to understand the implications of SSRIs or herbal treatments on the serotonergic physiology in pregnant mice. Israel Science Foundation, National Institute for psychobiology and the Open Univ. of Israel

Background: Iron deficiency (ID) during infancy is associated with altered cognitive, motor, and social-emotional outcomes. For instance, ID infants show more shyness, poorer orientation-engagement and soothability, decreased positive affect and less optimal mother-infant interaction than infants without ID. The purpose of the present study was to evaluate the effects of ID on frontal EEG asymmetry as an indicator of social-emotional development. Frontal EEG asymmetry scores reflect social-emotional status such that right frontal asymmetry is related to behavioral withdrawal and negative emotional state, and left frontal asymmetry is related to approach behavior and positive emotional state (Davidson, 1984). In this study, we focused on the effects of timing of ID (pre- or postnatal) on frontal EEG asymmetry in 3 conditions: resting, stranger approach, and peek-a-boo. We hypothesized that ID early in life would be associated with behavioral withdrawal and more negative emotional state, as indexed by more right frontal asymmetry. Results: In mixed model analyses for iron group (pre- & postnatal ID, n=9; pure prenatal ID, n=21; pure postnatal ID, n=20; iron-sufficient [IS], n=30) and condition (resting, stranger approach, peek-a-boo), controlling for background factors, there was a main effect for iron group (F(3,68)=2.731; p=.05). Negative asymmetry scores were found in the pre- and postnatal ID group (estimated mean±SE = -.184±.068) compared to the pure prenatal ID group (.002±.044), pure postnatal ID group (.029±.045), and IS group (.02±.037). There were no statistically significant differences between the 3 conditions and no significant interaction between iron group and condition. Conclusions: Right frontal EEG asymmetry, which indicate behavioral withdrawal and negative emotional state, was associated with chronic ID in early life, i.e., pre- and postnatal. Combined pre- and postnatal ID is common worldwide.

Using olfactory aversive conditioning during sleep to reduce the urge to smoke Arzi A. *, Holtzman Y. , Samnon P. , Eshel N. , Harel I., Sobel N. Neurobiology Dept., Weizmann Institute of Science, Rehovot, Israel Cigarette smoking is a public-health problem associated with significant morbidity and mortality, however smokers often fail to quit due to nicotine withdrawal symptoms. Behavioral strategies complement to pharmacotherapy may have a

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significant contribution to the quitting process. Recently it was shown that new associations could be learned during sleep and this learning is sleep stage dependent. Specifically, retention of the new association in wake occurs after stage 2 but not after REM sleep. Combining these findings we set out to ask whether conditioning between cigarette odor and profoundly unpleasant odors during sleep can reduce the urge to smoke. To test this, 43 adult smokers wanting to quit, slept one night in the sleep lab while olfactory aversive partial conditioning took place: cigarette odor was followed by unpleasant odor of rotten fish or rotten eggs during either Stage 2 or REM sleep (odor duration=3 seconds, 30 repetitions, ITI=25-40 seconds, pairing ratio of 2:1). As a control the same unpleasant odors were presented but without the cigarettes odor. Participants completed a smoking diary for seven days prior to coming to the sleep lab and for seven days after the stay at the sleep lab, detailing the number for cigarettes smoked in each day. Analysis of variance of smoked cigarettes number, with condition of time (before sleep/After sleep), sleep stage (REM/Stage 2) and group (experimental/Control) revealed a main effect of time (F(1,42)=22.9, p<0.00005). Post-hoc analysis revealed that participants that were presented with the aversive conditioning during stage 2 sleep smoked ~30% less cigarettes in comparison to the control group (F(1,19)=5.0, p<0.05), however participants that were presented with the aversive conditioning during REM sleep did not smoke less (F(1,19)=0.15, p>0.7). To conclude, we have found that aversive odor conditioning between cigarette odor and unpleasant odors during stage 2 sleep can facilitate smoking cessation. Anxiety modulates the effect of negative prime-valance on visuo-spatial information processing Avnit A. *, Kalanthroff E. , Ganor N. , Henik A. Dept. of Psychology, Ben-Gurion Univ. of the Negev, BeerSheva, Israel Background: Studies examining global-local processing style have found that anxious individuals use a more local visuo-spatial information processing style, and that sad mood or stress can elicit a more local processing bias. The effect of briefly presented emotional stimuli on a basic global-local task has not been investigated previously with anxious participants. The current study aims to investigate the interaction between prime-valence and anxiety by studying the global-local processing style of anxious participants and controls, with and without presenting task-irrelevant emotional pictures. Method: Fifteen anxious participants and sixteen healthy controls completed two tasks: (1) a standard global-local arrow task, and (2) an emotional global-local arrow task— similar to the standard task but with a neutral or negative valence-prime preceding the target.

Results: In the first task, the anxiety group did not differ from the control group—both groups showed a global processing bias. In the second task, following a negative prime, healthy controls showed a slightly reduced global processing bias, whereas anxious participants shifted their visuo-spatial attention and showed significantly more local processing— the global bias was completely eliminated. Conclusions: We conclude that a briefly presented negative prime can diminish global bias, especially for individuals suffering from anxiety. The present study results can account for much of the known findings in the literature on attention and general performance among anxious individuals. Furthermore, considering the findings that global processing helps avoid attentional capture and assists with overcoming obstacles, our results shed new light on the mechanisms underlying anxiety symptoms. Klotho increases remyelination in a mouse model of MS Abraham, CR. Departments of Pharmacology and Experimental Therapeutics and Biochemistry, Boston University School of Medicine, Boston, Massachusetts Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system that often progresses to significant chronic disability. Impaired remyelination is a common pathologic feature of MS and may largely account for disability and incomplete remissions in MS. There is strong evidence that in MS there are sufficient oligodendrocyte precursor cells around MS plaques but they do not develop into mature, myelin-forming oligodendrocytes. We discovered that the anti-aging protein Klotho is reduced in the aging white matter of mammals and, in vitro, Klotho induced the maturation of the oligodendrocyte precursor cells (OPCs) into myelinating oligodendrocytes. Furthermore, Klotho deficient mice have very hypomyelinated corpus callosum and optic nerves. Finally, our recent work in Klotho OE mice is a strong proof of concept that enhancing Klotho is beneficial for MS. Klotho overexpressing (KLOE) and control wild type littermates (WT) were given in their chow cuprizone, a poison that causes demyelination. After 6 weeks of cuprizone they consumed 3 weeks of normal chow to allow for spontaneous remyelination. The demyelination was identical in both groups but the KL-OE mice had twice as many myelinated fibers than the WT mice after 3 weeks of remyelination. P value is 0.01 with only 6-8 mice per group. Thus, increasing Klotho levels improved significantly the remyelination. We have identified Klothoenhancing compounds in a high throughput screen and optimized the lead compounds which are now ready to be tested in MS animal models. The hope is that compounds that increase expression of Klotho would have similar activity as Klotho itself.

J Mol Neurosci

Neuroprotective effects of the major metabolite of the anti-Parkinsonian drug rasagiline, 1-(R)-aminoindan in animal model of aging Badinter F. 1, Weinreb O. 1*, Bar-Am O. 1, Amit T. 1, Youdim M.B. 1 1 Eve Topf Centers of Neurodegenerative Diseases Research, Technion-Faculty of Medicine, Haifa, Israel Background: Previously we have demonstrated the neuroprotective effects of the major metabolite of rasagiline (Azilect®), 1-(R)-aminoindan in vitro and in-vivo models of Parkinson's disease. This study was undertaken further to explore the neuroprotective/neurorescue effects of 1-(R)aminoindan in animal models of aging. Results: Chronic treatment (2 months) of aged mice and rats (23-24 months-old) with 1-(R)-aminoindan (1 and 5 mg/kg) and rasagiline (0.2 mg/kg) had a significant positive impact on behavioral age-related impairments. Our results also demonstrated that similar to rasagiline, 1-(R)aminoindan caused a significant increase in levels of striatal dopamine and serotonin in drug-treated, compared to vehicle-treated aged animals. In addition, 1-(R)-aminoindan treatment increased striatal mRNA expression levels of D1 and D2 dopamine (DA) receptors, DA transporter, Bcl2 and tyrosine hydroxylase (TH). Both rasagiline and 1-(R)aminoindan up-regulated cerebral catalase mRNA expression levels and enzyme activity, suggesting their antioxidative effects. Another interesting finding is that 1-(R)aminoindan up-regulated mRNA expression levels of glial cell-derived neurotrophic factor (GDNF), brain derived neurotrophic factor (BDNF), tyrosine kinase (Trk)-B and synapsin-1, indicating that this major metabolite of rasagiline may possess regulatory effects on neurotrophic signaling pathways. Conclusions: These findings suggest that 1-(R)-aminoindan may contribute to the overall neuroprotective/neurorescue activities of the parental compound, rasagiline. Teva Pharmaceutical Industries Ltd. (Israel) More pain more gain: longer training on time-compressed speech widens the scope of generalization to untrained tokens Banai K. 1*, Lavenr Y. 2 1 Dept. of Communication Sciences and Disorders, Univ. of Haifa 2 Dept. of Computer Science, Tel-Hai College Background: Brief experience with distorted (e.g., timecompressed) speech, which is often incomprehensible to naïve listeners, yields both learning and generalization. Whether such learning continues beyond a few dozen sentences is not clear, because the outcomes of intensive training and brief exposure were rarely compared for the same type of distortion. Although a prolonged learning-phase was documented in

some studies, the difficulties experienced by even highly experienced non-native speakers in their second language suggest that this learning might generalize to a lesser extent than initial learning. Our aim here was to determine whether protracted training on time-compressed speech yields additional learning and generalization to those induced by brief exposure. Results: Naïve listeners practiced the semantic verification of time-compressed sentences for one or three sessions of 300 trials each. Identification of tokens compressed to 0.3 of their original duration was then compared between the trained listeners and 'brief exposure' group on the trained and untrained conditions. Significant learning was observed in both trained groups throughout training. Both trained groups learned significantly on the trained condition compared with the brief-exposure group and generalized this learning to a new speaker. However, significant generalization to new tokens was only observed after three training sessions. Conclusions: Learning on a time-compressed speech task continues beyond an initial exposure phase for at least three sessions of 300 trials each. Furthermore, longer training was associated with more learning and wider generalization than shorter training. These findings suggest that although learning of distorted speech can occur rapidly, more stable learning and generalization might be achieved with longer, multi-session practice. Marie Curie IRG-224763 and the National Institute of Psychobiology in Israel Transitions in the transcriptome of the serotonergic and dopaminergic systems across the human brain during adolescence Bar-Shira O. 1*, Shoval G. 2, Zalsman G. 2, Mann J.J. 3, Chechik G. 1 1 Gonda Brain Research Center, Bar-Ilan Univ. 2 Geha Mental Health Center 3 Division of Molecular Imaging and Neuropathology, Dept. of Psychiatry, Columbia Univ. Background: Adolescence is a period of profound neurophysiological, behavioral, cognitive and psychological changes, but little is known about the underlying molecular neural mechanisms. Serotonin and dopamine are believed to be involved in these changes, but the exact genes and receptors involved are not characterized. We analyzed the mRNA expression profiles of genes that code for all components of serotonergic and dopaminergic synapses, in 16 brain areas from human and nonhuman primates from public domain databases, to detect genes whose expression changes during adolescence. Results: Analyzing mRNA measurements collected from 16 brain regions of human subjects, including 4 prefrontal cortical regions, we found that two serotonin receptors, HTR1E and HTR1B, exhibit a sharp rise in their expression

J Mol Neurosci

in all prefrontal regions during adolescence: the ventrolateral, dorsolateral, medial and orbital prefrontal corteices. A more moderate transition in these genes is observed in six other cortical areas. A similar but smoother rise in expression levels is observed in HTR4 and HTR5A, and an earlier rise is observed in HTR1A. We found no similar transition in the dopaminergic system. We found HTR1E and HTR1B to exhibit a similar though smoother rise in two other expression datasets collected from human brains. Also, a smooth and significant rise during the parallel adolescence period was observed in the expression of HTR1E in microarray measurements in macaque monkeys. In addition to the age effect, the expression of HTR1E and HTR1B is correlated across subjects within each age group, suggesting that they may be controlled by common mechanisms. Conclusions: These results point to HTR1E and HTR1B as major candidate genes involved in adolescence maturation processes and to their operation through common control mechanisms. The maturation profiles may also involve several other serotonin receptors, including the genes HTR5A, HTR4 and HTR1A. High resolution analysis of sniffing-whisking patterns during object-approach in autism-related mouse models Barak N 1*, Deutsch D 1, Shapiro A 1, Gordon G 1, Assa E 1, Oram T 1, Yizhar O 1, Ahissar E 1, Kimchi T 1 1 Dept. of Neurobiology, Weizmann Institute of Science, Rehovot 7610001, Israel Background: Autism spectrum disorders (ASD) patients commonly present abnormalities in sensory regulation, hyper/hypo reactivity to sensory inputs, unusual interests in sensory aspects of the environment, and often also motor deficits. Studying sensory and sensory-motor deficits in rodent models of autism should preferably focus on their major sensory modalities: touch (via whisking) and olfaction (via sniffing). Like seeing in humans, touching and smelling in rodents are active sampling processes whose accuracy depends on their exact motor-sensory coordination. Here we present a method to examine the behavior of individual sensory modalities, and their interactions, at high resolution. Methods: Using high-speed (500fps), high-resolution (1280x1024px) videography we track the approach patterns of mice towards unfamiliar objects, focusing on locomotion, whisking and sniffing. Using automatic tracking tools we analyze approach patterns at high resolution in both normal developing mice and ASD model mice. Conclusions: This work suggests a new potential fine evaluation tool for sensory-motor deficits in rodents. We expect that this tool will reveal deficits in sensory-motor patterns that may explain core deficits in sensory-motor behaviors of ASD patients.

The whole is different from the sum of its parts Barak O. 1*, Ben Dayan Rubin, D. 2 1 Faculty of Medicine, Technion - Israeli Institute of Technology 2 ICRI, Intel Collaborative Research Institute, Intel Labs, Israel Background: The brain is composed of vast networks of neurons, capable of performing a myriad of impressive tasks. In particular, in the temporal domain, neural networks are able to integrate information over extended periods of time, despite the fact that an individual action potential of a single neuron is an event of roughly a millisecond. A large literature is dedicated to understanding this apparent discrepancy, illustrating how extended timescales can be viewed as emergent network phenomena. The single neuron, however, does not operate on a millisecond timescale, but rather has a large range of timescales up to many hours. This observation raises the question of what is the added advantage of networks, from the temporal perspective, compared to the performance of single neurons. Results: Here, we investigate the memory capacity of networks composed of neurons with slow timescales. Using numerical simulations, within the context of reservoir computing, we show that slow timescales can improve memory capacity, but the timescale itself is not the sole determinant of this improvement. Rather, the form of coupling between the slow and fast variables affects performance, and slow timescales can sometimes be detrimental to memory capacity. Furthermore, we show that by modifying connectivity, networks can extract the task relevant timescales from their constituent neurons, while suppressing those that might harm the task. Conclusions: Our results indicate that slow timescales present in single neurons can both aid and damage network performance. Long term plasticity can sculpt the temporal landscape of single neurons into one that is more fitting to the task at hand. GDNF is an endogenous protector against excessive alcohol consumption and relapse Barak S. 1,2*, Ron D. 3,4 1 School of Psychological Sciences, Tel Aviv Univ. 2 The Sagol School of Neuroscience, Tel Aviv Univ. 3 The Gallo Research Center, Univ. of California, San Francisco 4 Dept. of Neurology, Univ. of California, San Francisco Background: Moderate social consumption of alcohol is common, however some individuals transit to excessive drinking and alcohol addiction. The molecular and neural mechanisms that protect most individuals from developing alcohol addiction are not well-understood. We previously showed that infusion of glial cell line-derived neurotrophic factor (GDNF) into rats' ventral tegmental area (VTA) suppresses alcohol reward, consumption and relapse, via activation of the mesolimbic dopaminergic system. Here, we tested

J Mol Neurosci

whether GDNF controls the transition from moderate to excessive alcohol consumption and relapse, and whether these effects are mediated by mesolimbic dopamine projections. Results: GDNF levels were downregulated or upregulated in the nucleus accumbens (NAc) or VTA via viral-mediated gene delivery. Small hairpin (sh)RNA-mediated downregulation of GDNF in the NAc resulted in a rapid escalation to excessive alcohol consumption and substantially enhanced relapse. Conversely, GDNF overexpression in the mesolimbic system blocked the escalation to excessive alcohol drinking. In addition, we found that GDNF overexpression increases the firing rate of VTA neurons, whereas withdrawal from excessive alcohol consumption reduces VTA dopaminergic firing. Importantly, GDNF reversed alcohol-induced DA deficiency. Conclusions: These findings suggest that endogenous GDNF in the mesolimbic system gates the transition from moderate to excessive alcohol drinking and relapse via reversal of neuroadaptations in mesolimbic dopaminergic neurons. Thus, while GDNF reverses withdrawal-associated allostatic dopamine deficiency, it does not possess abuse liability, but rather acts to inhibit alcohol reward and seeking. This work was supported by NIAAA R01 AA014366 and the State of California. Rapid reactivation of the axonal Na+ channels during interspike intervals underlies high frequency burst firing Baranauskas G. 1,2, Fleidervish I.A. 1* 1 Dept. of Physiology and Cell Biology & Zlotowski Center for Neuroscience, Ben-Gurion Univ. 2 Background: Action potentials (APs) in layer 5 cortical pyramidal neurons are typically followed by an afterdepolarization (ADP), which in some neurons gives rise to a burst of spikes. Such burst firing is characterized by brief interspike intervals of less than 10 ms (firing frequency > 100 Hz) at room temperature and it is believed to play an important role in information processing, neuronal plasticity as well as in initiation and propagation of epileptic discharges. Understanding of the mechanisms of burst generation therefore is of great interest. During the burst firing, most APs arise from voltages of ~20 mV above the rest, at which, in accordance with the voltage clamp estimates, there should be almost no Na+ channels available. Results: We tested the somatic and axonal Na+ channel availability at different voltages using the phase plot analysis of AP upstroke in combination with measurements of Na+ fluxes using fast fluorescence imaging of a Na+-sensitive indicator, SBFI. APs were elicited either by delivering brief current pulses via the somatic whole cell pipette or by antidromic stimuli. We found that: i) the resting axonal Na+ channel availability was nearly maximal, as stepping the membrane to very negative potentials caused no significant increase in Na+ influx; ii) during ADP, Na+ channel

availability recovered rapidly to >50% of its resting value; iii) the antidromic AP threshold was nearly unchanged during the ADP. Conclusion: Contrary to expectations, >50% of the axonal Na+ channels are available at the near threshold voltages. Voltage dependence of steady state inactivation of these channels is significantly rightward shifted and the recovery from inactivation rate is more rapid than that estimated in voltage clamp experiments. Supported by the Israel Science Foundation grant 1593/10 The therapeutic impact of thalidomide analogue, 3,6'-dithiothalidomide, on recovery from minimal traumatic brain injury Barazt-Goldstein R. 1*, Rubovitc V. 1, Tweedie D. 2, Scheriber S. 1,3, Greig N.H 2, Pick C.G 1 1 Dept. of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv Univ., Israel 2Drug Design and Development Section, IRP/NIA/NIH, Baltimore, Maryland, USA 3 Dept. of Psychiatry, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel Introduction: Traumatic brain injury (TBI) is a leading cause of deathand lifelong disability in individuals under the age of 50. The main reasonsfor TBI are car accidents, attacks and falling. mTBI (mild traumatic braininjury) accounts for 8090% of total brain injuries. mTBI may lead to short andlongterm cognitive, emotional, and behavioral deficits. As yet, there is no effective treatment or cure for patientswith mTBI. Tumor necrosis factor-alpha (TNF-a) is a cytokine that is fundamental in the systemicinflammatory process. TNF-a l ev e l s a r e a l t e r n a t e d p o s t T B I a n d c a n l e a d t o secondarydamage to the brain tissue and instigate an apoptotic cascade in susceptibleneurons leading to dysfunction or death. 3,6'-dithiothalidomide has been synthesized to reduce TNFRmRNA stability via its 3'-UTR, both the cytosolic and the transmembrane TNF-a. Previous experiments from our labhave shown that mTBI may lead to cognitive impairments. Theseimpairments were reversed in mice that were treated with 3,6'-dithiothalidomideafter the injury. Methods and Results: In the present study we investigated changes in neuronal loss,apoptosis and astrocyte number after treatment with 3,6'-dithiothalidomide. 3'6,dithiothalidomide was injected 1 hr. post closed head weight dropinjury. Brains were removed 72 hr. post injury. We found increased neuronal loss(NeuN), astrocyte number (GFAP) and apoptotic death (Bid) post mTBI in theDentate Gyrus and in the cortex. 3,6'-dithiothalidomide reduced these elevation, and therewere no differences between mice that received the treatment and the shamgroup. Conclusions: These findings may suggest a new therapeutic strategy totreat damages induced by mTBI. The current study may also shed new light on themechanisms that underlie 3,6'dithiothalidomide action.

J Mol Neurosci

Gene therapy with neurotrophic factors improved recovery after sciatic nerve injury in mice Glat M 1*, Benninger F 2, Ben-Zur T 3, Barhum Y 3, Steiner I 2, Yaffe D 4, Offen D 3 1 Sagol School of Neuroscience, Tel Aviv Univ. 2 Neurology Dept., Sackler Faculty of Medicine, Tel-Aviv Univ. 3 Felsenstein Medical Research Center 4 Dept. of Molecular Cell Biology, Weizmann Institute of Science Background: Damage to the sciatic nerve (Sciatica) is a common medical condition causing great morbidity. The usual causes include direct trauma, prolonged external pressure on the nerve, and pressure from disk herniation. Possible complications include loss of sensation in the leg and loss of motor control. In mild cases, conservative treatment is feasible but following a severe injury to the nerve, recovery may not be possible. Previously we have shown that transplantation of bone marrow derived stem cells or muscle progenitor cells that ectopically secrete neurotrophic factors improve and accelerate recovery of sciatic nerve damage. The aim of our current study was to evaluate the effect of neurotrophic factors in a sciatic nerve crush injury mouse model facilitated via viral vectors. Results: Mice injured at the sciatic nerve showed motor deficits and reduction in compound muscle action potential (cMAP) amplitude as well as reduced nerve conduction velocity. Recovery was monitored up to 40 days after injury and a significantly faster recovery was demonstrated in animals injected with viral vectors containing BDNF, GDNF, IGF-1, and VEGF genes as well with a mixture of these genes, compared to those injected with GFP gene or saline as controls. Conclusion: Our preliminary results indicate an enhaced recovery after sciatic nerve injury in mice transfected with one or all four neurotrophic factor genes. This indicate for further investigations and possible future clinical studies using direct transfection of neurotrophic factor genes to enhance recovery after nerve injury and prevent long term disability. Influence of Infant Aquatics on the neural development of premature infants Barmatz C. 1, Lazitz-Dor A. 1, Casher H. 2, Mekadesh K. 2, Morag I. 2, Bar-Yosef O. 3, Friedman H. 4* 1 Hydrotherapy, Sheba Medical Center, Israel 2 Neonatology Dept. Sheba Medical Center, Israel 3 Pediatric Neurology Institute, Safra Children’s Hospital, Sheba Medical Center, Israel 4 Dept. of nursing, Faculty of Social Welfare & Health Sciences, Univ. of Haifa, Israel Background: Infant Aquatics have been found to benefit infant health, being based on the physical properties of water and their physiologic outcomes on the motor, cardio-vascular, and respiratory functions. Preterm infants, a continuously growing population, are at risk for neurodevelopment

impairments ranging from Minor Neurological Deficits to Cerebral Palsy, mainly due to PeriVentricular Leucomalacia. Early detection and intervention for developmental impairments is crucial. Infant's spontaneous movements reflect neurodevelopment stages and abnormalities long before they are fully pronounced. Infant Aquatics adapted for young premature infants may strengthen function of autonomic nervous system, and advance brain development. The objective of this research is to examine the influence of Infant Aquatics on the neural development of preterm infants, as reflected by their spontaneous movements and extended developmental scales. Results: 50 premature infants are video recorded to assess their spontaneous random movements till they are 53 wPMA. Infant Aquatics is conducted in NICU and hydrotherapy pool (SMC Israel). Babies are placed in warm water in vertical and horizontal positions, supported by the buoyancy of water. Working technique employed exercises from "Halliwick", "Watsu" and "Jahara" approaches, modified for premature infants, including passive mobilization, combined rotations and more. Preliminary results show improved eye contact in vertical position and improved spontaneous movements' muscle tone and range of motion in supine float. Better feeding and improved sleep patterns were reported by the parents. Intervention and developmental tests will be extended till premature infants reach 12 months. Conclusions: Studies proved that early intervention may minimize developmental deficit for infants at risk. Our preliminary results show that early initiation of Infant Aquatics can improve motor and cognitive outcomes of preterm infants. A probabilistic model for auditory streaming Barniv D. 1*, Tsodyks M. 2, Nelken I. 1,3 1 The Edmond & Lily Safra Center for Brain Sciences, Hebrew Univ., Jerusalem, Israel 2Weizmann Institute of Science, Rehovot, Israel 3 Dept. of Neurobiology, Silberman Institute of Life Sciences, Hebrew Univ., Jerusalem The auditory scene is perceptually segregated into auditory streams. This phenomenon is often studied using a sequence of alternating tones, which can be perceived either as one or two streams, depending on stimulus parameters. The same sequence may be perceived intermittently as integrated or segregated, so that perception is bistable. Here we model streaming as the consequence of an online classification process of the incoming stimulus elements. We assume that stimulus parameters are generated by a Gaussian mixture model (GMM). Each incoming element is classified as generated by one of the components of the mixture, and the distribution is updated to account for the new element. We show that under the appropriate conditions, two competing dynamical processes emerge – one process is related to classification and the other is a hidden process. The competition yields

J Mol Neurosci

periodic switching dynamics between high probabilities of integration and high probabilities of segregation. We assume that these processes are randomly sampled by attentional mechanisms, yielding the observed random transitions between segregation and integration. The model reproduces many of the known properties of streaming. Pitch estimation of complex tones using reservoir computing Barzelay O. 1*, Barak O. 2, Furst M. 1 1 School of Electrical Engineering, Faculty of Engineering, Tel-Aviv Univ. 2 Rappaport Faculty of Medicine, Technion – Israel Institute of Technology Our auditory environment contains diverse acoustic signals such as speech, music, animal communication, and other ambient sounds. These sounds often contain temporal periodicities that our auditory sensory system can exploit. One such prominent sensation created by our brain is pitch – our ability to categorize different periodic sounds into groups and to order them on a scale from low to high. This scale roughly corresponds to the signal's temporal periodicity, or its reciprocal – the fundamental frequency (F0), that doesn't have to exist in the signal's spectrum. A prominent class of models used to explain pitch perception is temporal theory models, and in particular, the autocorrelation function is used to infer the signal's period. Implementing such a model requires tapped delay lines of up to 30 msec and usually a matrix-like architecture of coincidence detector cells; however, to date there is no significant physiological evidence for such architecture in the mammalian brain. We propose a mechanistic model that does not rely on long delay lines or a specific architecture. Instead, we use a simplified recurrent neural network (RNN) as the pitch estimator. It uses analog neurons which represent firing-rates, and the hyperbolic tangent is used as the neurons' activation function. The RNN is trained using the "reservoir computing" paradigm, i.e., training weights of a few readout elements. In the training process the network is given two unresolved complex harmonics sequences with arbitrary F0s. Its goal is to detect which signal has a lower F0, disregarding a particular harmonic structure. We show that such a network can differentiate between two complex harmonics with or without arbitrary selected harmonics, such as F0 (the "missing fundamental case"). Furthermore, the trained RNN exhibits pitch ambiguity along integer ratios of F0, mirroring psychophysical results on humans. Thus, distributed coding of pitch can emerge without a special architecture. Hippocampus and medial Pre-Frontal Cortex involvement in Prior knowledge influences on the encoding of new events Bein O. 1*, Maril A. 1,2 1 Cognitive Science Dept., The Hebrew Univ. of Jerusalem 2 Psychology Dept., The Hebrew Univ. of Jerusalem

Background: Recent investigations of semantic influences on episodic memory suggest that items related to our knowledge are encoded via a medial Pre-Frontal Cortex (MPFC)-cortical path, which supports assimilation of new events in existing knowledge-structures (schemas). Items unrelated to our schemas (no-schemas), however, are encoded by creating a separated representation via Hippocampus (HPC)-mPFC interplay. The current study addressed these issues by examining memory for items (e.g., CHICKEN) encoded with or without their schema (e.g, with 'egg' with 'earrings'). Results and Conclusions: Higher HPC-mPFC correlated activity, as measured by PPI analysis (psychophysiological interactions), was found for later remembered versus later forgotten no-schema items. This result provides the first direct evidence linking HPC-mPFC interplay with subsequent memory of no-schema items. Additionally, a within-ROI between-conditions correlational analysis conducted in the HPC revealed lower correlation (higher dissimilarity) between activation-patterns of remembered and forgotten items in the schema compared to the no-schema condition. We suggest that the HPC is involved in encoding of schema items by means of its activity-pattern. Possibly, schema items are encoded by allocation of a better-defined representational pattern; alternatively, schema items may be supported by reactivation of existing representational patterns. We conclude that the encoding of schema and no-schema items differ qualitatively, but possibly along different dimensions than current approaches in the field suggest. Nato3 regulation of spinal cord development Zisman S.1,2, Mansour A.A.1, Netser Y.1, Gonzales B.J.1, Klar A.2 and Ben-Arie N.1,* 1 Department of Cell and Developmental Biology, Institute of Life Sciences, Hebrew University of Jerusalem, Jerusalem 91904, Israel 2Department of Medical Neurobiology, Institute for Medical Research – Israel-Canada, Hebrew University of Jerusalem, Hadassah Medical School, Jerusalem 91120, Israel In amniotes, the entire central nervous system develops during embryogenesis from the neural tube. A combination of morphogenes induces rostro-caudal and dorso-ventral regionalization that give rise to the formation of various distinct structures. The dorso-ventral patterning is regulated by two organizing centers, the dorsal roof plate and the ventral floor plate. Despite significant progress made in deciphering the induction of the floor plate and the diversification of neural progenitors in the ventral spinal cord, the detailed mechanisms that regulate these processes are not fully understood. Here, we found that the spatio-temporal expression profile of the transcription factor Nato3 coincides with fate determination and specification of FP cells,

J Mol Neurosci

suggesting a possible role in establishing FP identity. Thus, we took gain- and loss-of-function approaches, in which we used in ovo electroporation in chick embryos along with genetic manipulation in mouse to study Nato3 function during neural tube development. In both organisms, we found a role for Nato3 in the establishment of spinal cord patterning during differentiation of mid-ventral cells in the neural tube. Critical role for cyclophilins in the maturation and function of Presenilin1 and 2 Ben-Gedalya T. 1, Moll L. 1, Bejerano-Sagie M. 1, Cohen E. 1* 1 Biochemistry and Molecular Biology, Hebrew Univ. Medical School Background: Protein misfolding and aggregation underlie neurodegenerative maladies including Alzheimer's disease (AD) and Prion disorders, raising the prospect that malfunction of folding chaperones may take part in the development of these disorders. Searching for a shared chaperoneassociated mechanism we compared familial mutations in the sequences of different disease linked proteins. Results: We identified similar Proline substitutions in the PXXP motif of PrP and presenilin proteins which abolish the recognition and assisted folding by cyclophilin chaperones. PrP, and presenilin correct folding and localization depends on cyclophilins. Kinetic fluorescence analysis revealed that PS1 and PS2 form stable aggregates that accumulate within a deposition site known as the ER quality control compartment (ERQC). The aggregation of Presenilin 1 and 2 was found to impair mitochondrial distribution and function and alter autophagic degradation. We now study whether these misfolding events affect gamma secretase activity. Conclusions: cyclophilins are required for the correct folding, cellular localization and normal functions of Presenilin 1 and 2. When the chaperone recognition motif in the sequence of Presenilin 1 is abolished, familial AD develops. Others have shown that cyclophilins shift from a soluble to insoluble fraction with age in the nematode C. elegans implying that aging- associated decline in cyclophilin activity may underlie sporadic cases of AD. Our results confirm the hypothesis that a common mechanism can be associated with the development of more than one neurodegenerative malady and point at a novel research avenue towards the development of new therapies. This study was supported by AFAR, NIPI, TBG supported by the Lady Davis Post doctoral fellowship Effects of dopaminergic reward circuits on immunity Ben-Shaanan T L. 1, Azulay-Debby H. 1, Starosvetsky E. 1, Shen-Orr S. 1, Rolls A. 1* 1 Immunology, Technion

Accumulating evidence suggests that our mental state can alter our physiology. We are specifically interested in understanding how mood-regulating pathways can affect the immune response. We will present data indicating that the activity of dopaminergic neurons in the ventral tegmental area (VTA) alters the immune response to immunological challenge. The VTA and its projections to the Nucleus accumbens (NAc) are a key components of the reward circuitry. Structural and functional changes in this pathway are related to drug addiction and mood disorders. Studies show that mood disorders affect the immune system, showing co-morbidity of mood disorders and immune dysfunction. In addition, administration of opiates such as heroin has an immunosuppressive effect, indicating a possible connection between the reward circuitry and immune system. We used Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to directly activate or inhibit the activity of the dopaminergic neurons in the VTA during an immunological challenge with lipopolysaccharides (LPS). Our findings suggest that VTA activity alters the immune response to LPS, including a significant reduction in the number of spleenocytes. Our findings demonstrate for the first time a direct link between the activity of the dopaminergic neurons in the VTA and the regulation of the immune response, offering an insight to the underlying neuronal mechanisms. Encoding strain and reproductive state by accessory olfactory bulb neurons Kahan, A 1, Ben-Shaul, Y 1* 1 Medical Neurobiology, Faculty of Medicine, The Hebrew Univ. Adaptive social behavior towards conspecifics requires identification of both permanent (e.g. sex, genetic background) and transient characteristics such as the current reproductive status. In this study, we examined the neuronal representation of the female mouse genetic identity and reproductive state by neurons in the first brain relay of the vomeronasal system, the accessory olfactory bulb. To identify which bodily secretions provide information to AOB neurons about these aspects, we tested responses in male mice to urine, saliva, and vaginal secretions from estrus and non-estrus BalbC and C57 female mice. We find that all secretions elicit responses in AOB neurons, and that while these responses can convey information about both genetic background and the reproductive state, genetic background is generally the more robustly encoded parameter. Furthermore, the response profiles of most individual AOB neurons are not consistent with a high level representation of either strain or state, suggesting that brain regions downstream of the AOB must integrate information from multiple channels before extracting behaviorally relevant information. EU7 Marie Curie grant, AK supported by the Lady Davis fellowship trust

J Mol Neurosci

Can deficits in the sensory system cause depression? Ben-Shimol E 1, Goelman G 2*, Sartorius A 3, Gass N 3 1 Neurobiology, The Hebrew Univ. of Jerusalem 2 Medical Biophysics, The Hebrew Univesity of Jerusalem 3 Dept. of Neuroimaging and Psychiatry and Psychotherapy, Mannheim, Germany Background: Depression is a major cause of disability whose mechanism is mostly unknown. Here we hypothesize that altered sensory functionality can cause depression. An established rat models of selectively breeding that was based on their susceptibility to develop learned helplessness (LH) (induced by exposure to foot shock) were used in the study. One is the congenital LH (cLH) which demonstrates chronic depressive features and the other congenital non-LH (cNLH) which demonstrates resistant to stress. Results: Resting-state functional connectivity MRI was used with the cLH, cNLH and wild type rats to estimate the effective connectivity. Two complementary analyses were used. One estimates local- (the radial correlation contrast) and the other global- connectivity (seed based). Global connectivity volumes were found to be similar between all three groups (75%) and of extreme similarity (95%) between the cLH and the cNLH groups. Differences in global connectivity between the cLH and the cNLH rats were mainly related to the limbic, motor and sensory regions. Certain regions with altered local connectivity were found including the prelimbic cortex. They were used in a data-driven approach, to generate seed-maps. Only four had significant different lower seed-maps volumes in the cLH versus the cNLH rats. All were regions within the right primary sensory cortex. Conclusions: The high similar global connectivity between the cLH and the cNLH rats is probably due to their homogeneous gene pool (both share the same ancestors). Assuming brain connectivity and behavior correlate, their different behavior is reflected by the small difference in their global and local connectivity. Since the main changes were associated with the sensory system we suggest that depressive behavior, in those rats, is related to a failure in their sensory systems resulting with amplification of sensory input including stress. This can cause depression. Emotional processing of personally familiar faces in the vegetative state Sharon H. 1,2,3*, Ben-Simon E. 1,2, Pasternak Y. 1,2, Gruberger M. 1,4, Giladi N. 5,6,2, Krimchanski B.Z. 7, Hassin D. 3,2, Hendler T. 1,2,4,6 1 Functional Brain Center, Wohl Institute for Advanced Imaging, Sourasky Medical Center, Tel Aviv, Isr 2 Sackler School of Medicine, Tel Aviv Univ., Tel Aviv, Israel 3 Dept. of Internal Medicine, Sourasky Medical Center, Tel Aviv, Israel 4 School of Psychological Sciences, Tel Aviv Univ., Tel Aviv, Israel 5 Dept. of Neurology, Sourasky Medical Center, Tel Aviv, Israel 6 Sagol School of Neuroscience, Tel Aviv Univ., Tel Aviv, Israel

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Rehabilitation Intensive Care Unit, Loewenstein Rehabilitation Hospital, Raanana, Israel Background: The Vegetative State (VS) is a severe disorder of consciousness in which patients are awake but display no signs of awareness. Yet, recent fMRI studies have demonstrated evidence for covert awareness in VS patients by recording specific brain activations during a cognitive task. However, the possible existence of incommunicable subjective emotional experiences in VS patients remains largely unexplored. This study aimed to probe whether VS patients are able to selectively process external emotional stimuli and look for evidence of covert emotional awareness in patients. Findings In order to explore these questions we used the emotive impact of observing personally familiar faces, known to elicit specific perceptual and emotional brain activations. Four VS patients and 13 healthy controls underwent an fMRI scan while viewing pictures of non-familiar faces, personally familiar faces and pictures of themselves. In a subsequent imagery task participants were asked to actively imagine one of their parent's faces. Analyses focused on face and familiarity selective ROIs and inter-regional functional connectivity. Similar to controls, all patients displayed face selective brain responses with further limbic and cortical activations elicited by familiar faces. In patients and controls, connectivity was observed between emotional, visual and face specific areas, suggesting aware emotional perception. This connectivity was strongest in the two patients who later recovered. Notably, these two patients also displayed selective amygdala activation during familiar face imagery, with one further exhibiting face selective activations, indistinguishable from healthy controls. Conclusions: Taken together, these results show that selective emotional processing can be elicited in VS patients both by external emotionally salient stimuli and by internal cognitive processes, suggesting the ability for covert emotional awareness of self and the environment in VS patients.

Pop-out visual search of moving targets in the archer fish Ben-Tov M. 1,2, Donchin O. 3,2,4, Ben-Shahar O. 5,2, Segev R. 1,2* 1 Dept. of Life Sciences, Ben-Gurion Univ. of the Negev, BeerSheva 84105, Israel 2Zlotowski Center for Neuroscience, BenGurion Univ. of the Negev, Beer-Sheva 84105, Israel 3 Dept. of Biomedical Engineering, Ben-Gurion Univ. of the Negev, Beer-Sheva 84105, Israel 4 Dept. of Neuroscience, Erasmus MC, Rotterdam, The Netherlands 5 Dept. of Computer Science, Ben-Gurion Univ. of the Negev, Beer-Sheva 84105, Israel From detecting food to locating lurking predators, visual search – the ability to find an object of interest against a background – needs to be accurate and fast to ensure survival. In mammals, this led to the development of a parallel search mode, pop-out, which enables fast

J Mol Neurosci

detection time that is not dependent on the number of distracting objects. This parallel search mode is believed to be based on a population of pop-out cells in the visual cortex that generates saliency maps. A key question in the study of visual search is to what extent the visual cortex is a crucial component in supporting popout search mode. To address this issue, we tested the ability of the archer fish, which lacks a fully developed cortex, to perform pop-out visual search, and explored the neural mechanism underlying this behavior in its optic tectum – the main visual area in the brain. We found that the archer fish can perform pop-out visual search of moving targets. Specifically, a target moving bar that differed in motion features such as phase and speed from a set of distractor moving bars is salient for the fish and elicited reaction times that did not depend on the number of distractors. To understand the mechanism underlying this behavior, we recorded from the optic tectum and found pop-out cells that elicited higher response when the stimulus in their receptive field differed in motion features from the stimulus outside of their receptive field. Furthermore, we found a strong correlation between behavioral responses and cellular characteristics. On the behavior level, when the target and the background differed in two motion features, the pop-out effect was stronger than when they differed in only one feature. On the cellular level we found a subset of cells that showed similar additivity when the stimulus differed in two motion features. Thus, pop-out cells in the optic tectum generate saliency maps that might be the basis of pop-out visual search in the archer fish. This work was supported by The Israel Science Foundation grant (NO. 207/11) Neurogenesis-promoting and neuroprotective effect of static magnetic fields Ben-Yakir Blumkin M. 1, Loboda Y. 1, Schächter L. 2, Finberg J.P.M. 1* 1 Dept of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion 2 Faculty of Electrical Engineering, Technion Low intensity static magnetic fields (SMFs) interact with various biological tissues, thereby affecting key biological processes. In the CNS, magnetic fields affect gene expression, cell proliferation and differentiation and regulate cell fate by a sequence of events, initiated by a primary physical interaction with a particular molecular target, resulting in its modulated biological activity. Due to the implications on neurodegenerative conditions, our goal is to characterize various aspects of SMFs' protective effect in cultured primary cortical neurons. Our findings point to a dual effect exerted by SMFs, protecting the neurons both by promoting neurogenesis and

by decreasing the extent of apoptosis. Cultures exposed to SMFs exhibited a 2.8-fold increase in the number of BrdUincorporating nuclei, and a 3.5-fold increase in cells coexpressing BrdU and the neuronal marker NSE. 60% of the BrdU-expressing cells in SMF-exposed cultures were immunoreactive to NSE and hence identified as neurons. Additionally, SMF exposure protected the neurons against etoposide induced apoptosis in a dose-and time- dependent manner, yielding a 20%-70% reduction in apoptosis accompanied by a marked reduction in the expression of the pro-apoptotic proteins: cleaved PARP, cleaved caspase-3 , active caspase-9 and H2A.X. Employing the potentiometric probe molecule JC-1, we further show that SMF exposure stabilizes the mitochondrial membrane potential by decreasing the extent of its collapse in etoposide-treated cultures by 57%, compared with control.In light of the involvement of apoptosis in the dysfunction and death of neurons underlying neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, the observed pro-neurogenic anti-apoptotic effect stimulated by SMFs may prove useful in the development of new strategies for treating neurodegenerative disorders. Not all tasks are created equal: the influence of visual degradation on reading in dyslexia Ben-Yehudah G. 1*, Gilutz, Y. 1 1 Dept. of Education and Psychology, The Open Univ. of Israel Studies using visual degradation of text typically report a slow-down in reading speed. Word inversion (180° angular rotation) is one form of degradation that disrupts reading and restores a childlike dependency of fluency on the number of letters in a word (word length effect, WLE). Research on the reading profile of adult dyslexics, who read in a shallow orthography (i.e., transparent letter-sound mapping), shows that they are sensitive to word length. In this study, naming and semantic decision tasks were used to examine the influence of word inversion and word length on reading in two populations of native Hebrew speakers: adults with a history of developmental dyslexia and age-matched typical readers. When words were displayed upright, dyslexic participants did not show a WLE on either task. Possibly, the non-transparent nature of unpointed Hebrew biased dyslexic individuals towards a reading procedure that is less sensitive to word length. When words were inverted, a WLE emerged for both groups, indicating a shift in information processing. On semantic decision, the dyslexic group was more sensitive to inversion than typical readers. In contrast, on the naming task, both groups were similarly impacted by inversion. Examining aloud versus silent reading, our results suggest that dyslexic and typical readers use similar procedures to read aloud (naming) upright and inverted words. During silent reading (semantic decision), full phonological specification of the upright word is not required; this might benefit dyslexics'

J Mol Neurosci

performance on this task. Once the word is inverted, however, their performance is disrupted to a greater degree than typical readers. The novel finding that dyslexic adults do not show a WLE for upright words is consistent with recent claims regarding the strong relationship between the specific structure of Hebrew words (relatively short words and rich morphology) and the organization of orthographic representations in native Hebrew readers. This study was supported by the German Israeli Foundation. Polymeric neurointerfaces for modulation of neural activity: toward a bio-organic artificial retina Benfenati F. 1*, Ghezzi D. 1, Antognazza M.R. 2, Feyen P. 1, Endeman D. 1, Martino N. 2, Mete M. 3 1 Dept. Neuroscience and Brain Technologies, The Italian Institute of Technology, Genova, Italy 2 Center for Nanoscience and Technology,The Italian Institute of Technology, Milano, Italy 3Dept. Ophthalmology, Sa Background: Sight restoration is one of the new frontiers for prosthetic devices. Diseases that affect the retinal pigment epithelium and photoreceptors but preserve the inner retinal layers are preferential targets for implantation of visual prostheses. We recently discovered that primary neurons can be successfully grown onto a transparent photovoltaic organic polymer and electrically stimulated by light. Results: We investigated the ability of the polymer layer to restore light sensitivity in retinas from rats bearing with photoreceptor degeneration. Light stimulation of the degenerate retina was observed by monitoring multi-unit activity and filed potentials with an extracellular electrode positioned in the retinal ganglion cell layer. Multi-unit activity recordings showed that a light stimulus 16-fold lower than the safe limit for pulsed illumination elicited intense spiking activity in degenerate retinas placed on polymer-coated substrates to levels indistinguishable from those recorded in control retinas. Spiking activity was observed in degenerate retinas over the polymer with a response threshold below 300 nW/mm2, a linear increase in a range corresponding to daylight irradiance, and a response saturation above 0.1 mW/mm2 (considered the safe limit for chronic illumination). A 4-fold increase in the amplitude of the light response at saturation and a significant left shift of the dose-response curves were obtained in retinas placed over the polymer-coated interface respect to degenerate retinas on glass substrates. Conclusions: Our findings indicate that the interface fully mimicked functional photoreceptors in activating the processing of the inner retina and was able to rescue normal light sensitivity. These results broaden the possibility of developing a new generation of fully organic prosthetic devices for subretinal implants. The research was supported by FP7-PEOPLE-2012-ITN “OLIMPIA”, IITand Telethon – Italy

Condition odor aversion affects the innate behavioral decision making in male mice Beny Y. 1, Kimchi T. 1* 1 Dept. of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel. Background: The detection of specific pheromones in the external environment leads to appropriate behavioral responses which are crucial for the reproduction and survival of the animal, as mating with a potential partner or avoiding a predator. In our research we set out to test the influence of negative past experience, induced by sex-specific olfactory conditioning, on the innate responses to sex specific pheromones. Methods: We applied a conditioned olfactory aversion (COA) paradigm on adult wild-type (wt) male mice. Mice, allocated to lithium-chloride (LiCl) and Saline groups, were exposed to soiled bedding from either females' or males' cages, followed by LiCl or saline injections, respectively. Next, we assessed the effect of the aversive association on sexual olfactory preference and on several copulatory and aggressive behavioral parameters. Results: The COA protocol had a long-lasting influence on sexual behavior responses but not on aggressive responses. Following the matched association between visceral malaises and females' pheromones, LiCl males lost their innate olfactory preference for females, and exhibited impairments in execution of sexual behaviors. Unexpectedly, aversive males exhibited a serious of defensive behaviors towards the female intruder, such as freezing and fleeing. Moreover, hormonal changes were also detected following COA protocol such as a general increase in plasma corticosterone level among the LiCl group as compared to the Saline group. In addition, increase in plasma testosterone following sexual experience, as seen in the Saline group, was abolished among LiCl group Conclusions: In this study we managed to influence the decision-making process in response to females', but not males', pheromones. These results imply that different neuronal circuits control aggressive and mating behaviors, and the latter are more flexible to environmental changes. Impairments in the synthesis of the first complex of the respiratory chain as a possible cause for mitochondrial dysfunction in schizophrenia Bergman O, Karry R, Ben-Shachar D Laboratory of Psychobiology, the Ruth and Bruce Rappaport Faculty of Medicine, Technion.. Background: Mitochondrial malfunctioning and impairments in their respiratory chain have been observed in schizophrenia. Given that abnormal complex I - CoI assembly has

J Mol Neurosci

been reported in patients with CoI deficiencies in which psychotic symptoms are often observed, we hypothesize that defects in CoI assembly can be a crucial player in mitochondrial dysfunction in schizophrenia. Methods: In the present study we investigated mitochondrial respiration, CoI protein level, enzymatic activity, synthesis rate and mitochondrial import of 35S-methionine labeled NDUFV2, in Epstein-Barr virus transformed lymphocytes from healthy subjects and schizophrenia patients. Results: A significant reduction in basal respiration (23±0.46%, P<0.001) and an increased inhibitory effect of dopamine (24±8.7% vs. 12.5±5.4%, P<0.001) was observed in schizophrenia-derived cell lines compared to the controls. While no difference was observed in CoI protein levels, its activity showed a significant decrease in schizophrenia patients (69.6±11.8 vs. 113.6±10.9 OD/mg protein/h, P=0.008). No difference was observed in complex IV levels and its activity. CoI activity defect was associated with a decreased synthesis rate of CoI in patients (1.02±0.15 vs. 1.96±0.18, P=0.01). Preliminary results show a one-fold lower import of patients derived NDUFV2 compared to the import of healthy controls derived NDUFV2 into healthy mitochondria (4.47 vs. 49.05%). In addition, healthy controls derived NDUFV2 import into mitochondria of schizophrenia patients was lower by 37±5.5% as compared to that into mitochondria from healthy individuals. No difference was observed in the import of patients derived NDUFV2 into mitochondria from both cohorts. Conclusion: The results of the present study suggest that the impaired NDUFV2 import into the mitochondria could contribute to the lower rate of CoI synthesis thereby leading to reduced CoI activity and to mitochondrial dysfunction in schizophrenia. Mindful reading: mindfulness meditation positively affects reading, attention and brain activity among dyslexic students Berman Z. 1,2, Keidar, R. 2, Friedmann N. 1,2, Tarrasch R. 1,3* 1 Sagol School of Neuroscience, Tel Aviv Univ. 2 Language and Brain Lab, School of Education, Tel Aviv Univ. 3 Dept. of Special Education and Educational Counseling, School of Education, Tel Aviv Univ. Background: Mindfulness refers to a nonjudgmental and compassionate moment-to-moment awareness of one's experiences. The mindfulness-based stress reduction (MBSR) technique has been shown to reduce stress and anxiety, enhance cognitive functions and to affect brain activity. Dyslexia is a reading impairment affecting ~5-17% of all children. Its persistence and highly disabling nature highlight the need for effective and comprehensive long-term treatment for this disability. Recent research has indicated that attention plays a

crucial role in reading, and that there is substantial comorbidity between dyslexia and attentional deficits. Furthermore, some types of dyslexia are influenced by attentional processes. We hypothesized that an MBSR workshop will improve attention and alter brain activation patterns, and as a result improve reading abilities among dyslexics. Results: A significant improvement was observed in a large number of psychological functions including perceived stress, anxiety, depression and sleep quality, as well as in sustained, selective and executive attention functions. Among the dyslexic group, a significant reduction was found in the number of reading errors, together with increases in N170 amplitude and in high theta and alpha power during reading. In addition, improved reading performance was strongly correlated with improved selective attention and with increased P1 amplitude in the left hemisphere. Mindfulness practice was also shown to be associated with enhanced brain activation during both meditation and rest states, including increased low gamma and alpha and reduced delta activities. Conclusions: Our study suggests that a simple tool as MBSR can be used to significantly improve cognitive/ neural functioning and quality of life of individuals with dyslexia. Immunoneutralization of TRAIL improves inflammation and cognitive impairment in a triple transgenic mice model of Alzheimer’s disease Bernardini R. *1, Di Benedetto G. 1, Puzzo D. 2, Palmeri A. 2, Loreto C. 3, Cantarella G. 1 1 Dept. of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, Univ. of Catania, School of Medicine, 95125 Catania, Italy; 2Dept. of Bio-Medical Sciences, Section of Physiology, Univ. of Catania, 95125 Catania, Italy; 3Dept. of Bio-Medical Sciences, Section of Anatomy, Univ. of Catania, 95125 Catania, Italy. Alzheimer’s disease (AD) is one of the most common cause of death worldwide. However, so far, poor progress has been done for its treatment. A tissue landmark of AD is accumulation of the anomalous protein amyloid in specific areas of the brain. Whether inflammation present in the AD brain is the effect of amyloid, or rather causes formation and enlargement of amyloid plaques and tangles is still an object of debate. We have shown that TRAIL, a proapoptotic cytokine of the TNF family, mediates and eventually amplifies neurotoxic effects of amyloid. Here, it was verified whether neutralization of TRAIL could result in attenuation of amyloid toxicity in a 3xTg, age related, mice model of AD in vivo. An anti-TRAIL monoclonal antibody was injected intraperitoneally in aging mice with cognitive impairment. The age related expression of TRAIL, as well as the effects of immunoneutralization on either cognitive parameters, expression of TRAIL, amyloid, inflammatory mediators and GFAP were measured in both

J Mol Neurosci

cortex and hippocampus of 3xTg-AD mice. Anti-TRAIL treatment resulted in robust improvement of cognitive parameters as assessed by the Morris’ water maze test. Such result was associated with decreased brain expression of TRAIL, amyloid, inflammatory mediators and GFAP. Finally, neutralization of TRAIL implied improvement of cognitive parameters and prevented overshooting of immune response in the brain of 3xTg-AD mice. Thus, it appears plausible to regard TRAIL and its receptors as potential targets for efficacious treatment of amyloid-related neurologic disorders. Default mode network white matter microstructure in posttraumatic stress disorder Levin N. 1, Bick A.S. 1*, Shragai T. 2, Giesser R. 3, Reuveni E. 4, Lazarovits G. 4, Bonne O. 4 1 Dept. of Neurology, Hadassah Hebrew-Univ. Medical Center 2 Dept. of Psychiatry, Hadassah Hebrew-Univ. Medical Center 3 Dept. of Psychiatry, Hadassah Hebrew-Univ. Medical Centerw-Univ. Medical Center 4 Dept. of Psychiatry, Hada Background: The default mode network (DMN) is a network of brain regions that that has been suggested to be activated when individuals are engaged in internal tasks such as retrieving memories and self-referential thought. Posttraumatic stress disorder (PTSD), an anxiety disorder that may develop after an exposure to a traumatic event is characterized by unwanted intrusive thoughts causing significant distress. Thus a putative role of the DMN in the pathophysiology of PTSD is apparent. Herein, we will use diffuse tensor imaging (DTI) to investigate white matter DMN integrity in PTSD patients, and its correlation to their clinical symptoms. Method: Data was acquired from 19 subjects with PTSD and 18 healthy controls. The DMN maps were identified in resting state scans using independent component analysis. White matter integrity, as determined from fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD), using DTI was measured and compared between groups. Symptoms severity was assessed by Clinician Administered PTSD Scale (CAPS), Hamilton Depression Rating Scale (HAM-D) and Hamilton Anxiety Rating Scale (HAM-A). Results: We found a significant decrease in FA (0.51 vs. 0.46) and AD (1.26 vs. 1.2) in the PTSD group compared to controls. We found a positive correlation between symptoms of depression in patients and MD (r=0.61, p=0.03) and RD (r=0.64, p=0.01). Conclusion: White matter integrity of the fibers constructing the DMN is decreased in subjects with PTSD. However, this change may be attributed to co-morbid conditions, like depression, rather to PTSD itself.

Cytokines and sodium channels - from slow inactivation to fast nociception Binshtok A. 1,2* 1 Dept. of Medical Neurobiology, IMRIC, Faculty of Medicine, The Hebrew Univ. 2The Edmond and Lilly Safra Center for Brain Sciences Tetrodotoxin (TTX)-resistant sodium channels are the key players in determining the input-output properties of peripheral nociceptive neurons. Modulation of the expression levels, or changes in gating kinetics of these channels during inflammation lead to sensitization - the increase of neuronal output in response to the same level of input. In some cases these changes can even cause direct activation of the nociceptors. These hyperexcitable changes ultimately lead to inflammatory pain. Proinflammatory cytokine tumor necrosis factor a (TNFa) is involved in generation of inflammation, and is also strongly associated with the rapid onset of inflammationmediated nociceptive hyperexcitability, via acute, p38 mitogen-activated protein kinase (p38 MAPK)-dependent, increase in TTX-resistant sodium current. However, the underlying mechanism of TNFa's rapid effect on TTXresistant sodium channels and in acute pain hypersensitivity is unclear. We show here, that, in rat acutely dissociated nociceptor-like dorsal root ganglion neurons, TNFa rapidly relieves voltage dependence of slow inactivation of TTX-resistant sodium channels, in a p38 MAPKdependent manner, thus enhancing the TTX-resistant sodium current density. This TNFa-mediated increase in TTXresistant sodium channel availability leads to decrease in the threshold for action potential generation and increase in the gain of nociceptors, thereby producing acute pain hypersensitivity in adult rats. Moreover, pharmacological enhancement of slow inactivation of TTX-resistant sodium channels prevents TNFa-mediated nociceptive hyperexcitability and reverses the acute phase of TNFa-induced thermal and tactile hypersensitivity. Thus, modulation of voltage dependence of slow inactivation of TTX-resistant sodium channels controls the gain of peripheral nociceptive neurons during the acute inflammation. Is playing music beneficial for dyslexic readers? A behavioral and ERP study Binur N. 1*, Zehavi O. 2, Breznitz, Z. 1 1 Edmond J. Safra Brain Research Center for the Study of Learning Disabilities, Univ. of Haifa 2 The Music Dept., Univ. of Haifa Background: Musical aptitude and training are associated with language and reading skills. Accumulated evidence suggests that musical training leads to better linguistic abilities. This transfer presumably involves shared neural resources for both low-level (auditory) and high-level

J Mol Neurosci

(structure, meaning) processing. Phonological skills, which are considered to be an important mediator of this transfer, are widely agreed to be a core deficit in dyslexic readers, which are also impaired in musical processing. Apparently, dyslexic readers are impaired behaviorally, anatomically and functionally where expert musicians are enhanced. However, studies of dyslexic musicians were neglected in the literature. Therefore, linguistic and musical tests were applied on dyslexic musicians (MD) dyslexic nonmusicians (D), skilled readers musicians (MR) and nonmusicians (R) using ERP methodology. Results: The preliminary results showed that MD performance in phonological awareness tasks was better compared to D. MD outperformed D in both accuracy and speed; moreover, they were indistinguishable from R and even slightly faster. In words reading task, MD read approximately 20 correct words per minute more than D but were slower than R in the same ratio; MR were faster than R. Surprisingly, MD were significantly faster than D and identical to R in naming tasks, despite their equally impairment as D in speed of processing measures compared to R. Behavioral and electrophysiological data on single-pattern processing in language, music and reading will be presented. Conclusions: MD showed trend of superior reading and phonological skills versus D. Establishing and understanding the neural mechanism underling these results will shed light on using musical training as an efficient and enjoyable tool for dyslexia remediation. This study was supported by the Edmond J. Safra Philanthropic Foundation Hyperbaric pressure effects on GluN1 variants of NMDA receptor. Bliznyuk A. 1*, Aviner B. 1, Hollman M. 2, Golan H. 1, Grossman Y. 1 1 Dept. of Physiology and Cell Biology, Ben-Gurion Univ. of the Negev 2 Dept. of Biochemistry I – Receptor Biochemistry, Ruhr Univ. Bochum Background: Professional divers may suffer from direct high pressure (HP) effects. Various animals and humans exposed to ambient pressure above 1.1 MPa develop the High Pressure Neurological Syndrome (HPNS). The glutamate N-methyl-Daspartate receptor (NMDAR) has been implicated with CNS hyperexcitability as part of HPNS. Furthermore, NMDAR subunit GluN1 subtypes were implicated with selective pressure effect (Mor et al. 2012). In order to explore this possibility we studied HP effects directly on six specific alternatively spliced GluN1 subtypes expressed in frog Xenopus leavis oocytes. Results: GluN1 subtypes were co-expressed with GluN2A subtype. All the subtypes' ionic currents were increased by HP

with different magnitude.I/V curves constructed while the receptor was in the open state revealed that the conductance also increased under HP conditions. Data presented below as %Δ of 5.0 / 0.1 MPa, Mean±SEM: Amplitude (%Δ): I/V slope (%Δ) GluN1-1a: 62.47±10.31, n=7 ** GluN1-1b: 25.16±3.91, n=9** GluN1-2a: 44.99±10.74, n=7** GluN1-2b: 32.08±8.06, n=10** GluN1-3a: 27.65±6.11, n=10** GluN1-3b: 41.89±7.44, n=6**

59.64±14.47, n=5** 25.19±5.37, n=7** 75.43±29.25, n=5* 80.07±44.96, n=6* 44.91±5.82, n=5** 36.35±9.15, n=5**

n number of experiments- oocytes, * p< 0.05, ** p< 0.01 statistical significance of paired t-test. Conclusions: The increase of NMDARs currents at HP depends on GluN1 subunit. The current augmentation is caused mainly (but not solely) by conductance increase at the open state. These results strongly confirm the important role of NMDARs in HPNS. Supported by US ONR grant # N00014-10-1063 to Y.G. Pancreatic islets grafting to olfactory bulb: A novel treatment of traumatic brain injury combined with hypoglutamatergic insult Bloch K. 1*, Gil-Ad I 2, Tarasenko I 2, Vanichkin A 3, Taler M 2, Vardi P 1, Weizman A 4 1 Laboratory of Diabetes and Obesity Research 2 Laboratory of Biological Psychiatry 3Laboratory of Transplantation 4 Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Tel Aviv Univ. Background: Traumatic brain injury (TBI) is a leading cause of morbidity including cognitive deficits and neuropsychiatric disorders. Pancreatic hormones (insulin, glucagon, somatostatin) and neurotrophic factors were reported to attenuate neuronal cell injury and to improve cognitive functions. Pancreatic islets secrete a unique combination of neuroprotective hormones and neurotrophic factors. Recently, we found that islet transplantation into intracranial subarachnoid cavity of diabetic rats resulted in long-term normoglycemia. In the current study, we evaluated the efficacy of intracranial islet transplantation on the recovery from TBI/ hypoglutamatergic (MK-801)-induced behavioral impairments in rats. Results: TBI was created by dura and arachnoid perforation induced by drilling a 2-mm hole in the frontal bone. The hole was used also for syngeneic islet transplantation onto the glomeruli of the olfactory bulb. Behavioral tests were initiated two weeks after the TBI. Animals under basal conditions or following acute or sub-acute administration of MK801 were exposed to the Open Field (OF) or to the Morris Water Maze

J Mol Neurosci

(MWM) challenges. In the OF, intact rats treated with MK801 showed significant hyper locomotion, TBI rats did not differ in motility parameters, however, MK801 treated TBI rats presented hyper-responsiveness in motility, and this effect was normalized by the grafted islets. In terms of field exploration, TBI animals differed from intact rats and explored more the center of the field (MK801-like), this effect was further augmented by MK801 and reversed in rats with grafted islets (sub-acute model). In the MWM paradigm, TBI animals performed similar to intact rats. However, TBI rats treated with MK-801 showed potentiating of the impaired spatial memory, while grafted islets corrected it partially. Conclusion: Brain grafted islets may attenuate neuropsychiatric and cognitive impairment in rats with TBI combined with hypoglutamatergic insult. Neurobehavioral implications in rats following prolonged exposure to the nerve agent VX Bloch-Shilderman E. 1*, Lazar S. 1, Katalan S. 1, Yaacov G. 1, Rabinovitz I. 1, Egoz I. 1, Brandeis R. 1, Grauer E. 1, Allon N. 1 1 Dept. of Pharmacology, IIBR The highly toxic organophosphorous compound VX may evaporate from urban surfaces long after the initial insult. As a consequence, even the expected low levels should be examined for their potential to induce functional impairments. In the present study we evaluated VX effects in rats exposed to 22.5, 13.5 and 2.25 μg/kg/day (0.5, 0.3, 0.05 LD50/day) for one month via implanted mini osmotic pumps. The rapidly attained continuous and marked whole-blood cholinesterase inhibition following 0.3 LD50/day (~85%), partially recovered 1 week post pump removal. Under these conditions, body weight, blood count and chemistry, water maze acquisition task, sensitivity to the muscarinic agonist oxotremorine, peripheral benzodiazepine receptors density and brain morphology as demonstrated by routine histopathology, remained unchanged. However, abnormal initial response in an Open Field test, sleep disorders and ECoG spectral power transformations in the low frequency brain waves theta and alpha were monitored. Using MAP2 cytoskeletal protein immunolabeling demonstrated a decreased immunoreactivity in dendrites processes and an increased immunoreactivity in pyramidal cells soma in the CA2 sub region of the hippocampus, in the thalamus and in piriform cortex brain areas. GFAP labeling for astrocytes revealed an activated astrocytes in all brain regions and up regulation (~3 folds) in the expression of the exocytotic protein VAMP in hippocampal neurons was detected. These changes could not be detected one month following termination of exposure. Our findings indicate that following prolonged exposure to the chemical warfare agent VX some important processes might be considerably impaired. Yet, its potential health ramifications at much lower doses should be addressed.

Pharmacological treatment reverses the pathological and cognitive effects of apoE4, the main genetic risk factor for Alzheimer's disease Boehm-Cagan A. 1*, Michaelson D.M. 1 1 The Sagol School of Neuroscience, Tel Aviv Univ., Israel Background: Apolipoprotein E, the most abundant lipoprotein in the brain, exists in 3 isoforms, of which apoE4 is the most prevalent genetic risk factor for Alzheimer's disease. Recent findings suggest that the pathological effects of apoE4 are related to loss of structural properties associated with impaired lipidation of apoE. The RXR system regulates the expression of the main apoE-lipidating proteins, ABCA1 and ABCG1. This system can be upregulated by Bexarotene, an FDA-approved RXR agonist. Results: We examined the hypothesis that the pathological effects of apoE4 are due to its diminished lipidation relative to the AD-benign apoE3, and the extent to which this can be reversed by activation of the RXR system using Bexarotene. This was pursued utilizing apoE4-targeted replacement mice, which we have recently shown to have cognitive, synaptic and AD-related pathologies. Application of Bexarotene resulted in increased mRNA and protein levels of ABCA1 and ABCG1, and the abolishment of the apoE4-related brain pathologies. Accordingly, Bexarotene decreased the accumulation of key AD-hallmark pathologies, accumulation of hyperphosphorylated tau and of Aβ42, in hippocampal neurons of apoE4 mice. Bexarotene also reversed the corresponding synaptic impairment, such that the lower levels of the presynaptic glutamatergic vesicular transporter VGlut1 were elevated to match the apoE3 mice. Furthermore, Bexarotene corrected the learning and memory deficits of the apoE4 mice as observed in the Morris water maze and the novel object recognition test. Importantly, the levels of apoE were not affected by Bexarotene, thus supporting the hypothesis that the reversal of the apoE4-driven pathologies are due to increased lipidation, rather than increased apoE levels. Conclusion: Activation of the lipidation system via the RXRagonist Bexarotene abolished key pathological effects of apoE4 in vivo. This suggests a novel approach for the treatment of the apoE4-related pathologies. Knocking-down mGluR1 and mGluR5 in the SOD1/G93A mouse model of amyotrophic lateral sclerosis ameliorates survival and disease progression Bonanno G. 1,2*, Milanese M. 1,2, Bonifacino T. 1,2, Melone M. 3,4, Musante I 5,6, Vergani L. 1 Dept. of Pharmacy, Univ. of Genoa, Italy 2 Center of Excellence for Biomedical Research, Univ. of Genoa, Italy 3 2Dept. of Experimental and Clinical Medicine, Polytechnic Univ. of Marche, Ancona, Italy 4 Center for Neurobiology of Aging, INRCA IRCCS, Ancona, Italy 5 Dept. of Neuroscience, Ophthalmology, Genetics and Child Health, Univ. of Genoa, Italy 6 Medical Genetics Unit, Gaslini Institute, Genoa Italy

J Mol Neurosci

Background: Glutamate (Glu)-mediated excitotoxicity plays a major role in amyotrophic lateral lsclerosis (ALS) and reduced astrocytic uptake was suggested as a cause for the increased Glu availability (1). On the basis of our studies, we have proposed that abnormal release may represent another source for excessive extracellular Glu and that acting at the altered Glu release mechanisms may represent a possible strategy for new therapeutic approaches to ALS (2, 3). Our previous results indicated the existence of excessive Glu release in the spinal cord of SOD1/G93A mice following activation of Group I metabotropic Glu receptors (mGluR1 and mGluR5) (4). Results: To provide a genetic tool to evaluate the mGluR1 and mGluR5 role in ALS, we generated mice carrying half expression of mGluR1 or mGluR5 in the SOD1/G93A background. SOD1/G93A-mGluR1+/- double mutant mice showed prolonged survival probability, slower disease progression and improved motor performances respect to SOD1/G93A mice. Histological studies performed at the late symptomatic disease phase showed a significant reduction on MNs death in spinal cord, lower astrocyte and microglia activation and normalization of metallothionein mRNA expression in SOD1/G93A-mGluR1+/- double mutant ventro-lateral horns. Reduced mitochondrial damage was observed in soma, dendrites, axons and axons terminal. Also the previously detected mGluR1- and mGluR5-induced abnormal Glu release (4) was reduced in SOD1/G93A-mGluR1+/-. Similarly, SOD1/G93A-mGluR5+/- mice, lacking of mGluR5, showed remarkable prolonged survival and phenotype amelioration. Conclusions: These results would provide the rationale for pharmacological approaches to ALS by selectively blocking mGluR1 and mGluR5. References: (1) Rothstein J D, et al., Ann. Neurol., 1995; 38: 73-84. (2) Milanese M, et al., J. Neurochem., 2011; 116: 10281042. (3) Uccelli A, et al., Mol. Med., 2012; 18: 794-804. (4) Giribaldi F, et al., Neuropharmacol., 2013; 66: 253-263. Supported by Italian Ministry of Univ. and Resarch (PRIN project n. 2006058401) Are hub neurons an innate functional feature of cortical circuits? Experimental evidences from cultured finite size circuits Bonifazi P School of Physics and Astronomy, Tel Aviv University, Tel Aviv, Israel One of the main challenges of modern neuroscience is to understand how network dynamics are related to anatomical connectivity. Recently, it has been demonstrated the existence of functional connector “hubs” in the developing hippocampus where such a function is met by a heterogeneous subpopulation of pioneer GABAergic interneurons that display widespread axonal projections. GABAergic hub cells play a central role in the coordination of early

network synchronizations combining high functional, effective and structural connectivity. Are hub neurons common components of all growing neuronal networks or other mechanisms/topologies emerge? We try to address this question in finite-size neuronal circuits grown in culture which may represent a general model of self-organized neuronal circuits not depending on a specific architecture. Given the small size of these circuits, a detailed dynamical-morphological characterization was obtained through calcium imaging and immunocytochemistry. Finite size circuits, as most dissociated neuronal cultures, display spontaneous network synchronizations or bursts. Similarly to the developing hippocampus, functional connectivity analysis revealed the existence of highly connected neurons with a significant proportion of them represented by GABAergic neurons. Optogenetics stimulation with single cell resolution in combination with calcium imaging is used to probe the impact of hub perturbation on network dynamics. These preliminary results support the hypothesis that GABAergic hub neurons are an innate functional feature of cortical circuits. Behavioral and neural dissociations of rhythmic temporal expectations from memory-based expectations Breska, A. 1*, Deouell, L. Y. 1,2 1 Psychology Dept., The Hebrew Univ., Jerusalem 2 Edmond and Lily Safra Center for Brain Sciences, The Hebrew Univ., Jerusalem Background: Sensory input with predictable dynamics can be used to create temporal expectations. It has been suggested that when the input is rhythmic, temporal expectations are created to in-phase time points due to oscillatory synchronization with the rhythm period. However, they can also be created by intentionally memorizing a fixed interval and applying it recursively. Using performance measures and EEG in 20 subjects, we dissociated these two processes. In one condition, targets appeared in-phase with a rhythmic sequence of stimuli in 80% of the trials. In another condition, they appeared in 80% of the trials at an interval that was recursively presented to allow memorization, but without creating a rhythmic sequence. In both conditions, a cue indicated explicitly that the next stimulus is the target. Results: The behavioral validity effect of rhythmic stimulation was stronger than that of interval memorization, suggesting that the former is more temporally accurate. The CNV, an ERP which reflects temporal anticipation to the target, was more negative in the rhythmic condition, suggesting increased expectation. Furthermore, the effect of cue invalidity on the terminal CNV and on the latency of the P3, an ERP reflecting target evaluation, was more evident in the rhythmic condition, suggesting faster evaluation. Finally, in expected target times there was increased

J Mol Neurosci

alpha desynchronization, previously shown to occur when directing attention. Conclusion: Although the amount of temporal information was matched, the expectation created by rhythmic stimulation was superior over interval-based temporal expectation, both in behavior and in expectation-related neural activity. These findings are inconsistent with the idea that rhythmic expectation is no more than recursive applying a memorized interval, and instead suggest involvement of either an additional mechanism or a different one. Social transmission of extinction memory Brill-Maoz N. 1, Maroun M. 1* 1 Sagol Dept. of Neurobiology, Faculty of Natural Sciences, Univ. of Haifa Background: Based on social transmission of information, treatment of post-traumatic stress disorder (PTSD) and phobias can include group therapy and support groups. It was previously reported that fear responses (e.g. freezing), in the fear conditioning paradigm, can be attenuated by the presence of a naive companion, in a variety of species (Epley 1974). In contrast, a recent study has shown that rats which were exposed to an unfamiliar tone in the presence of a cage-mate (who was previously fear-conditioned with the same tone), showed increased freezing to the stimulus the next day. These findings suggest that during memory retrieval, fear of stimulus can be socially transmitted to a cage-mate (Bruchey et al., 2010; Periera et al., 2012). In this study we aim to address the possible effect of social interaction on fear extinction in adult rats. Results: All rats underwent contextual fear conditioning, and were divided into two groups prior to the extinction process. Rats in the experimental group were paired and underwent extinction training in together for two consecutive days. Rats in the control group underwent the same procedure but individually without the presence of cage-mate. Our results show that both groups acquired the association of fear similarly, however, the rats that underwent extinction training in pairs had accelerated extinction rate. Furthermore, reinstatement of fear following extinction was shown to be significantly different in both groups. Conclusions: Our findings suggest that the presence of a cagemate, results in increased fear extinction. We are now addressing the role of oxytocin in the mediation of these effects. Imbalance of monoaminergic neurons leads to spontaneous fluctuations in manic- and depressive-like behaviour Jukic M. 1, Bar M. 1, Baron T. 1, Zega K. 1, Jovanovic V. 1, Agam G. 2, Kofman O. 3, Brodski C. 1* 1 Physiology and Cell Biology, Ben-Gurion Univ. of the Negev 2 Biochemistry and Clinical Pharmacology, Ben-Gurion Univ. of the Negev 3 Psychology, Ben-Gurion Univ. of the Negev

Changes in mood which are not correlated to apparent exogenous events are part of normal behavior. In bipolar disorder, fluctuations of manic- and depressive behavior, which are often not associated with obvious external events, are essential characteristics of its clinical manifestation. Despite the importance for normal and pathological behavior, the mechanisms underlying endogenous fluctuations in mood are virtually unknown. A major obstacle preventing progress of our understanding of this behavior has been the lack of appropriate animal models. Previously, we demonstrated that the transcription factor Otx2, which has been suggested as a susceptibility gene for bipolar disorder orchestrates the development of monoaminergic neurons. Here we use mouse mutants overexpressing Otx2, to study endogenous fluctuations in manicand depressive-like behavior. We found that Otx2 mutants show in their home cage, extended periods of hyperactivity spontaneously alternating with periods of reduced activity. Repeated measurements in the open field demonstrated for Otx2 mutants increased intra-individual fluctuations in locomotor activity, habituation and different risk-taking behavioural parameters. In the sugar preference test, which was used as a measure for hedonic-like behavior Otx2 mutants showed increased intra-individual changes in sweet preference. Olanzapine, lithium and carbamazepine, which are used for the treatment of bipolar disorder reversed behavioural alterations of Otx2 mutants. We conclude that Otx2 is critical to maintain intra-individual behavioural stability. In addition we suggest that a dysfunction of Otx2 is involved in intraindividual behavioural fluctuations found in bipolar disorder by altering normal monoaminergic neurotransmission. NIPI grant 209-11-12 and Israeli Ministry of Health grant 37433 to C.B.. The time-course of automatic motion processing: evidence from a Stroop task Burnett, K. E. 1*, Arend, I. 1, Henik, A 1 1 Ben-Gurion Univ. of the Negev Background: Because of its biological relevance, motion processing may be prioritized, or in order words, processed automatically. We tested this idea by combining shape and motion dimensions in the same task. Results: An arrow pointing to the left or right contained a flowfield of left- or right-moving dots, and participants responded to either arrow direction or motion direction. A congruity effect was present for both tasks. However, reaction time (RT) was faster for the arrow than for the motion task. There was also a significant Task X Congruity interaction, as the arrow direction produced a larger congruity effect on the motion task than the motion direction produced on the arrow task. This remained the case when the visibility of the arrow shape was reduced, when the speed of the motion was increased and when the tasks were completed in mixed blocks.

J Mol Neurosci

Analyses of the RT distribution by means of a binning procedure showed a significant congruity effect for the motion task across RTs. For the arrow task, a significant congruity effect emerged only for late RTs. Polynomial contrasts confirmed a significant linear trend for the Congruity X Bin interaction for the arrow task, but not for the motion task. Conclusions: The congruity effects demonstrate that the taskirrelevant dimensions were processed automatically, though the interference from the task-irrelevant dimension was not symmetrical: Arrow direction led to a larger congruity effect than motion direction. We suggest that this pattern is due to the different time-course associated with processing each dimension. Time-course analysis revealed that motion direction interfered at late response times, consistent with the neuro mechanisms supporting shape and motion processing. Motion processing requires the summation of signals further down the processing stream and therefore takes longer and is more susceptible to conflicting visual information. Nevertheless, we present evidence that motion processing is automatic. Spatiotemporal mapping of striatal dopamine release using molecular-level fMRI Cai, LX 1*, Lee, T 1, Jasanoff, AP 1 1 Biological Engineering, MIT Dopamine signaling is critical to brain systems controlling voluntary movement, learning and reward. Although there exists extensive millisecond temporal resolution studies of dopaminergic neural activity using electrophysiology and electrochemistry, no method currently exists to comprehensively examine in vivo spatial characteristics of dopamine signaling. To address this issue, we use a protein-based contrast agent that detects dopamine in magnetic resonance imaging (MRI). For the first time, we (1) demonstrate molecularlevel functional imaging and (2) spatially map dopamine release in the rat ventral striatum during electrical stimulation of the medial forebrain bundle (MFB), a widely used artificial reward paradigm. Ischemic tolerance down-regulates tumor necrosis factor-related apoptosis-inducing ligand expression and generates a neuroprotected phenotype Cantarella G.*1, Pignataro G.2, Di Benedetto G.1, Parenti C.3, Anzillotti S.2, Vinciguerra A.2, Cuomo O.2, Di Renzo G.F.2, Annunziato L.2, Bernardini R.1 1 Dept. of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, School of Medicine, Univ. of Catania, 95125 Catania, Italy; 2Dept. of Neuroscience, Division of Pharmacology, School of Medicine, Federico II Univ. of Naples, 80100 Naples, Italy; 3Dept. of Drug Science, Pharmacology and Toxicology Section, School of Pharmacy, Univ. of Catania, 95125 Catania, Italy.

Brain ischemia is associated with progressive enlargement of damaged areas and prominent inflammation. The brain’s compliance to ischemic injury is transiently augmented by exposure to a non-injurious preconditioning stimulus. TNF-related apoptosis inducing ligand (TRAIL), a proinflammatory/ proapoptotic member of the TNF superfamily, appears involved in neuronal damage that follows brain ischemia. Here, the role of TRAIL was studied in an in vivo model of harmful focal ischemia in the rat. Animals underwent transient 100 minutes middle cerebral artery occlusion, followed by 24 hours reperfusion. In preconditioning experiments, ischemia was preceded by 30 minutes of tMCAO. Results show that the neuroprotection elicited by ischemic preconditioning occurs through both up-regulation of TRAIL decoy receptors, and down-regulation of TRAIL itself and its death receptors. As a counterproof, immune-neutralization of TRAIL in tMCAO animals resulted in significant restraint of tissue damage and functional recovery. In conclusion, neutralization of TRAIL brought about effective reduction of ischemia-related neuronal damage. Data shed new light on the mechanisms of brain ischemia, and highlight new molecular targets for therapeutic intervention. Finally, modulation of the TRAIL system could represent a novel mode for treatment of stroke. Anti-TRAIL treatment could be thus regarded as an immunepharmacological strategy to ameliorate the outcome of cerebral ischemia. Microtubule dysfunction in Parkinson’s disease: where does the end begin? Cappelletti G. 1*, Cartelli D: 2, Casagrande F. 2, De Gregorio C 2, Calogero A. 2, Passarella D. 3, Pezzoli G. 4, Battaglia G. 5 1 Dept. BioSciences, Università degli Studi di Milano, Milano (Italy), [email protected] 2 Dept. BioSciences, Università degli Studi di Milano, Milano (Italy)3 Dept. Chemistry, Università degli Studi di Milano, Milano (Italy), 4 CTO, Parkinson's Institute, Milano (Italy) 5 IRCSS Neuromed, Pozzilli (Italy) That microtubule (MT) dysfunction may contribute to the pathogenesis of Parkinson's disease (PD) is a concept evoked by several data coming from both toxin-based and gene-based experimental models. However, the open question to be faced regards its role: is it the cause or simply a by-product of neurodegeneration? More interestingly: are MTs targetable for neuroprotection in PD? To get an insight into this intriguing issue, we investigated MTs in multiple PD models. In the context of studies on PD-induced neurotoxins, we showed that MPP+ reduces MT polymerization and dynamics in vitro and that it alters MT physiology in neuronal cells before impairment of intracellular transport, mitochondria damages and apoptosis induction become evident. Moving to MPTPtreated mice, we pointed out that alterations of MT stability occur very early in dopaminergic fibres and precede axonal

J Mol Neurosci

transport impairment, tyrosine-hydroxylase depletion, and, ultimately, dopaminergic neuron degeneration. In the context of studies on genetic models of PD, we investigated MT system in Parkin-silenced neuronal cells and in Parkinknock out mice, and found that Parkin deficiency impacts MT dynamics. Notably, we analysed Parkin-knock out mice at different ages and showed that alterations accumulate over time with MT dysfunction preceding defects in axonal transport. Collectively our data converge on the idea that MT dysfunction occurs very early in the onset of neuronal damage in PD models and suggest that MTs can play a role in neuroprotection. Thus, we tested this hypothesis and showed that repeated daily administration of the MT-stabilizer Epothilone D rescued MT defects and attenuated nigrostriatal degeneration induced by MPTP in mice. We conclude that MT dysfunction contribute to actually cause neurodegeneration and is manageable for neuroprotection in PD. This work was funded by "Fondazione Grigioni per il Morbo di Parkinson" and "Regione Lombardia". Design and characterization of human nerve growth factor muteins with reduced algesic properties Capsoni S. 1* 1 Laboratory of Biology, Scuola Normale Superiore, Pisa, Italy Background: In Alzheimer's disease, a therapy based on human recombinant Nerve Growth Factor (NGF) to prevent or slow the cognitive decline has a strong scientific rationale, based on its pro-survival activity on basal forebrain cholinergic neurons and its potent anti-amyloidogenic action in cell and animal models. However, NGF delivery to the brain limiting the adverse effects of NGF in activating nociceptive responses has represented a significant challenge. We developed a human NGF double mutant (hNGFP61S/R100E, painless NGF) that has identical neurotrophic properties to hNGF, is traceable against endogenous NGF and has a greatly reduced pronociceptive activity. The objectives of this study are to assess the biodistribution, and the therapeutic efficacy of hNGFP61S/R100E in 5xFAD mice over-expressing mutant human APP, as well as to demonstrate the absence of pain after intranasal delivery and investigate the mechanisms underlying the rescue of neurodegeneration in these mice. Results: hNGFP61S/R100E was intranasally delivered to 5xFAD mice which were then tested on behavioral task measuring memory, electrophysiological recording, and markers of neurodegeneration. We found that hNGFP61S/R100E distributes in brain areas of interest for neurodegeneration, inducing a clear rescue of synaptic dysfunctions and neurodegeneration. Mechanisms involving microglia activation and APP processing were also explored.

Conclusions: These findings extended the therapeutic effectiveness of hNGFP61S/R100E in APP-based models, showing that its actions goes well beyond the expected neurotrophic activity on cholinergic neurons. Painless NGF is therefore a viable option to increase NGF activity in the brain in a non invasive way, without unwanted safety issues related to pain. This work has been supported by the Alzheimer’s Drug Discovery Foundation grant n. 20120601. Characterization of Arc/Arg3.1 conditional knockout mice Castro-Gomez S. 1, Gao X. 1, Graf S. 1, Kuhl D., Ohana O. 1* 1 Inst. for Molecular and Cellular Cognition, ZMNH, Univ. Medical Center Hamburg-Eppendorf, Germany Background: Arc/Arg3.1 is an activity regulated effector gene whose expression is rapidly up-regulated by acquisition of experience and by synaptic plasticity-producing stimuli. We previously generated conventional Knockout (KO) mice which constitutively and completely lack the Arc/Arg3.1 gene. These mice show a profound impairment in the consolidation of synaptic plasticity in the hippocampus and a complete loss of explicit and implicit long term memories. Because Arc/Arg3.1 is expressed early after birth, it may affect the development of cortical and hippocampal networks as well as their later function in memory consolidation. In order to discriminate between developmental and adult contribution of Arc/Arg3.1 expression on memory formation we generated conditional KO (cKO) mice in which Arc/Arg3.1 is ablated at different stages of development and tested their performance in memory tasks. By crossing our Arc/Arg3.1 loxP-flanked mice (Arc/Arg3.1flox/flox) with CamKIIα-iCre mice we obtained mice in which Arc/Arg3.1 is perinatally ablated in principle cells of the forebrain. For comparison, we generated complete KO mice by crossing Arc/Arg3.1flox/flox mice with CMV-Cre deleter mice in which Arc/Arg3.1 is ablated at early embryogenesis in all cells. Results: Behavioral assessment using contextual and cued fear conditioning confirms a profound impairment in the consolidation of explicit and implicit long term memories in the complete KO, while cKO mice show a specific deficit in consolidation of remote fear memories. These preliminary data confirm the central role of Arc/Arg3.1 in memory formation and further suggest that the spatial and temporal pattern of Arc/Arg3.1 ablation in the brain could determine the form of memory impairment. Conclusions: Cre-mediated ablation of Arc/Arc3.1 at early embryogenesis confirms a profound impairment of long term memory consolidation. Perinatal deletion of Arc/Arg3.1 in the forebrain of cKO mice disrupts remote memory consolidation. Support is provided by DFG – SFB 936 MultiSite Communication in the Brain

J Mol Neurosci

Optogenetic regulation of transcription: modulation of the RE1-silencing transcription factor (REST) Paonessa F. 1, Scarongella H. 1, Pruzzo G. 1, Maragliano L. 2,3,4, Benfenati F. 2,3,4, Cesca F. 2,3,4* 1 Istituto Italiano di Tecnologia, Neuroscience and Brain Technologies Dept. Genova - Italy 2 Istituto Italiano di Tecnologia 3 Neuroscience and Brain Technologies Dept. 4 Genova - Italy Background: The possibility to manipulate signaling using optogenetic technologies has opened new ways of intervention on cellular function. However, due to the complexity of the mechanisms involved, few attempts have been made so far to modulate transcription of endogenous genes in higher mammals. The RE1-silencing transcription factor (REST) is a transcriptional repressor controlling several neuronal genes, regulating nervous system development and lineage specification. REST is normally expressed at low levels by mature neurons, but is strongly upregulated in several brain diseases including epilepsy. We propose to engineer recombinant proteins able to spatially and temporally modulate REST action, by employing the LOV2 domain of Avena sativa (AsLOV2), a photosensitive protein that undergoes reversible lightdependent conformational changes. Results: in order to inhibit REST function we followed two alternative strategies: (i) to compete with REST-DNA binding, we decided to block the Zn finger domains of the repressor by engineering light-sensitive chimeras of the RILP/Prickle protein; (ii) to interfere with the recruitment of specific co-factors, we targeted mSin3a recruitment by direct competition of its binding sites on REST. To engineer the fusion proteins we performed computational modeling and molecular dynamics simulations of putative structures. All light-sensitive chimeras are expressed in mammalian cell lines and, upon specific patterns of illumination, modulate the transcription of REST-dependent genes on artificial promoters (luciferase assays) as well as on endogenous genes (RT-PCR). Conclusions: We have engineered and validated a series of photoswitchable AsLOV2-peptides able to modulate REST activity when subjected to specific patterns of illumination. These probes provide a way to modulate REST-dependent transcription, and to counteract the long-term changes in gene expression that take place in the pathological environment of the epileptic brain. This project is funded by FP7-HEALTH-2013-INNOVATION1 (Proposal n: 602531-2); Acronym: “DESIRE” PrPC controls via PKA the direction of synaptic plasticity in the immature hippocampus Cherubini E, Legname G and Caiati DM Dept. Neuroscience, International School for Advanced Studies (SISSA), Trieste, Italy

The non pathogenic form of prion protein, PrPC, is a conserved glycoprotein, highly expressed in the brain, where it can be converted into its abnormally folded and aggregated isoform PrPSc to cause neurodegenerative diseases. Interestingly, PrPC is developmentally regulated and in the hippocampus it parallels the maturation of mossy fibers (MF), the axons of granule cells in the dentate gyrus. Moreover, its predominant synaptic localization suggests a crucial role of this protein in synaptic signaling. Here, we tested the hypothesis that, at immature MF-CA3 synapses, which during the first week of postnatal life are mainly GABAergic, PrPC interferes with synaptic plasticity processes. To this aim, a pairing procedure was used to trigger MF stimulation with the rising phase of spontaneously occurring Giant Depolarizing Potentials (GDPs) a hallmark of developmental networks. While in WT animals, this protocol induced LTP, in Prnp0/0 mice it caused LTD. The induction of LTP in WT animals was prevented by loading the recording neuron with BAPTA or by performing the pairing procedure in voltage clamp mode. In these conditions, LTD instead of LTP occurred. In WT animals, LTP was also blocked when the postsynaptic cell was loaded with the PKA inhibitor PKI suggesting that cAMPdependent PKA in the postsynaptic neuron is involved in pairing-induced synaptic potentiation. In Prnp0/0 mice, LTD was presynaptic and was prevented by the selective GluK1 antagonist UBP 302 or by the phospholipase C inhibitor U73122, suggesting that it was reliant on G protein-coupled GluK1 receptors. Postsynaptic infusion of a constitutively active isoform of PKA catalytic subunit (Cα) into CA3 principal cells of Prnp0/0 mice caused a persistent synaptic facilitation and occluded LTP induced by subsequent pairing. These data suggest that PrPC plays a crucial role in regulating via PKA synaptic plasticity and information processing in the developing hippocampus. Transcription networks provide a window into the neural circuitry of addiction Citri A 1,2* 1 Safra Center for Brain Sciences, Hebrew Univ., Jerusalem 2 The Life Science Institute, Hebrew Univ., Jerusalem This is an exciting period in neuroscience research, in which our capacity to translate molecular knowledge into novel tools for detailed investigation of neural circuits is undergoing a revolution. I will present our work aimed at deciphering the molecular, synaptic and neural circuit mechanisms promoting experience-dependent plasticity underlying the development of drug addiction. Utilizing detailed investigation of transcriptional dynamics during the development of behavioral sensitization to cocaine, we identified a number of intriguing molecular events potentially underlying the stability of the neural trace induced by drug experience. Exemplifying our approach, I will present work in which we utilize transcriptional analysis,

J Mol Neurosci

mouse genetics and stereotactic viral manipulations in order to identify and define a neuronal ensemble within the nucleus accumbens responsive to cocaine experience. The effects of oxytocin and levels of intimacy on preferred interpersonal space: A pharmacological neuroimaging study Cohen D 1*, Perry A. 1, Gilam G. 2, Okon-Singer H 1, Sharabani R1, Gonen T 3, Hendler T 4,5, Shamay-Tsoory S.G 1 Psychology, Univ. of Haifa 2 School of Psychological Sciences, Behavioral Cognitive Neuroscience Program at Tel Aviv Univ. 3 School of Psychological Sciences, Tel-Aviv Univ. 4 Dept.s of Physiology and Pharmacology and Psychiatry 5 Sagol School Neuroscience Tel Aviv Univ. Background: Intimacy between friends may affect various aspects of social behavior including preferred interpersonal space. Although, one of the most important aspects of friendship is the level of intimacy two friends share, the neural underpinning of intimacy is unknown. Considering that oxytocin (OT), a hormone which plays a key role in social behavior, has been shown to modulate interpersonal space, the current study examined the hypothesis according to which the administration of OT would affect the preferred space depending on the level of intimacy. Methods: using a within-subject crossover design, 20 subjects were scanned while performing an interpersonal distance task following the administration of either placebo or OT. The task involved watching different protagonists (a friend, stranger or ball) approaching and stopping them when feeling uncomfortable. Before scanning, participants completed an intimacy scale about their best friend to assess individual differences in levels of intimacy. Results: The results show an interaction between one's intimacy level and the treatment. Following intranasal administration of OT, low intimate individuals preferred standing further apart from all approaching figures while high intimate individuals had no change in preferred distance. The vmPFC (BA10), a region involved in perspective taking and self-other distinction, was differentially activated depending on the type of the protagonist, regardless the levels of intimacy. In addition, bilateral activation of the temporal gyrus was modulated by OT, intimacy and the type of figure. Conclusions: The findings suggest a complex role for OT as a modulator of interpersonal distance in interaction with intimacy levels. From worms to therapy - the mechanisms that link aging, proteostasis and neurodegeneration Cohen E 1,2,3*, Tayir El-Ami 1,2,3, Lorna Moll 1,2,3 1 Biochemistry and Molecular Biology 2 The school of medicine 3 The Hebrew Univ. of Jerusalem

Aging manipulation is an emerging strategy aimed to postpone the manifestation of late-onset neurodegenerative disorders such as Alzheimer's (AD) and Huntington's diseases (HD) and to slow their progression once emerged. Reducing the activity of the Insulin/IGF signaling cascade (IIS), a prominent aging regulating pathway, protects worms from proteotoxicity of various aggregative proteins, including the AD-associated peptide, Aβ and the HD-linked peptide, polyQ40. Similarly, IGF1 signaling reduction protects mice from AD-like disease. IIS reduction induces several biological activities that detoxify protein aggregates including dis-aggregation, protein degradation and protective hyper-aggregation. Recently we found that NT219, a novel IIS inhibitor, mediates a long-lasting, highly efficient inhibition of the IIS signaling cascade by a dual mechanism; it reduces the auto-phosphorylation of the IGF1 receptor and directs the Insulin Receptor Substrates 1 and 2 (IRS 1/2) for degradation. NT219 treatment promotes stress resistance and protects nematodes from AD- and HDassociated proteotoxicity without affecting lifespan. Our discoveries strengthen the theme that IIS inhibition has a therapeutic potential as a cure for neurodegenerative maladies and point at NT219 as a promising compound for the treatment of these disorders through a selective manipulation of aging. This study was supported by the Rosetrees Trust and by the European Research Council Near infrared imaging of EGF receptors down-regulation during NGF-induced PC12 cells differentiation Cohen G and Lazarovici P* School of Pharmacy Institute for Drug Research, The Hebrew Univ. of Jerusalem, Jerusalem Nerve growth factor (NGF), a neuronal differentiation factor, causes a very significant down-regulation process of mitogenic epidermal growth factor (EGF) receptors during the differentiation of sympathetic neurons. This process occurs also in brain cholinergic neurons during prenatal development and in vitro during NGF-induced PC12 cell culture differentiation. The role of EGF receptors down-regulation, upon differentiation of the prenatal towards post-mitotic neuron, is to prevent the re-entry of the mature neuron into the cell cycle, a situation which may be catastrophic for the neuron since it can cause apoptotic cell death. Bio-imaging technologies are not available today to visualize this process in vitro and in vivo. To achieve this bio-imaging goal, we took advantage of a EGF probe conjugated with near infrared (NIR) dye (EGF-NIR, IRDye800CW) and demonstrated its specific and selective pharmacological properties by measuring its receptor binding activities in vitro, using NIR imaging with two lasers Odyssey® infrared imager. Using PC12 cultures differentiated for one week by 50 ng/ml NGF, we demonstrated a significant 85% reduction in EGF-NIR specific binding to the cells indicative of a significant down regulation of EGF receptors.

J Mol Neurosci

These findings were confirms by binding experiments with 125I-EGF and western blotting of EGF receptors. EGF-NIR is an useful molecular imaging agent to evaluate its receptors level in the developing brain during prenatal development and in vitro during differentiation of neuronal cells in culture. * PL holds the Jacob Gitlin Chair in Physiology at Hebrew Univ. and is affiliated and acknowledges the support by the David R. Bloom Center for Pharmacy and the Dr. Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at The Hebrew Univ. of Jerusalem, Israel. Cohen G is supported by “Eshkol” fellowship from the Israeli Ministry of Science and Technology. Mother-pup interaction and the balance between excitation and inhibition in auditory cortex Cohen L. 1,2, Mizrahi A. 1,2* 1 Dept. of Neurobiology, Inst. of Life Sciences, The Hebrew Univ. of Jerusalem 2The Edmond and Lily Safra Center for Brain Sciences, The Hebrew Univ. of Jerusalem Becoming a mother is an intensive natural experience associated with different forms of physiological alterations including transient hormonal changes and brain plasticity. The impact of these changes on mother-pup interaction and sensory processing within the mother's brain are largely unknown. Here we report how the transition to motherhood and interaction with newborns, affects the response properties of cortical neurons in the primary auditory cortex (A1) of female mice. Specifically, we studied two cell types in layer 2/3 from A1, 1) cortical inhibitory neurons, the parvalbumin (PV+) - expressing cells and 2) pyramidal neurons (Pyr). We used in vivo multi-photon targeted cell attached recording to compare the response properties of PV+ and Pyr neurons. Using this approach we tested how the transition to motherhood reshapes the excitatory/inhibitory balance of sound processing in A1. The transition to motherhood shifted the best frequency of PV+ cells by a full octave, lateral to that of Pyr neurons with no significant effect on Pyr cells best frequency. Yet, in the presence of pup odor PV+ neurons' spontaneous and sound evoked activity was reduced. This reduction of feedforward inhibition, coincide with complementary expansion of Pyr neurons frequency response area. This pup odor induced disinhibition of Pyr neurons is selective for ultrasonic frequencies, facilitating response to pup distress calls. We conclude that experience dependent plasticity in mothers' auditory cortex is tunneled via plastic modulation of feed-forward inhibition. Computational benefits of sensory expectation cancellation Cohen U. 1*, Sompolinsky H. 2,3 1 Interdisciplinary Center for Neural Computation, Hebrew Univ., Jerusalem 2 Edmond and Lily Safra Center for Brain Sciences, Hebrew Univ., Jerusalem 3 Center for Brain Science, Harvard Univ., Cambridge, Massachusetts

Background: Weakly electric fish of the Mormyridae family perform active electrosensing, including electrolocation, using slow-rate pulse-like discharges from an electric organ located at their tail. Sensory images created by electroreceptors along their body are processed in the ELL area, which is known to use anti-Hebbian plasticity to perform "expectation cancellation", where predictable parts of the signal are removed. Results: We have modeled the first 4 steps of sensory processing in Mormyridae electrolocation: (1) A simple electrostatic model of the transdermal potential measured by receptors along the body and its perturbation due to of small nearby objects, with dependency on tail position. (2) A phenomenological model for receptors' latency coding of transdermal potential. A simple threshold-adaptation scheme explains how receptors' responses may depend only on amplitude modulation compared to baseline, an unexplained physiological fact. (3) A minimalistic model of the transformation performed by granular cells in the ELL. (4) A computational model for expectation cancellation by cells of the ELL, which uses information about tail position and electric organ motor command to remove from the signal the predictable contribution of tail position. We show analytically how anti-Hebbian plasticity results in recovering the expected signal and allows for its cancellation. Conclusions: By analyzing the model's response to different object locations we evaluate the computational benefits of the expectation cancellation. We show that when limiting readout to use only spike rates the effect of expectation cancellation is to bring the output of different receptors to a common baseline, correcting for both tail-position related variance and variance in single-receptor properties. By evaluating the performance of simple readout schemes which estimate object location from the output of ELL cells we show how they benefit from the common-baseline property. PolyADP-ribosylation of PARP-1 in the central amygdala is a prerequisite for cocaine-induced place preference Yadid G. 1,2 Lax E. 1,2, Friedman A. 1, Abraham L. 2, Visochek L. 3, Cohen-Armon M. 3 1 The Leslie and Susan Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar-Ilan Universi 2 The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan Univ., 52900 Ramat-Gan, Israel 3 Dept. of Physiology and Pharmacology and Cardiac Research Institute, Sackler Faculty of Medici Reward-related memory is arguably a factor in cocaine addiction. Activation of poly(ADP-ribose) polymerase-1 (PARP-1) was recently proposed as a necessary signaling mechanism for long-term memory formation. Using Pavlovian conditioned place preference (CPP), in which animals learn to associate drug effects with a distinct locality; we investigated PARP-1

J Mol Neurosci

participation in cocaine-induced CPP. Activation of PARP-1 in the central amygdala (CeA) was significantly more pronounced in rats expressing cocaine-CPP than in salineconditioned rats. Infusion of the potent PARP inhibitor PJ34 into the CeA 30 minutes before CPP testing abolished preference for the cocaine compartment. Results of locomotor and object-recognition tests in cocaine-conditioned rats ruled out the possibility that PARP-1 inhibition had impaired locomotion or formation of short-term or long-term memory. These findings suggest that PARP-1 activation in the CeA possibly resulting in poly(ADP-ribosylation)-induced modifications in memory retrieval and reconsolidation, mediates the response to environmental cues previously associated with cocaine. Supported by NIH The role of emotional valence and arousal in lexical decision of abstract Hebrew words Armony-Sivan R 1,2*, Cojocaru L. 3, Babkoff H. 1 1 Dept. of Psychology, Ashkelon Academic College 2 Center 3 Dept. of Economics, Ashkelon Academic College Background: The effects of emotional valence and arousal on word processing have been documented in various languages (e.g. English, German). Response times to positive or to higharousal negative words are reported to be generally swifter than those to neutral or low-arousal negative words. In the present study, we used the lexical decision paradigm to evaluate response times to emotionally valenced and arousal-rated abstract Hebrew words and non-words constructed from the same letters. Results: Mean response time to words was shorter than to non-words. As reported in other studies, response times to positive words were significantly faster than to neutral or negative words. We found a significant interaction between emotional valence and level of arousal as a predictor of lexical decision response time. The slope of the function relating response time to the emotional valence of the word stimuli was significantly steeper when the words were rated low in arousal than when rated high in arousal. When the words were rated as high in arousal, the slope tended to zero and all response times were relatively fast. Using the JohnsonNeyman technique we found that the effect of high emotional valence in facilitating lexical decision response times was significant up to the 90th percentile in the word arousal distribution, whereas above this level, the impact of the emotional valence of the word stimulus was attenuated. Conclusion: These results support previous studies in other languages suggesting that in single word recognition there is an advantage both to word positivity and to a high-arousal level with negative words. Our study is the first in Hebrew to suggest that both emotional valence and arousal level are important interacting factors in visual word processing.

Testing the effect of dopamine agonists and of drugs of addiction on structural plasticity of dopaminergic neurons: translation from mouse primary cell culture to human iPSC-derived neurons Collo G. 1*, Bono F. 1, Cavalleri L. 1, Spano PF. 1 1 Dept. of Molecular and Translational Medicine Univ. of Brescia, Italy Background: Innovative treatments for neurological and psychiatric disorders can be discovered by interfering on the molecular mechanisms operating in neurons that are present in dysfunctional brain circuits described in patients. This is the case for mesencephalic dopaminergic neurons, whose liability to damage or capacity to adapt with structural plasticity is well established in Parkinson's Disorder (PD) and, more recently, in Substance Abuse. To address these problems in our laboratory we use an in vitro model of primary cultures of mesencephalic neurons from wildtype and dopamine D3 receptor KO (D3KO) mice and, recently, we have established a protocol to obtain neurons from human iPSC we have generated. In the present work we have investigated the putative neurotrophic effects of D2D3R agonists such as quinpirole, ropinirole, 7OHDPAT and of drugs of abuse such as cocaine, nicotine and ketamine. Results: Primary mesencephalic neuronal cultures from wild type and D3KO mice were prepared at 12.5 embryonic day. After pharmacological testing the cultures were immunostained to detect DA neurons. Morphometric assessments showed a time- and dose-dependent increases of dendrite arborisation and soma area of DA neurons from wild type, while it was ineffective in cultures from D3KO mice. Using confocal microscopy and western blot analysis we showed a D3R-dependent activation of the Akt-mTORC1 pathway. These effects were pharmacologically blocked by D3R antagonists and absent in cultures from D3KO mice. Conclusions: These results suggest a key role for D3R in dopamine-induced structural plasticity of mesencephalic dopaminergic neurons. Supported by Italian Project of Main National Interest, Woman Health Center-Camillo Golgi Foundation CRH is involved in the mechanism underlying stress resilience and vulnerability Cramer T1,2., Kisliouk T1., Yeshurun S1,2. Meiri N1* 1 Institute of Animal Science, ARO, The Volcani Center, Bet Dagan 50250, Israel 2 The Robert H. Smith Faculty of Agriculture, Food and Environment, the Hebrew Univ. of Jerusalem, Herzl St., Rehovot 76100, Israel Background: Determining whether a stressful event will lead to future stress-resilience or vulnerability depends on a delicate balance of a probably adjustable stress response set-point.

J Mol Neurosci

The adjustment of this set-point is most likely effective during sensory postnatal development and involves the hypothalamus-pituitary-adrenal (HPA) axis. Here we demonstrate that heat stress during the critical period of thermal control establishment in 3-days-old chicks, renders habituated or sensitized response, a week later, depending on the ambient temperature i.e. moderate heat lead to future heat resistance while harsh temperatures lead to heat vulnerability. Results: These two different responses are correlated with the amount of activation of the HPA axis. The expression of the mRNA of Corticotrophin releasing hormone (CRH) in the hypothalamic paraventricular nucleus (PVN) and plasma corticosterone (cort) were elevated a week after heat conditioning in chicks which were trained to be vulnerable to heat, while it declined in chicks that were trained to be resilient. In order to study the role of plasticity in the HPA axis, CRH was intracranialy injected into the third ventricle causing an elevation both in body temperature and plasma cort level, which was memorized a week later, as if the chicks were exposed to mild heat stress. This effect was used to reverse resilience into vulnerability. Chicks that have been injected with CRH followed by exposure to mild heat stress, normally inducing resilience, demonstrated, a week later, a very high elevation in body temperature and CRH expression similar to heat sensitized response. Conclusion: These results demonstrate that exposure to different levels of stress during the critical period of thermal control establishment, reveal a potential role for CRH at determining either stress resilience or vulnerability response later in life. Supported by ISF Characterization of the placebo response rate, consistency and kinetics in different pain paradigms Czerniak E. 1,2, Treister R. 3,4, Weiser M. 1,5, Biegon A. 6, Eisenberg E. 7,8, Pud D. 9* 1 Sackler Faculty of Medicine, Tel Aviv Univ. 2 J. Sagol Neuroscience Ctr., Sheba Medical Ctr., Tel Hashomer 3 The Rappaport Faculty of Medicine, Technion – Israel Inst. of Technology, Haifa; Israel 4Dept. Neurology, MA Gen. Hospital Harvard Med. School, Boston MA; USA. 5 Dept. Psychiatry, Sheba Medical Center, Tel Hashomer; Israel. 6 Stony Brook Univ., NY; USA. 7 The Rappaport Faculty of Medicine, Technion – Israel Inst. of Technology, Haifa 8 Inst. of Pain Medicine, Rambam Health Care Campus, Haifa 9 Faculty of Social Welfare and Health Sciences, Univ. of Haifa; Israel Background: The placebo response (PR) is a well-recognized phenomenon in experimental pain. Reward expectation, involving increased release of brain dopamine, is thought to play an important role in the PR, but it is not clear whether different pain paradigms and outcome parameters are equally susceptible to placebo. In this study, we compared the rate, consistency and kinetics of the PR across different paradigms and outcomes.

Methods: Healthy volunteers (n=105) who received placebo in a randomized double-blind cross-over trial of apomorphine (1) were assessed for cold pressor test (CPT) threshold and tolerance (sec) cold and heat thermal sensitivity thresholds (°C) at baseline and 10, 55 and 100 min after placebo injection. A >30% improvement over baseline was defined as a PR. Subjects exhibiting 2 or 3 PRs were considered consistent responders. The change from baseline over time was used to evaluate the kinetics of the PR. Results: The PR rate was highly sensitive to the pain stimulus, with 40, 25 and 26 responders in the CPT threshold, cold sensitivity threshold and CPT tolerance respectively and no PR in heat threshold (p<0.0001). PR consistency was significantly higher (p<0.005) in the cold threshold (25/25) and CPT tolerance (23/26) parameters relative to CPT threshold (27/40). A significant effect of time (F=4.0, p<0.02) and a significant time x measure interaction by ANOVA followed by Posthoc analysis revealed a larger PR in the last time point; which derived from the CPT tolerance parameter. Conclusions: Our results demonstrate that the rate of PR in experimental pain depends on the pain stimulus and is highly consistent within pain measures. Furthermore, the selectivity and kinetics of the PR are largely similar to those demonstrated in response to apomorphine (1), supporting a role for dopaminergic tone in this phenomenon. 1. Treister R, Pud D, Ebstein RP, Eisenberg E (2013) PLoS ONE 8(5): e63808. doi:10.1371 This work is supported by Mr. Sami Sagol PhD fellowship. Computation of visual information in the dendritic trees of the fly Dan O.J. 1, Hopp E. 2, Borst A. 2 Segev I. 1,3* 1 Dept. of Neurobiology, The Hebrew Univ. of Jerusalem, Israel 2 Max Planck Institute of Neurobiology, 82152 Martinsried, Germany 3 Interdisciplinary Center for Neural Computation , Hebrew Univ., Jerusalem 91904, Israel Flies are phenomenal performers with respect to threedimensional agile maneuvers. To perform such maneuvers, estimations of transient changes in the local visual environment must be taken into consideration. Indeed, this kind of information is extracted by non-trivial computations, which are performed in the visual system of the blowfly, Calliphora vicina, and in particular by the vertical system (VS) cells. VS cells receive both spatial sensitive and direction selective dendritic input, which shape their complex receptive fields. However, the principles governing the implementation of the visual sensitivity of the VS cells are not fully understood. In this work we explored possible dendritic mechanisms underlying the VS cells dendritic-to-axonal input/output computations. The work is based on experimentally-measured responses (Ca2+ imaging) at various well-characterized dendritic loci of VS cells, together with measurements of the receptive field properties of

J Mol Neurosci

the axonal output of the same cell. We used passive compartmental model of 3D reconstructed VS cells and utilized cable theory to simulate visual input to the modeled cells. The input simulated oriented bars moving in different directions and in different locations of the receptive field. These inputs were translated into voltage response at any of the given dendritic branchlets; the magnitude of the response was constrained by the experimental results. Our simulations sought to match the axonal receptive field (the global output) to a set of visuallydriven dendritic receptive fields (the local input). Our initial exploration of the passive case suggests that the various dendritic loci contribute equally ("location independent") to the axonal input summation, but that this linear case does not explain the full input-output transformation performed by VS cells' dendrites. Further mechanisms, including nonlinear dendritic processing, are under investigation. Multi-modal perception and decision making in the Egyptian fruit bat Danilovich A. 1,2*, Bar Yossef M. 1, Yovel Y. 1,2 1 Dept. of Zoology, George Wise Faculty of Life Sciences, Tel Aviv Univ., Tel Aviv 69978, Israel 2 Sagol School of Neuroscience, Tel Aviv Univ., Tel Aviv 69978, Israel Background: How sensory information acquired by one sense is translated into a brain representation available to another sense, and how decisions are made using different senses are fundamental questions in behavioral neuroscience. The Egyptian fruit bat (Rousettus aegyptiacus) presents an ideal model for attending these questions. Rousettus bats rely both on echolocation and vision to build a sensory representation of the world and are unique among bats in their tendency to switch between these modalities according to ambient light levels. The use of echolocation requires the bat to emit a pulse in order to sample the environment. This allows us to assess how much information the bat collects before it makes a decision. Results: 3 Rousettus bats were trained and tested in a discrimination task between cubes differing in texture in complete darkness, thus using only echolocation. All bats performed high above chance level. Next, the bats were tested in dim light with the same cubes covered with transparent plastic tablets to allow the usage of vision but not echolocation. Here, the bats immediately preformed high above chance level, even though they have never seen the objects visually. Echolocation and flight trajectories recordings from test trials in complete darkness show that the bats developed a preferred approach strategy, flying from a specific point in the room and scanning both objects before making a decision. Conclusions: Rousettus bats are able to transfer information acquired using echolocation to the visual modality, suggesting they can create an echo-based representation of the world that is accessible to other sensory modalities. This result implies the presence of a high brain region responsible for integration

of the two modalities. The decision making results suggest that bats adopt a typical flight trajectory that is informationefficient and make their decision based on a comparison between the two choices. Gene knockout in wild mice: A powerful tool for genetic mapping of social behavior traits Dayan M. 1, Halfin L. 1, Kimchi T. 1* 1 Dept. of Neurobiology, Weizmann Institute of Science, Rehovot, Israel. The purpose of this study was to establish a mouse model that would incorporate gene-targeted mutations into undomesticated wild mice to allow screening for novel gene-behavioral phenotype associations that could not be determine in the classical inbreed laboratory mouse strains. We have backcrossed a laboratory knockout mouse with pathogen-free wild mice and received a mouse line that is statistically expected to carry ~99.9% of the wild mouse genetic background, incorporating the targeted gene mutation of the donor laboratory mouse strain. The wild backcrossed mice, were smaller, consumed less food, and exhibited higher stress-hormone levels, stronger anxiety/ fear-related behavioral responses. In addition, the wild backcrossed mice demonstrated a repertoire of robust social behaviors toward conspecific alien individuals that was qualitatively and quantitatively similar to that shown by the wild mice. Notably, the female wild backcrossed mice displayed a battery of social behaviors, such as pup-directed aggressive (infanticidal) and female-female aggressive behavior which, although typically robust in wild mice, are hardly ever seen in any of the classical inbred laboratory strains. Lastly, we performed genome-wide microarray expression analysis in the hypothalami of female wild and laboratory mice and found that differential gene expression between wild and laboratory females was significant in a couple hundreds of genes. Among them several participate in regulation of the reproductive system, social behavior, and social/reproductive-related diseases. Wild-backcrossed animals presented gene expression similar to that presented by the wild mice. These findings support our contention that wild backcrossed mice would serve as better models than laboratory mice for studying the genetic basis of social and reproductive behavior behavior (particularly in females), as well as for studying human social-related disorders. The complement system, an important player in brain ischemic injury De Simoni M.G. 1* 1 Dept. of Neuroscience, IRCCS-Mario Negri Institute, Milan, Italy The complement system is a powerful arm of the inflammatory response that becomes rapidly activated after injury. It contributes to the evolution of injury by several potential

J Mol Neurosci

mechanisms, including activation of inflammasome, inflammatory molecule synthesis, recruitment of cells to the site of injury, activation of phagocytosis, induction of endothelial damage and increased vascular permeability, and by directly inducing cell death. Our studies document the pivotal role of mannose binding lectin (MBL), a circulating protein which acts as activator of the lectin complement pathway, in brain ischemic injury. After cerebral ischemia, the lectin pathway is activated and that MBL is deposited selectively on the ischemic endothelium. By using three independent lines of evidence, we demonstrated that MBL inhibition is protective. Firstly we documented that MBL knock-out mice showed a lower susceptibility to ischemia compared to wild type mice. Secondly we showed that Polyman2, a dendrimeric molecule exposing multiple copies of synthetic mannoside and binding to MBL with high affinity, induced a significant reduction of neurological deficits and ischemic volume when given up to 24h after injury induction. Furthermore Polyman2 administration is associated with reduced complement activation in plasma and MBL deposition on the ischemic endothelium. Thirdly we demonstrated that the administration of an antiMBL antibody, that functionally inhibits rat MBL, reduced both neurological deficits and infarct volume when given up to 18h to ischemic rats. Our studies show the importance of the complement system in brain injury. In addition, by providing a mechanistic insight into the role of MBL in brain ischemia and the demonstration that its inhibition is protective, strongly support the concept of MBL as a relevant therapeutic target in humans, one with a wide therapeutic window of application. When ‘sighted’ brain reads Braille – an fMRI study Debowska W. 1*, Wolak T. 2, Kossut M 3 1 Nencki Institute of Experimental Biology, Laboratory of the Neuroplasticity 2 World Hearing Center 3 Nencki Institute of Experimental Biology When 'sighted' brain reads Braille – an fMRI study. Introduction: Remarkable ability of the brain to change its organization due to experience is a subject of extensive studies. The processes underlying acquisition, consolidation and the storage of information receiving/coming from the environment are under special investigations. Here we present results from studies concerning adult brain capability to undergo experience-dependent plasticity, taking as an example acquisition of Braille reading skill. Methods: Eighteen right-handed sighted subjects (10 women, 8 men, mean age: 25.1 +/- 3.2) with no history of neurological or psychiatric disorders, participated in the study. Our procedure comprised of extensive sensory training and two scanning sessions, before and after the training. Training procedure consisted of 15 Braille reading lessons and tactile object recognition exercises conducted for three weeks. Subjects

were tested using fMRI with the same tactile discrimination task. Results: Analysis revealed that activations accompanying active touch of tactile signs change as a result of extensive training. Here we found significantly different pattern of activations obtained pre and post sensory training. We observed blood oxygenation level-dependent (BOLD) signal increase after training in comparison to pre training test in a wide range of areas including bilateral primary somatosensory cortex, premotor and lateral-occipital (LOC) cortices, as well as ipsilateral dorsolateral prefrontal cortex (DLPFC) and contralateral ventromedial frontal cortex. Conclusions: Apparently, acquiring ability of decoding tactile pattern into meaningful signs and successive improving of the new skill demands not only stronger involvement of the primary sensorimotor cortices but also engages higher-order areas. We consider these results as an evidence for neuroplastic changes induced by tactile training. NCS grants no. 8203 to WD, 3608 to MK. Tilt-After-Effect visual illusion induced by exposure to natural images Dekel R. 1, Sagi D. 1* 1 Dept. of Neurobiology, Weizmann Institute of Science Background: The human visual system continuously adjusts to the current environment. To investigate this, researchers measured aftereffects of exposure to many types of stimuli, and attempted to generalize the results. Frequently, synthetic stimuli composed of spots of light, lines, or Gabor patches were used. These patterns match the receptive fields of individual visual neurons, but cover a small subset of actual visual stimulation. Therefore, researchers recently investigated aftereffects of exposure to synthetic patterns mimicking several aspects of natural stimulation, with interesting results. Still, aftereffects of natural stimulation per-se remain largely unexplored. Results: Here, we measured a change in perceived orientation resulting from exposure to carefully selected (biased) but otherwise unaltered natural images. This Tilt-AfterEffect (TAE) was measured for a vertical Gabor patch at fixation. Presented images were selected by a Fourier power spectrum criterion which favored images depicting content tilted roughly 25° clockwise to vertical, at frequencies roughly an octave above and below the frequency of the Gabor patch. Viewing such images resulted in ~1° counterclockwise TAE (p<0.000001 for no effect, one-tailed paired t-test). Conclusions: Our results validate that similar TAEs obtained from exposure to synthetic patterns are not unique to the pattern used, and suggest that exposure to any strongly oriented stimuli results in a TAE. Further, our method of presenting biased natural images can be applied in a variety of conditions, to check additional aftereffects.

J Mol Neurosci

External sensory input diminishes internal cortical-states switching Deneux T. 1,2, Grinvald A. 1* 1 Dept. of Neurobiology, the Weizmann inst. of Sci. Rehovot, Israel. 2 Unité de Neurosciences Intégratives et Computationnelles, UPR CNRS 2191, Centre National de la Rech Background: Previously we have shown in anesthetized rodents, cats and monkeys that spontaneous activity is large and highly structured at the cortical column level and modulates sensory evoked activity. Furthermore, spontaneous activity, also referred as internal, or ongoing activity or activity at "rest", plays a major role in cortical function in awake human subjects. However, the complementary question of how sensory inputs interact with subsequent internal activity at the fundamental cortical column level remains largely unknown. Here, we explored whether the internal activity is affected by a sensory-evoked activity. Results: Utilizing optical imaging of new voltage-sensitive dyes we found that the spontaneous up/down cortical states were largely diminished even after a single weak whisker deflection in the somatosensory cortex of anesthetized rats. This reduction of internal population activity lasted approximately two seconds and was the largest at the corresponding barrel. Using 2-photon calcium imaging of single cell activity rather than a population, we found that during this period a majority of cells decreased their spontaneous firing rates. Conclusions: Our findings indicate that sensory input momentarily reduces additional internal messages, thus leaving more time for post-processing in the proper context at the time of the stimulus. Thus evoked activity and internal activity are interacting bidirectionaly. Anesthetized and awake rodents offer a preparation in which the internal activity can be monitored and manipulated down to the molecular level. Testing this elaborate interaction on awake subjects is warranted. Supported by the grodetsky center for research of higher brain functions. PTSD-like memory is associated with epigenetic alteration in the hippocampal-amygdalar network Mennesson M 1, Marighetto A 2, Mons N 1, Desmedt A 2,3* 1 Institut de Neurosciences cognitives et intégratives d’Aquitaine, CNRS UMR 5287 2Neurocentre Magendie, INSERM U862 3 Bordeaux Univ. Normal 0 21 false false false MicrosoftInternetExplorer4 Long term formation of normal stress-related memory is associated with plasticity-related gene activation through epigenetic mechanisms such as modulation of acetylation/methylation states of histone H3 both in the hippocampus and the amygdala. Because post-traumatic stress disorder (PTSD)- like memory is associated with an altered pattern of neural

activation within the hippocampal-amygdalar network, the present study tested the hypothesis that a switch from normal to PTSD-like memory might involve a deregulated balance of histone acetylation (mark of transcriptional activation)/methylation (mark of transcriptional repression) in this neural network. Combining fear conditioning, neuropharmacology and immunohistochemistry, the present study shows that the altered hippocampal (hypoactivation)-amygdalar (hyperactivation) network observed in mice with PTSD-like memory impairments is associated with (i) a shift from H3K9 hyperacetylation to H3K9 hypermethylation in hippocampal CA1 region and (ii) a reduction of H3K27 methylation in the amygdala. These findings indicate that PTSD-related memory disturbances are associated with epigenetic alteration based on deregulation of histone H3 acetylation/methylation balance within the hippocampal-amygdalar network. The identification of molecular biomarkers of PTSD-related memory should unveil new therapeutic targets in the treatment of this anxiety disorder. Normal 0 21 false false false MicrosoftInternetExplorer4 Normal 0 21 false false false MicrosoftInternetExplorer4 FRC; LEA France-Israel Laboratory of Neuroscience Cortical activity in the barrel cortex during a localization task Deutsch D. 1*, Ebert C. 1, Schneidman E. 1, Ahissar E. 1 1 Dept. of Neurobiology, Weizmann institute of science, Rehovot Background: Rats use their whiskers to scan their near environment. The tractability of the whiskers together with the oneto-one mapping of a single whisker to a single column ('barrel') in the cortex makes the whisker system an ideal model to learn the neuronal basis of active sensing. It has been shown that nose-poking rats are able to discriminate between positions of objects that differ in their azimuthal coordinate with a hyperaccurate resolution, using their whiskers (Knutsen et al., 2007). We found that freely moving rats can reach similar discrimination resolution as nose-poking rats, and that whiskers are essential for fine-resolution (Deutsch et al., in preparation). The neural basis of object localization is still elusive. Previous studies with head fixed rats have shown that the barrel cortex is essential for object localization (O'connor et al., 2010). Works in anesthetized animals revealed differences in selectivity, dynamics and coding properties of neurons from different cortical layers in a single barrel (see e.g., Derdikman et al., 2006; Khateb et al., ISFN 2012; Yu et al., 2013). Methods: We use multi-site Silicon probes (Neuronexus) to record bi-lateral extracellular activity from multiple layers of the barrel cortex of freely moving rats while engaging in a localization task. We record ~10 single units simultaneously in a session, while tracking rat's behavior (head and whiskers) at a millisecond resolution.

J Mol Neurosci

Results: Task-related dynamics of individual cortical neurons at various layers, their relation to behavioral events and object location, their mutual interactions, and their relation to rat's perceptual decisions will be presented. The role of GITRL/TRAIL interactions in neurodegenerative processes Di Benedetto G.*, Cantarella G., Bernardini R. Dept. of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, School of Medicine, Univ. of Catania, 95125 Catania, Italy. Cytokines, with special regard to the TNF superfamily, play a relevant role in the central nervous system damage. Tumour Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), released during neuronal injury, has proven to potently mediate and sustain neurotoxic processes leading to neuronal death. Moreover, evidence shows that the neutralization of TRAIL death pathway protects a human neuronal cell line from amyloid-beta toxicity. Similarly to TRAIL, the cytokine Glucocorticoid-induced TNF receptor ligand (GITRL) is able to transduce proapoptotic signals. In spite of the array of reports suggesting relationships between TRAIL and other cytokines, scanty data are, so far, available about a GITRL/TRAIL crosstalk. Here, we investigated possible interactions between TRAIL and the GITRL system in neurodegenerative processes. Real-time PCR analysis showed that the human cortical neuronal cell line HCN-2 do not express GITRL mRNA, but it is induced after treatment with TRAIL. In addition, cells do not express GITR mRNA, either at baseline or upon treatment with TRAIL. All mRNA data were confirmed by western blot at the level of protein expression. Cell viability assay shows that TRAIL, when associated to GITRL, is able to exert additive toxic effects. A counterproof to the latter data was provided in experiments performed blocking GITRL which significantly reduced TRAIL-mediated toxicity. Results suggest that the GITRL/ TRAIL interactions are relevant to induction of neuronal damage. Finally, characterization of new molecular targets within such interactions may represent a platform for innovative treatment of neurodegenerative diseases. Adolescent Cannabis exposure differentially affects Heroin Reinforcement and Accumbens Dopamine transmission in Lewis and Fisher344 rats Di Chiara G 1*, Cadoni C 1, Lecca D 1 1 Dept. of Biomedical Sciences Univ. of Cagliari, Italy Background: Vulnerability to drug addiction depends on acquired as well as genetic factors (Swendsen & Le Moal 2010). Among acquired factors is previous exposure to other drugs of abuse. Thus, exposure to Cannabis has been suggested to predispose to heroin abuse and dependence

(Gateway Hypothesis) (Kandel et al. 2006). Here we studied the influence of adolescent delta 9-THC exposure on heroin reward and renforcement and on the in vivo dopamine stimulant properties of heroin in two inbred rat strains differentially vulnerable to drugs of abuse, the addiction prone Lewis and the addiction resistant Fisher344 strain. Results: THC increased extracellular DA, as estimated by microdialysis, in Lewis but not in Fischer 344 rats. Adolescent THC exposure potentiated DA stimulant effects of heroin in the shell and core of Lewis and only in the core of Fischer344 rats. Control Lewis rats developed stronger conditioned place preference (CPP) to heroin and resistance to extinction compared with Fischer344 strain. In Lewis rats, THC exposure did not increse heroin CPP but potentiated the effect of heroin priming. In Fischer344 rats, THC exposure increased heroin CPP and made it resistant to extinction. Lewis rats showed marked seeking reactions during extinction and hedonic reactions in response to heroin priming. THC pre-exposure increased responding for iv heroin self-administration on FR3 and FR5 and on progressive ratio 3-4 in Lewis but not in Fisher344 rats. After extinction, presentation of discriminative stimuli associated to drug availability on the active nose-poke as well as priming by passive heroin exposure, reinstated responding more effectively in Lewis rats pre-exposed to THC than in saline controls. Conclusions: These observations suggest that, in genetically predisposed individuals, adolescent Cannabis exposure can increase vulnerability to heroin addiction by augmenting heroin reinforcing properties. These studies were founded by the Dipartimento politiche antidroga, Presidenza del Consiglio, Italy Molecular mechanisms involved in neurotoxic effects of polychlorinated biphenyls Di Renzo G 1*, Formisano L. 2,3, Guida N 2, Cocco S. , Boscia F. 1, Esposito A. 1, Sirabella R. 1, Secondo A. 1, Canzoniero L.M.T. 6 7 1 Division of Pharmacology, Dept. of Neuroscience, Reproductive and Odontostomatologic Science 2 Division of Pharmacology Dept. of Biological, Geological and Environmental Sciences, 3 School of Medicine, Fedeico II Uniiversity of Naples 4 Univ. of Sannio, Benevento, Italy Background: Polychlorinated biphenyls (PCBs) are a structurally related group of stable and highly lipophilic toxic chemicals with widespread distribution throughout the environment. They cause a wide spectrum of toxic effects in the brain through several mechanisms, most of which remain unidentified. Recently we demonstrated that exposure to Aroclor1254 (A-1254), a mixture of PCBs, increases the RE1-silencing transcription factor (REST) expression leading to neuronal death. In the present study, we tested the

J Mol Neurosci

hypothesis that A-1254 could increase REST expression through ERK pathway in SHSY-5Y neuronal cells. Results: At 10μg\ml, A-1254 caused a time-dependent decrease in extracellular signal-regulated kinase 2 (ERK2) phosphorylation associated with overexpression of Sp1 and Sp3, but not Sp4, proteins and an increase of REST protein expression. In contrast, the phorbol ester tetradecanoylphorbol acetate (TPA), which induces ERK2 phosphorylation, prevented the decrease in ERK2 phosphorylation , the increase in Sp1, Sp3, and REST protein expression cello death induced by A-1254. Accordingly ERK2 overexpression counteracted A-1254-induced increase in Sp1 and Sp3 protein expression and prevented A-1254-induced Sp1 and Sp3 binding to the REST gene promoter, thus counteracting the increase in REST mRNA expression induced by the toxicant. Furthermore, Sp1 and Sp3 silencing, by preventing REST mRNA overexpression, reduced A-1254-induced neurotoxic effects. Interestingly, the addition of TPA to SHSY-5Y cells overexpressing ERK2, as well as the double silencing of Sp1 and Sp3, completely prevented the increase in REST mRNA expression induced by A-1254. Conclusions: Collectively, we demonstrated that A-1254 downregulates ERK2 signalling, thereby triggering the binding of Sp1 and Sp3 to the REST gene promoter. This chain of events eventually results in an increase in REST mRNA transcription and cell death in SHSY-5Y cells. D-TMS in cocaine addiction: preliminary findings Panella R. 1,2,3, Bolloni C 1,2,3, Pedetti M 1,2,3, Frascella A. G 1,2,3, Diana M 1,2,3* 1 'G.Minardi' Cogn. Neurosci. Lab., Dept of Chemistry & Pharmacy, Univ. of Sassari. 2 Ser.T. Marsciano, Asl1 Perugia 3 Biomedicine and Neuroscience Dept., Univ. of Palermo In spite of the progress made in the understanding of the neurobiological mechanisms underlying addiction, expectations from a therapeutic point of view have not been satisfying. Given the modest efficacy of therapeutic tools available, Transcranial Magnetic Stimulation (TMS) seems to be a promising "non-pharmacologic" aid which is characterized by a decrease of dopaminergic activity (DA). Thus, 'restoring' pre-pathology DA activity may yield clinical benefits in addicts . Thus, the aim of the project is to apply bilateral dTMS to the PFC of cocaine abusers in order to deepen understanding the neural correlates of addiction, to identify optimal parameters of stimulation and, above all, to evaluate short/ long term therapeutic effects of dTMS. Since December 2011 we applied dTMS in ten cocaine abusers selected on DSM IV criteria and randomly assigned to real/sham stimulation protocols. Eight of them are currently included in the study while two abandoned due to personal problems (2 drop-out). We assessed the intake of cocaine through self-reports and hair analysis at different times pre- (T0) and post-treatment (T1 T2 T3..). The interim analysis shows that all subjects have reduced intake of

cocaine regardless of the frequency (1 or 10 Hz) of the stimulation protocol applied (sham condition was administered in only two subject). Six months after the treatment (T2) all treated subjects show a reduction in cocaine intake with no distinction among groups (real vs sham nor 10 vs 1 Hz). More cases are needed in 1 Hz and sham conditions to "balance" the groups. The follow-up data, however, shows a strong persistence of the effect in the real group, and decidedly weaker maintenance in sham. We hypothesize an initial placebo/sham effect which disappears over time in the sham patients group. Nevertheless these preliminary data encourage further investigation to evaluate the potential effects of dTMS in the treatment of cocaine abusers and in the prevention of relapses. Supported by Dipartimento Politiche Antidroga Studying the anatomy and neurophysiology of autism Dinstein I. 1,2* 1 Dept. of Psychology 2 Dept. of Cognitive and Brain Sciences Our research attempts to identify anatomical and neurophysiological abnormalities in individuals with autism, which may shed light on the biological mechanisms of the disorder and enable early identification. I will describe three lines of research that we are currently pursuing. First, assessment of gross anatomical measures such as brain volume, cortical thickness, and cortical surface areausing anatomical MRI scans. Second, assessment of white matter integrity usingDTI scans. Third, assessment of basic sensory responses in the visual,auditory, and somatosensory domains using fMRI and EEG. I will particularlyfocus on our efforts to work with young 2-3 year old children. Longitudinal functional characterization of neurodegeneration induced by Cdk5 aberrant activation Dolgopyat I. 1, Kavushansky A. 1, Kahn I. 1* 1 Rappaport Faculty of Medicine, Technion, Haifa, Israel. Background: Although studied extensively, the precise dynamicsof cortical networks, particularly during disruptive processes, remain unknown.Here we aim to characterize large-scale neuronalnetworks in their normal state and during neurodegeneration. We examined the changes in brainwidespontaneous fluctuations in the fMRI signal (termed intrinsic functionalconnectivity MRI), a measure of functional-anatomic connectivity, following degeneration. Ck-p25 is an Alzheimer's-like inducible mousemodel, that overexpress p25 in cortical pyramidal neurons. P25 induction disrupts the synapticplasticity and ultimately leads to cell death, producing network connectivityalterations. Results: Functional imaging using fcMRI, revealed changes insomatosensory-motor and hippocampal memory systems. Two weeks following p25 induction, increasednetwork

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functional connectivity was observed between primary somatosensorycortex (S1) and primary motor cortex (M1), piriform cortex (Pir), ectorhinalcortex, and contralateral S1. After 4weeks, correlation decreased almost to the baseline level. In the CA1 in the hippocampus we observedincreased functional connectivity to S1 2 weeks following p25 activation anddecreased correlation bellow the baseline level after 4 weeks. Similarly, thenetwork that correlates with the caudateputamen (CPu) in the striatum, includingM1, S1, Pir showed decreased correlation over the time. Conclusions: The results demonstrate a gradual change in large-scale networkorganization. Previous studies indicate beneficial synaptic plasticity changesin ck-p25 mouse 2 weeks after p25 activation followed by cognitive decline,decrease in plasticity and cell death. Consistently,we demonstrate increase in functional connectivity followed by decline in asimilar time course. Interestingly, theCPu, a subcortical region that does not overexpress p25 underwent changes similarto the cortex in intrinsic functional connectivity without neuronal death. Is the perceptive field size larger in very young children in contrast to grown-ups? Doron R 1, Lev M 1, Polat U 2* 1 Tel-Aviv Univ., Faculty of Medicine, Goldschleger Eye Research Institute, Sheba Medical Center. 2 Tel-Aviv Univ., Faculty of Medicine, Goldschleger Eye Research Institute, Sheba Medical Center Background: Our recent work suggests that the development of collinear facilitation in the fovea in young children enables the development of contour detection and a reduction of the crowding effect. These results may support the idea that in young children with a normal visual system there is a common neuronal basis for developing the mechanisms underlying context processing. It is shown that context processing is largely affected by the size of the perceptive field (PF), whereas suppression is larger from inside the PF but collinear facilitation exists outside the PF. We recently developed a paradigm for estimating the PF size in adults. In this study we tested the hypothesis that the changes in the context effect in children are due to a reduction of the PF's size with development. Methods: We applied our paradigm to estimate the PF size; contrast detection of a Gabor target was embedded between two lateral collinear flankers in differing target-flanker separations. The task enables us to estimate the border between the suppression and the facilitation zones, which indicates the PF's size. Results: Our results indicate that the PFs' size decreases with age; very young subjects (aged 3-5) exhibit a larger PF, whereas grown-up subjects (aged 12-15) have a smaller PF. In addition, the crowding effect in the older group is reduced in parallel with a decrease in the PF. Conclusions: Our results enable us to estimate the PF size in children with normal development and to probe how the PF

changes with age. The results suggest that the PF's reduction enables the maturation of the context effect with age, i.e., increasing collinear facilitation and decreasing crowding. In cases of abnormal development (such as amblyopia) the PF size may remain larger, thus explaining why there is increasing crowding in amblyopia. The effects of prenatal exposure to escitalopram compared with novel herbal treatment on offspring development. Doron R 1,2,3*, Atrakchi D 1, Ashuah-Schneider S 1, Rehavi M 4 1 Dept. of Behavioral Science, The Academic College of TelAviv Yaffo 2 3. School of Health and Life Sciences, Hadassah Academic College, Jerusalem 3 Dept. of Education and Psychology, The Open Univ. 4 6. Dept. of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv Univ. Depression and anxiety disorders are common among pregnant women and may be harmful not only to the mother but also to the fetus. Currently, the most common treatment for these disorders is selective serotonin reuptake inhibitors (SSRIs). Unfortunately, not enough research is attributed to the effects of this treatment on the offspring development. The aim of the present study was to evaluate the effects of prenatal exposure to the SSRI escitalopram, compared with a novel herbal treatment, on offspring development. On the eighth day of their pregnancy, female mice were treated with either: (a) herbal treatment (30mg/kg/day), (b) escitalopram (15mg/kg/ day), (c) vehicle (saline and 1% DMSO), or (d) naïve mice (not receiving any treatment). Following parturition, treated mothers were replaced with adoptive mothers that did not undergo any procedure (in order to prevent transfer of the drugs in breast milk and to any postnatal behavioral effects of these treatments). On post natal day 30, offspring's anxietylike behavior and physiological changes were evaluated. We have found that escitalopram, herbal treatment and controls groups had lower corticosteron levels compared with the vehicle group. In addition, we have found that the herbal treatment group showed reduced anxiety-like behavior in the elevated plus maze test, and that the escitalopram group showed reduced activity in the novel open field test. These results indicate that prenatal exposure to escitalopram and the herbal treatment can influence the development of the offspring, although the later may be a safer candidate for treatment of depression and anxiety disorders during pregnancy. Israel Science Foundation (ISF 738/11), by the National Institute for Psychobiology in Israel (NIPI) Childhood adversities and sex differences in brain structure evaluated by voxel-based morphometry (VBM) Dragan W. 1*, Marchewka A. 2, Zielinska A. 1, Jednorog K. 2 1 Faculty of Psychology, Univ. of Warsaw 2 Laboratory of Brain Imaging. Neurobiology Center. Nencki Institute of Experimental Biology

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Normal 0 21 false false false PL X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-stylename:Standardowy; mso-tstyle-rowband-size:0; mso-tstylecolband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0cm 5.4pt 0cm 5.4pt; mso-para-margin-top:0cm; mso-para-margin-right:0cm; mso-para-margin-bottom:10.0pt; mso-para-margin-left:0cm; line-height:115%; mso-pagination:widow-orphan; fonts iz e: 11. 0 p t; m so - bi di -f on t - s i ze : 10 . 0p t ; fo n t family:"Calibri","sans-serif"; mso-fareast-language:EN-US; mso-bidi-font-weight:bold;} Background Childhood adversities represent a strong risk factor for adult psychopathology and poor cognitive development. In the present study, we investigated the neurobiological underpinnings of this association. Results The VBM correlation analysis yielded reduced gray matter volumes (GMV) in the superior frontal gyrus, precentral gyrus, inferior frontal gyrus, inferior occipital gyrus, insula and precuneus in subjects with high Childhood Questionnaire (CQ) scores. We also found significant Sex x CQ score interaction in GMV in the precentral gyrus, superior temporal gyrus and inferior frontal gyrus. Negative relation between gray matter volumes and CQ scores was found only in women. Conclusion Childhood adversities are associated with structural changes later in adulthood. The observed effects are specific to women. The study was supported by NSF Grant No. DEC-2011/01/B/ HS6/01912 Association networks across the lifespan: the large-scale structure of free association networks, evidence for U-shaped developmental changes and semantic saturation Dubossarsky H. 1*, De Deyne S. 2, Hills T. T. 3 1 ELSC/ICNC Hebrew Univ. of Jerusalem, Israel 2 Dept. of Psychology, KU Leuven, Belgium 3 Dept. of Psychology, Univ. of Warwick, Coventry, UK Free associations are widely used in cognitive neuroscience to investigate memory, lexical decision tasks, child language acquisition, and the veridicality of semantic space models. However, despite the assumption that free associations manifest the internal semantic representations, the network structure of these representations and specifically its changes across the lifespan are still poorly understood. Here, we address these questions using data consisting of free association responses to 420 cue words that was acquired from few thousand individuals between 7 to more than 80 years of age. We used this data to construct free association graphs across the lifespan, with cue and association words representing nodes, and the cue-association responses representing edges. Over the lifespan, both word and graph level statistics reveal a pattern of systematic change, with increase in nodes degree and decrease in clustering coefficient

and in average minimal length during the formative years (up to age 18), and a plateau and possible change in direction across the adult lifespan. We propose and find evidence that these changes are the result of saturation in associations, with less associated words gaining the most associates over time. Our results indicate lifelong changes in the structure of free associations networks and offer answers to questions about how the associations are changed into late adulthood. Neural responses to differently oriented pop-out targets in the optic tectum of the barn owl Dutta A 1, Gutfreund Y 1* 1 The Rappaport Faculty of Medicine and Research Institiute, Technion, Haifa A visual stimulus embedded in a uniform background is called a pop-out target if it is different from the background. In humans and mammals, pop out targets are strongly perceived as salient. Little is known about the role of pop-out targets in birds' perception. In a recent study in our lab it was shown that neurons in the optic tectum (OT) of barn owls are sensitive to targets that are moving in a different direction from the movement of the background distracters (motion pop-out). However, no such sensitivity was observed for visual targets that were differently oriented from the distracters (orientation pop-out). The later finding was in contrast to the results of a recent study which showed that barn owls, like humans, perceive orientation pop-out targets as salient. To investigate this discrepancy between the behavioural and neural results, we further studied neural responses to orientation pop-out. For each recording site in the OT, first the visual receptive field was mapped, then an array of bars was displayed on the screen with one, the target, being differently oriented. We report that when the whole display was constantly moving in one direction and the oriented target sweeping through the receptive field at regular intervals, the neurons were significantly sensitive to the pop-out targets. When the display was static on the screen, no pop-out effect was found. The results may explain how, in freely moving owls, orientation pop-outs can affect the saliency of targets. These findings cannot be explained by a simple lateral inhibition model but require an additional, yet unknown mechanism. Orientation preferences were also studied at various depths in multiple sites of OT. Orientation selectivity was common but no systematic map of orientations was observed. This work was supported by grants from GIF and ISF Learning-induced changes in RNA editing of glutamate receptor subunits in the mouse brain Eilat N. 1, Yaela N. Golumbic 1, Gaisler-Salomon I. 1,2* 1 Psychology, Univ. of Haifa 2 Psychiatry, Columbia Univ., NY Background: Adenosine (A) to inosine (I) RNA editing is a post-transcriptional process catalyzed by the Adenosine

J Mol Neurosci

Deaminase Acting on RNA (ADAR) family of enzymes. Through the site-specific recoding of pre-mRNA, A-to-I RNA editing regulates important functional properties of neurotransmitter receptors in the central nervous system. In particular, the glutamate receptor subunits GluK1 and GluA2, implicated in learning and memory processes, undergo sequence-specific A-to-I RNA editing. RNA editing at these sites, which occurs at a steady rate, leads to a cascade of molecular events that limits the Ca2+ permeability of these receptors. We hypothesized that learning would be accompanied by an immediate decline in A-to-I RNA editing in brain regions essential for learning. This decrease would allow increased inward Ca2+ flow and would affect cell plasticity. In order to test our hypothesis, we trained mice in different fear conditioning protocols, which require intact amygdala and/or hippocampal function. We then examined A-to-I RNA editing at the GluK1 and GluA2 using a novel TaqManbased method for quantifying levels of RNA editing at glutamate receptors. Specifically, our assay uses two probes and one primer set per gene to detect the two transcript variants, differing by one nucleotide at the site of editing. Results: We found that editing levels of glutamate receptor subunits changed in a region-specific manner following particular training protocols. Specifically, RNA editing decreased in the amygdala following cued, but not contextual fear learning, and this effect was not found in the hippocampus. Conclusions: The findings support the hypothesis that the RNA editing process is temporally dynamic, and that editing levels are learning-dependent. This adds another level of complexity to the process of learninginduced synaptic plasticity. Supported by an Israel Science Foundation (ISF) grant to IGS. The GABAergic system and CREB signaling pathways in the molecular mechanism underlying SSRI-antidepressants and antipsychotics combination therapy in negative symptoms of schizophrenia Einoch R. 1,2, Weinreb O. 1, Youdim M.B.H 1, Silver H. 1,2* 1 Eve Topf Centers, Pharmacology, Technion-Faculty of Medicine, Haifa, Israel. 2 Molecular Neuropsychiatry, Shaar Menashe Brain Behavior Laboratory, Shaar Menashe MHC, Israel. Background: Clinical studies have shown that augmentation of selective serotonin reuptake inhibitor (SSRI) to ongoing antipsychotic regimen can ameliorate treatment resistant negative symptoms in schizophrenic patients. The efficacy of this novel combined drug treatment cannot be explained by summating pharmacological effects of the individual drugs. In the current study, we have examined the effect of chronic

administration (30 days) of the SSRI fluvoxamine (FLU, 10mg/kg) combined with the typical antipsychotic haloperidol (HALO, 1mg/kg) compared to the individual drugs and the atypical antipsychotic clozapine (CLOZ, 10mg/kg) on γaminobutyric acid-A (GABA-A) receptor signaling pathway in Sprague–Dawley rats. Results: SSRI-antipsychotic combination produces unique changes in GABA-A receptor and its regulating system, which are different from each individual drug treatment. HALO-FLU and CLOZ treatments affect cellular processes at both the translational and transcriptional levels on signaling pathways that modulate GABA-A receptor function, including cAMP response element-binding protein (CREB), tyrosine kinase B (TrkB), brain derived neurotropic factor (BDNF), protein kinase B (AKT) and glycogen synthase kinase (GSK)-3beta. HALO-FLU significantly increased the phosphorylation level of CREB, AKT and GSK3beta in the prefrontal cortex and BDNF levels in the hippocampus, compared to individual drugs-treated rats. Conclusion: The results from clinical studies demonstrate that SSRI augmentation in schizophrenia patients results in changes in blood mononuclear cell mRNAs encoding for GABA-A receptor and signaling proteins, which are similar to those observed in preclinical experiments and associated with the clinical improvement. Our findings reinforce our hypothesis that GABA-A receptor modulation may be part of the mechanism mediated by SSRI-antipsychotic synergistic effects that are relevant to the core features of schizophrenia negative symptoms and their treatment. Altered chemosignaling in young adults with autism spectrum disorder Eisen A. 1*, Frumin I. 1, Rozenkrantz L. 1, Weissbrod A. 1, Yoran-Hegesh R. 2, Zachor D. 3, Sobel N. 1 1 Dept. of Neurobiology, Weizmann Institute of Science Rehovot, Israel 2 Research Unit, Ness Ziona Mental Health Center, Israel 3 Autism Center, Asaf Harofeh Medical Center, Zerifin, Israel Consistent with the extensive overlap in neural substrates involved in olfaction and autism spectrum disorder (ASD), individuals with ASD display a unique olfactory profile. Moreover, a characteristic of ASD is impaired social communication. Social chemosignaling plays a role in social communication, and therefore impaired olfaction may not only reflect ASD, but may also contribute to ASD. To address this hypothesis, we set out to test the response to social chemosignals in ASD. We identified hexadecanal (HEX) as a component of both human sweat and tears, which may be responsible for their chemosignaling properties. To test this, we measured the influence of HEX on startle response; a particularly appropriate behavioral assay because: A. The startle response is a non-verbal test that is typically unaffected by ASD. B. Sweat obtained in emotional settings (fear) modulated the startle response in TD. TD subjects (n=22, 13M,

J Mol Neurosci

age=26.4) participated in an auditory startle experiment (100dB, 50ms) twice, once after exposure to an olfactory mask alone (eugenol), and once after an olfactory mask + HEX, counter balanced for order. Although the HEX was not perceived, it significantly reduced the amplitude of the startle response in TD by -13.57% (±44), from 28.5μV (±18.5) (carrier alone) to 20.1μV (±13) (carrier+HEX) (t(21)=3.1 p<0.01). In other words, HEX may indeed act as a human chemosignal. Next we replicated the same study in ASD. In contrast to the results in TD, in the 6 ASD subjects tested to date (age=23.8, 4M), there was no apparent effect of HEX (mean change = 6.16%, from 36.5μV (±30.6) (carrier alone) to 42.7μV (±46.5) (carrier+ HEX), (t(5)=0.51, p=0.63). That said, this sample remains too small for conclusive statements. Moreover, the mean change in ASD was not significantly different from the mean change in TD (p=0.43). We conclude that HEX, a component in sweat and tears, acts as a chemosignal is TD young adults, yet may not act as such in ASD. Autophagy in health and disease Elazar Z. Dept. of Biological Chemistry, The Weizmann Institute of Science Autophagy is an evolutionarily-conserved catabolic process initiated by the engulfment of cytosolic components in a crescent-shaped structure, called phagophore that expands and fuses to form a closed double-membrane vesicle, the autophagosome. Autophagosomes are subsequently targeted to the lysosome/vacuole with which they fuse to degrade their content. The formation of autophagosome is carried out by a set of autophagy-related (Atg) proteins, highly conserved form yeast to mammals. The Atg8s are ubiquitin-like (Ubl) proteins that play an essential role in autophagosome biogenesis. This family of proteins comprises a single member in yeast and several mammalian homologues grouped into three subfamilies: LC3, GABARAP and GATE-16. The Atg8s are synthesized as cytosolic precursors but can undergo a series of post-translational modifications leading to their tight association with autophagosomal structures upon autophagy induction. Autophagy dysfunction has been implicated in a group of progressive neurodegenerative diseases, and has been reported to play a major role in the pathogenesis of these disorders. We have recently reported a recessive mutation in TECPR2, an autophagy-implicated WD repeat-containing protein, in five individuals with a novel form of monogenic hereditary spastic paraparesis (HSP). We found that diseased skin fibroblasts had a decreased accumulation of the autophagyinitiation protein MAP1LC3B (LC3), and an attenuated delivery of both LC3 and the cargo-recruiting protein SQSTM1 (p62) to lysosomal degradation. The discovered TECPR2 mutation reveals for the first time a role for aberrant autophagy in a major class of Mendelian neurodegenerative diseases, and

suggests mechanisms by which impaired autophagy may impinge on a broader scope of neurodegeneration. Sonar phase precession of hippocampal place cells in flying bats Eliav T. 1, Geva-Sagiv M. 1,2, Ulanovsky N. 1* 1 Dept. of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel 2Interdisciplinary Center for Neural Computation, The Hebrew Univ. of Jerusalem, Israel Hippocampal place cells in rats exhibit a rhythmic modulation in their firing patterns, locked to the hippocampal 8-Hz theta rhythm. Moreover, the phase of the neuronal firing relative to the theta rhythm shifts earlier and earlier as the rat moves through the place field, a phenomenon called 'theta phase precession', which provides a temporal code for the animal's position. In contrast, the bat hippocampus does not exhibit theta rhythmic activity, which suggests that the animal's position is encoded by a rate-code (the firing rate of a place-cell) rather than by a temporal code. Here we have set out to examine whether a temporal code for space may nevertheless be present in the bat's hippocampus, but be locked not to an internally-generated 'clock' such as the theta rhythm (which is absent in bats) but rather to an external biological rhythm – the bat's sonar calls, which are emitted periodically at ~8-12 Hz. To test this, we trained Egyptian fruit bats to fly back and forth along a "linear flight track" in the dark, using sonar. We recorded cells from hippocampal area CA1 and the Subiculum of flying bats, using a tetrode-based recording system, while recording the sonar calls of the bat during flight. This allowed assessing the timing of the spikes relative to the sonar phase. So far, preliminary results did not demonstrate a clear modulation of firing patterns by the timing of sonar calls, nor the existence of sonar phase precession. Higher centers’ control of motor activity in cockroaches Gal R. 1, Kaiser M. 2, Emanuel S. 2, Libersat F. 2* 1 Dept. of Life Sciences, Ben Gurion Uni., Beer Sheva, Israel 2 Dept. of Life Sciences, Ben Gurion Univ. Beer Sheva, Israel Background: The parasitoid wasp Ampulex compressa uses cockroaches (Periplaneta americana) as food supply for its offspring. The wasp penetrates the cockroach's head capsule with its stinger and injects venom directly inside the brain, in a neuropile called the central complex (CC) and some in the mushroom bodies (MB), causing the cockroach first to groom extensively and then to become hypokinetic. Previous work shows that the venom contains neurotoxins that decrease neuronal activity. To mimic venom effect, we used a reversible non-selective sodium channel blocker (Procaine) in order to induce a local anesthesia of the CC or the MB separately and evaluate specific changes in behavioral activity.

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Results: Using Procaine injections and behavioral tests, we evaluate grooming and spontaneous walking. An injection of Procaine in the CC caused a statistically significant decrease in motor activity for the first 30 minutes of measurement, in comparison to the control group which showed no change in motor activity. After, the motor activity regained its control baseline level. These results suggest that the CC exerts a permissive control of motor activity. Injection of Procaine in the MB caused a statistically significant increase in motor activity for the first 30 minutes of measurement, in comparison to the control group which showed no change in motor activity. After, the motor activity regained its control baseline level. These results suggest that the MB exert an inhibitory control of motor activity. Conclusion: The results show that an injection of procaine to the CC or the MB reduces and increases motor activity, respectively. Hence, the brain houses different neuropiles (i.e., the CC and the MB) which act as the 'gas and brake pedal' on motor activity, respectively. This work is currently supported by the Israel Academy of Sciences and Humanities (1181/11). Heightened olfactory sensitivity under low doses of alcohol Endevelt Y., Chalamish Y., Sobel N. * Neurobiology, Weizmann institute of science Human olfaction is characterized by high acuity yet low awareness for odors. Several anecdotal reports portray immediate short-term heightened olfaction under the influence of drugs, and one report describes increased olfactory reactivity following neural trauma. Such rapid enhancement of olfactory performance led us to hypothesize that the human olfactory system might be under constant cortical inhibition. One may therefore hypothesize that reduced cortical inhibition will result in improved olfactory performance. In order to test this, we used methods aimed at decreasing inhibition (alcohol consumption and hypnosis) concurrent with tests of olfactory performance. We found that alcohol consumption alters olfactory sensitivity in a dose-dependent manner both in threshold and discrimination tasks. We measured olfactory performance before and after beverage consumption. We calculated the percent change in performance during the alcohol condition compared to the control condition. This ratio was correlated with alcohol doses both in threshold (N=20, r=-0.57, p<0.01), and discrimination (N=16, r=-0.57, p<0.05) tasks; implying that whereas high levels of alcohol (%BAC>0.06%) impaired performance, low alcohol doses (0<%BAC<~0.06%) improved olfactory performance. Alcohol may affect the olfactory system through both central and peripheral (e.g. ORN) mechanisms. In order to isolate its central component, we used hypnotic suggestion aimed at recreating a feeling of intoxication concurrent with olfactory detection threshold task. To date, of the 11 subjects (5 F, mean age = 26.5) that participated,

9 (81%, binomial p<0.05) exhibited improved sensitivity in a threshold task under hypnosis compared to normal waking state. We found that alcohol consumption (low doses) or hypnosis improve olfactory performance. This result suggests that top-down inhibition may play a significant role in olfaction perception by mechanisms that remain to be uncovered. Are you looking at me? motor mechanisms involved in perception of affective facial expressions Ensenberg, N. 1*, Perry A. 2, Bentin S. 1,3, Aviezer H. 1 1 Dept. of Psychology, Hebrew Univ. of Jerusalem, Jerusalem, Israel 2 Dept. of Psychology, Univ. of Haifa, Haifa, Israel 3 Interdisciplinary Center for Neural Computation, Hebrew Univ. of Jerusalem, Jerusalem, Israel Background: Imagine you are walking down the street while encountering a stranger yelling angrily at you. Now imagine a similar situation with the stranger yelling at the person walking right beside you. Undeniably, the subjective experience of being the target of one's expression greatly differs yet the neural mechanisms underlying this distinction are largely unknown. Simulation Theory proposes that we understand others' minds by simulating their actions, possibly via the Mirror neuron system (MNS), but is this system sensitive to the degree of social interaction and dynamic engagement? Results: Participants viewed video clips of actors expressing facial emotions turning towards or away from the viewers. Expressions turning towards the observer were found to be more engaging than those turning away, according to subjects' ratings. Additionally EEG Mu rhythms' suppression was measured as an indication of MNS activity. Preliminary data suggests expressions turning towards the observer elicited larger suppression. Conclusion: These data may enrich our understanding of the link between motor resonance and neural mechanisms of affective Theory of Mind. A warning signal to the use of microtubule stabilizing agents as drugs to counteract mutant-human-tau induced neuropathology Erez H. 1, Ojovan S. M. 1, Spira M. E. 1,2* 1 Depatrment of Neuroscience, Life sciences Inst. The Hebrew Univ. of Jerusalem, Jerusalem 2 Through the use of live confocal imaging and electronmicroscopy, we documented in earlier studies that mutanthuman-tau (mt-htau) induces hallmark Alzheimer's disease (AD) cell pathologies in cultured Aplysia neurons. These include: swelling of axonal segments, translocation of tau and microtubules (MT) to submembrane domains, reduction in the number of MTs along the axon, the reversal of the MT polar orientation, impaired organelle transport, accumulation of macro-autophagosomes and lysosomes, compromised neurite morphology and degeneration and impaired synaptic

J Mol Neurosci

transmission. The development of these neuronal pathologies is rescued by the incubation of neurons expressing mt-humantau in 10 nM paclitaxel (a MT stabilizing, antimitotic drug). Higher paclitaxel concentrations (100 nM) do not prevent the unfolding of the pathology but rather accelerate them. Since paclitaxel has poor blood-brain-barrier penetration and is known to cause severe side effects in cancer patients, attempts are made to test other antimitotic drugs to counteract tau induced pathologies. EpoD (epothilone D) a brain-penetrant MT-stabilizing agent was reported to prevent the unfolding of mt-htau induced cell athology and cognitive decline in established transgenic mouse model. We tested the effects of 5-10 nM EpoD on the cell biology and synaptic transmission of the cultured Aplysia-neuron and found that at these low concentrations EpoD by itself causes within 3-5 days robust pathologies leading to impaired synaptic transmission and neurodegeneration. These observations should serve as a warning signal to the execution of planned clinical trials. Charles E. Smith and Prof. Elkes laboratory for collaborative reserch in psychobiology Studying post-stimulus activity following naturalistic episodes using MEG Eshel N. 1*, Tal I. 2, Ben-Yakov A. 1, Shapira Lots I. 2, Abeles M. 2,3, Dudai Y. 1 1 Dept. of Neurobiology, the Weizmann Institute of Science, Rehovot, Israel 2 Gonda Multidisciplinary Brain Research Center, Bar Ilan Univ., Israel 3 The Hebrew Univ. of Jerusalem, Jerusalem, Israel In a series of previous experiments (Ben-Yakov & Dudai (2011), Ben Yakov, Eshel & Dudai (2013)) we identified hippocampal activity at the offset of short episodes, presented as movie clips, using functional magnetic resonance imaging (fMRI). This activity was found to be predictive of subsequent memory performance. We have now employed a similar episodic encoding paradigm using magnetoencephalography (MEG), in order to determine the temporal dynamics of the hippocampal offline activity in higher temporal resolution. To this end, 20 subjects watched 112 short movie clips while inside the MEG scanner and were later tested about the clips' gist. We analyzed the data both at the sensor level and using a localization method. Sensor level analysis was conducted in time, frequency and spectral (time-frequency) domains. Next, we utilized a beam former localization method (SAM – synthetic aperture magnetometry, Robinson & Verba, 1998) to inspect the hippocampal response to the stimuli. The results show a clear response to clip offset at a sensory level, apparent in most MEG channels. Further investigation is now conducted to identify sources of memory predictive activity.(This project is supported by the I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation (grant No 51/11).)

From mice to humans: common assessment of declarative memory in a radial maze. Etchamendy N 1,2*, Pantaleon L 1, Desmedt A 1,2, Marighetto A 1 1 (1) Neurocentre Magendie, U862, INSERM, Bordeaux, France. 2 (2) Dept. of Life Sciences, Univ. of Bordeaux Background: In humans, relational memory is taken to support long-term declarative memory, i.e., memory for the relations among constituents of scenes or events. We previously designed radial arm maze tasks for mice aimed at testing relational memory capacities. Both senescent and hippocampectomized mice (Marighetto et al., 1999; Etchamendy et al., 2003) initially learnt the position of arms containing food in the maze (stage 1) but failed to find the food when mice were presented with a choice between a novel and a familiar arm (stage 2). This dissociation between intact initial learning in stage 1 and mnemonic inflexibility in stage 2 was proposed as a mouse model for the altered spatial relational memory vs. spared procedural response memory associated with senescence and hippocampal dysfunction. The purpose of this work was to adapt to humans a version of these mouse RM paradigms, in a virtual 12-arm radial maze. Methods: In the initial learning phase, people were confronted in turn to six invariant pairs of arms and have to learn and remember within each pair of arms which one contained an object. To test their ability to use flexibly their knowledge, participants subsequently were submitted to a second stage during which the position of the objects remained unchanged but the arms were presented according to a novel arrangement (flexibility probes). Results: As previously observed with aged mice, aged healthy participants acquired initial discriminations (stage 1) with extensive training but failed to resolve the flexibility probes. This was associated with a decline in a serie of behavioral tasks assessing global cognitive deterioration, episodic memory and working memory. Conclusion: By enabling common relational memory assessment in mice and humans, this paradigm may be a valuable tool in identifying cellular and molecular bases of relational memory and its dysfunctions, and in increasing the predictive validity of preclinical therapeutic studies. Feature based Top-Down modulation of ERP signals in a visual change discrimination task with diversions Eve-Chen N. 1 *, Halily R. 1 , Pratt H. 2, Katz R. 3,4 , Zacksenhouse M. 3,4 1 Dept. of Electrical Engineering, Technion, Haifa, Israel 2 Evoked Potentials Laboratory, Technion, Haifa, Israel 3 Brain-Computer Interfaces for Rehabilitation Lab. 4 Dept. of Mechanical Engineering, Technion, Haifa, Israel Background: Changedetection is fundamental in many tasks involving the need to detect stimuli ofunique features in a

J Mol Neurosci

noisy scene with various diversions. Current state ofknowledge ties attention selection and its bias towards predefined features (top-downprocessing) to the dorsal attention network. Moreover, certain event-relatedpotential's (ERP) such as P2, N2, N2PC and P3b were shown to be modulated by thepresence of a top-down goal, though not necessarily by feature-basedtarget/diversion differentiation. Thus, it is interesting to investigate ERPcorrelates of taskrelevant stimuli processing, and how they depend on changedetection. Within this scope, we attempted in our study, to distinguish betweenERP correlates of (i) no change, (ii) detected task-related change, (iii)undetected task-relevant change, and (iv) task-irrelevant change (diversions). Method: We recordedEEG from subjects performing a change detection task. Subjects were asked toreport on task-relevant changes and ignore diversions (task-irrelevantchanges). Results: Theresulting ERP reveals time-dependent modulations by both detection (detectedversus undetected changes) and task-relevancy (task-relevant changes bothdetected and undetected versus diversions or no stimuli). Maximum modulationswere detected in frontal scalp areas (namely F7/ F8 and AF7/AF8), which iscompatible with the role of InferiorFrontal Junction in feature based top-downattention allocation. Conclusion: We candivide the evolution of the ERP into four segments, which we have chosen toname chronologically: "Relevance Modulation" (50-100ms),"Priority Evaluation"(120-220ms), "Object Processing" (200-280ms) and "Identification/Decision"(350-500ms). Center for Security Science and Technology at the Technion, under grant number 2016258. Larger dendrites, sharper spikes, improved encoding Eyal G 1, Mansvelder HD 2, de Kock CPJ 2, Segev I 1,3,4* 1 Dept. of Neurobiology, the Hebrew Univ. of Jerusalem 2 Dept. of Integrative Neurophysiology, VU Univ. Amsterdam, Netherlands 3 Interdisciplinary Center for Neural Computation, the Hebrew Univ. of Jerusalem 4 Edmond and Lily Safra Center for Brain Sciences, the Hebrew Univ. of Jerusalem Neurons, like any effective I/O device, must faithfully encode rapid modulations in their (synaptic) input via their (spiking) output. Theory and experiments show that the quality of this encoding (spike phase-locking) critically depends on the action potential (AP) onset rapidness; the faster the onset the better the encoding. We found that the cable properties of the dendritic tree powerfully affect AP onset in the axon; it is accelerated in neurons with larger dendritic surface area. This "dendritic size effect" was explored both analytically and numerically in simplified and detailed 3D models of reconstructed layer 2/3 cortical pyramidal cells of rats and humans. The impedance mismatch between dendrites and axon was assessed using a new parameter, ρaxon; it was estimated at 150 - 200 in L2/3 of young rats to 400-500 in mature humans.

The cutoff frequency of spikes phase-locking to modulated inputs increased from 100-200 Hz (rats) to 400 – 600 Hz (humans) and reached close to 1KHz in in vivo like conditions in humans. This work highlights a new and profound functional link between the dendritic tree and the axon, and explains why neurons with large dendritic tree are expected to have improved encoding capabilities. Nanoparticle-based systems for imaging of immune cell activation in CNS disorders Portnoy E. 1,2, Inbar D. 3, Bishara A. 1, Keinan G. 3, Polyak B. 4, Rai A. 4, Golenser J. 5, Vakruk N. 1,5, Magdassi S. 2, Ben Hur T. 3, Ekstein D. 3, Eyal S. 1* 1 Institute for Drug Research, The Hebrew Univ., Jerusalem, Israel 2 Casali Institute, The Hebrew Univ., Jerusalem, Israel 3 Dept. of Neurology, Hadassah-Hebrew Univ. Medical Center, Jerusalem, Israel 4 Dept. of Surgery, Drexel Univ., Philadelphia, PA, USA 5 Dept. of Microbiology and Molecular Genetics, The Hebrew Univ., Jerusalem, Israel A variety of neurological disorders, includingmultiple sclerosis, Alzheimer's disease, epilepsy, glioma, and cerebral malaria,are characterized by the presence of activated phagocytic cells within the CNS.This phenomenon can be exploited for imaging that will be used in clinic and inexperimental models of CNS disorders, for detection, localization, andmechanistic studies of disease and for monitoring of therapy. Our goal is thedevelopment of biocompatible, nanoparticle-based targeting systems aimed to beadministered systemically and detectable by both magnetic resonance and opticalimaging, as biomarkers for activated immune cells in the CNS. The nanoparticlesare currently being evaluated in two animal models of CNS disorders whichinvolve immune cell activation: mice infected with Plasmodium berghi ANKA, as amodel of cerebral malaria, and the rat lithium-pilocarpine model of temporallobe epilepsy. In vitro studies demonstrated that the nanoparticles areinternalized by macrophages. Our preliminary findings from the in vivo studies demonstratedthe presence of NP within activated phagocytes in the hippocampi of rats withspontaneous recurrent seizures, but not in control rats. Taken together, theseproof of-concept findings suggest that our NP may be used to track theinflammatory processes in brain diseases. Phosphrylation of synapsin I by CDK5 sets the ratio between the resting and recycling pools of synaptic vesicles at hippocampal synapses Fassio A 1,2*, Verstegen AJ 1, Tagliatti E 1,2, Lignani G 1, Antonella Marte 2, Stolero T 3, Orenbuch A 3, Corradi A 2, Valtorta F. 4, Gitler D. 3, Onofri F. 2, Benfenati F. 1 2 1 Dept. of Neuroscience and Brain Technologies, Fondazione Istituto Italiano di Tecnologia, Via M 2 Dept. Experimental Medicine, Univ. of Genova, Viale Benedetto XV, 3, 16132 Genova, Ital 3 Dept. of Physiology and Cell Biology, Faculty

J Mol Neurosci

of Health Sciences and Zlotowski Center for Neuro 4 S. Raffaele Sci. Institute and Vita-Salute Univ., Via Olgettina 58, 20132 Milano, Italy. Synapsins (Syns) are synaptic vesicle (SV)-associated phosphoproteins involved in the regulation of neurotransmitter release. Their phosphorylation by serine/threonine kinases is known to increase SV availability for exocytosis. SynI is one of the presynaptic substrates of cyclin-dependent kinase-5 (Cdk5) that phosphorylates it at Ser549 (site 6) and Ser551 (site 7) but the functional consequences of Cdk5 phosphorylation on SynI have not been investigated so far. Cdk5 was reported to downscale neurotransmission by sequestering SVs in the release-reluctant resting pool and the molecular targets mediating this activity remain unknown. We here demonstrate that Cdk5 phosphorylation of SynI fine tunes the recruitment of SVs to the active recycling pool and contributes to the Cdk5-mediated homeostatic mechanism. We report that SynI is constitutively phosphorylated by Cdk5 and that its phosphorylation increases its binding to F-actin. The effects of Cdk5 inhibition on the size and depletion kinetics of the resting pool were virtually abolished in SynI KO neurons. While expression of wild type SynI fully rescued the KO phenotype, dephosphomimetic SynI mutants at sites 6,7 or only at site 7 were virtually ineffective. The observation that the single-site mutant (7A-SynI) phenocopies the effects of the deletion of SynI identifies site-7 as the central switch in mediating the synaptic effect of Cdk5 and demonstrates that SynI is necessary and sufficient for achieving the effects of the kinase on SV trafficking. The phosphorylation state of SynI by Cdk5 at site-7 was regulated during chronic modification of neuronal activity and was essential in the Cdk5-mediated homeostatic responses. Venous photothrombosis induce BBB dysfunction and cellular injury Fassler M. 1,2*, Vazzana U. 1,2, Prager O. 1,2, Chassidim Y. 1,2, Friedman A. 1,2, Shelef I. 3,2 1 Dept. of Physiology and Neurobiology, Faculty of Health Sciences, Ben-Gurion Univ. 2 Zlotowski Center for Neuroscience, Ben-Gurion Univ. 3 Dept. of Cognitive and Brain Sciences and Medical Imaging, Soroka Medical Center Cerebral venous infarction represents an often under diagnosed cause for acute or slowly progressive neurological deterioration. The underlying pathophysiological basis is not well understood, but seems to differ from that of arterial infarction, reflecting the different anatomical and physiological features of the cerebral venous system. The blood-brain barrier (BBB) is the regulated interface between the peripheral circulation and the central nervous system. Dysfunction of the BBB is a characteristic finding in common neurological disorders and has been shown recently to underlie

neuronal dysfunction. In the present study we establish a rat model for venous infarction and investigate the effects of such pathology on vascular permeability and neuronal functions. Methods: The open cranial window method was used in anesthetized rats. Cortical vein infarction was induced by photoactivation of Rose bengal via laser-optic illumination. For BBB permeability and cellular injury assessment, sodium fluorescein and propidium iodide were injected (respectively) intravenously before and following photothrombosis. High frequency (30/s) images were acquired during injection using a CCD camera to allow for the quantification of dye leakage. Image analysis was performed offline using home-made Matlab scripts. Results: Pixel-permeability maps reveal that venous infarction induces a gradual spread and increase in BBB permeability over time (30 , 60, 120 and 180 min). In addition BBB permeability was found to be associated with cell damage as noted using propidium iodide. Conclusions: We demonstrate that selective venous infarction is associated with gradual increase in vessel permeability in the surrounding cortex, despite the lack of increased intracranial pressure or reduced perfusion. We confirmed that BBB dysfunction is associated with cellular injury. On-going studies are performed to underscore the mechanisms underlying cellular injury and their functional significance. Inter hemispheric synchrony of spontaneous orientation states in the anesthetized cat Fekete T. 1, Ohashi K. 1, Deneux T. 1, Grinvald A. 1* 1 Neurobiology, Weizmann Our lab has shown that early visual cortex in cat and monkey exhibits rich dynamics, in which spatial patterns resembling evoked representations emerge spontaneously. Such patterns reflect strong functional connectivity and were found to span the entire imaged area within a single hemisphere. While collosal connections have been shown to be fast and strong connecting corresponding retinotopic areas in the two hemispheres, orientation maps within each related hemisphere exhibit different patterns. This raises the question whether there is inter-hemispheric synchrony in spontaneously emerging orientation states. We applied voltage sensitive dye imaging to anesthetized cats bilaterally. We found that such spontaneously emerging patterns indeed span early visual cortex in both hemispheres synchronously. In fact patterns virtually identical to the sensory evoked maps associated with the cardinal and oblique orientations emerged as leading principal components of the spontaneous fluctuations, attesting to dominance of the lateral connectivity in the anesthetized state. As was found for a single hemisphere, transient orientation states were biased towards the cardinal orientations, although this

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bias could not be explained by the distribution of orientation preference across the imaged tissue. The strength of the transient orientation state was inversely proportional the rate of change suggesting that these maps might be quasi-attracting states, which in turn could lead to the highly stereotypical dynamics we observed: a random walk along a ring of transiently stable orientation states. The present results indicate that colossal connections are functionally precise for the orientation attribute. The very same findings suggest a possible mechanism through which sensory cortices become oblivious to external perturbation by restricting themselves to stereotypical state switching. This may be relevant to abolishment of consciousness under anesthesia or sleep. Optogenetic dissection of the neuronal circuits underlying spontaneousnetwork oscillations in the neocortex Fellin T 1* 1 Istituto Italiano di Tecnologia A main feature of the neocortex is its ability to self-generate recurrent network dynamics even in the absence of inputs coming from other brain areas. A major component of these intrinsic dynamics is the "slow oscillation", a < 1Hz rhythm thatcharacterizes NREM sleep and is believed to regulate memory consolidation andsynaptic strength. At cellular level, the slow oscillation is reflected bycyclic up- and down-state transitions in the neuronal membrane potential.Simultaneous in vivo whole-cellrecordings from multiple neurons show that the majority of up states first occur in layer V neurons, while a minority of them originates in layer II/IIIcells. However, whether there is a causal relation between the activities of layer II/III or layer V neurons and the generation of the slow oscillation is currently unknown. To address this issue, we combined in vivo electrophysiological recordings with the selective expression of excitatory and inhibitory opsins in layer II/III and in layer V excitatory neurons. Optogenetic activation of layer V pyramidal cells elicited network events that mimic natural up-state transitions, while inhibition of the same neurons dramatically reduced spontaneous slow oscillations. On thecontrary, photo-activation or photo-inhibition of layer II/III neurons did not significantly affect slow oscillatory dynamics. To understand the cellular and network mechanisms underlying the differential role of layer II/III and layer V in the generation of the slow oscillation, we performed in vivo patch-clamp recordings. Our data demonstrate that layer V neurons are more efficient than layer II/III pyramids in spreading prolonged,up state-like depolarizations within and across cortical layers. We propose that the leading role of layer V pyramidal neurons in the modulation of slow oscillatory activity is linked to the better ability of these cells to transfer sustained depolarizing events to neighboring neurons.

Representation of multiple spatial scales by place cells during 2D versus 3D navigation in bats Finkelstein A. 1, Ulanovsky N. 1* 1 Dept. of Neurobiology, Weizmann Institute of Science In their natural habitat bats crawl on two-dimensional (2D) surfaces, such as the walls of their cave, and also fly through three-dimensional (3D) space. Whether these two distinct navigational modes are represented in a similar or different manner in the brain's 'navigation circuit' is unknown. In order to investigate this, we conducted wireless neural-telemetry recordings of single neurons from hippocampal area CA1 of freely behaving bats, in a 'flight-hippodrome' ('batodrome') task. In this task, bats were trained to fly in circles and occasionally land and crawl on elevated platforms in search for food reward. This allowed a comparison between hippocampal representations of space during 2D surface locomotion (crawling) versus volumetric exploration of 3D space (flight), within the same physical environment. Our preliminary results indicate that hippocampal neurons could have 3D place-fields in mid-air and 2D place-fields on platforms, with larger placefields occurring in mid-air than on the platforms, suggesting a neural representation of space on multiple spatial scales. Synchronized activation of M1 muscarinic receptor (M1 mAChR) and sigma1 receptor (Sig1R): A novel target in treatment of Alzheimer's disease (AD) Fisher A. 1,2*, Medeiros R. 3, Bar-Ner N. 1, Natan N. 1, Brandeis R. 1, Elkon H. 1, Nahum V. 1, Grigoryan G. 4, Segal M. 4, LaFerla F. 3 1 Israel Institute for Biological Research, Ness Ziona, Israel 2 Weizmann Institute, Rehovot, Israel (sabbatical) 3 UCI, Irvine, CA, USA 4 Weizmann Institute, Rehovot, Israel The M1 muscarinic agonists AF102B (Evoxac: prescribed in Sjogren's syndrome, SjS) and AF267B (effective in SjS) are cognitive enhancers and disease modifiers with a wide safety margin. Notably, i)AF102B decreased CSF Abeta in AD patients (Nitsch et al, 2000); ii) AF267B rescued cognitive deficits and decreased Abeta42 and tau pathologies in 3xTgAD mice(Caccamo et al, 2006); and iii) AF102B and AF267B decreased brain alpha-synuclein aggregates in transgenic mice overexpressing human alpha-synuclein (Fisher et al, ADPD2011). Thus M1 muscarinic agonists can alter pathologies in AD, Parkinson's disease and Lewy body dementia. We have further hypothesized that synchronized activation of the M1 mAChR and the molecular chaperone Sig1R may have broader therapeutic advantages.To achieve this goal, we designed AF710B (MW 357.5) which shows a novel mechanism of action (MoA) via Sig1R activation and M1 muscarinic allosteric modulation, but not resembling sigma1, M1 allosteric or orthosteric and sigma1/M1agonists, respectively. AF710B (at nM range, in vitro) decreased Abeta,Tau-

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hyperphosphorylation, GSK3beta activation and prevented neurodegeneration, oxidative stress and mitochondrial dysfunction via increased Bcl2/Bax. AF710B is a remarkably powerful cognitive enhancer (rats: 1-30 and 10-100 mcg/kg,po in trihexyphenidyl- and MK801-induced passive avoidance impairments,respectively). AF710B is devoid of side effects, having an unprecedented safety margin (> 50,000; po). Furthermore, in 3xTg-AD mice AF710B (10 mcg/kg,ip/daily for 2 months) – i) mitigated cognitive impairments in Morris water maze; ii) decreased BACE1, GSK3beta activity, p25CDK5, inflammation, Abeta40, Abeta42 and tau pathologies. Conclusion: The unique MoA of AF710B may involve a super-sensitization of M1 mAChR through a hypothetical heteromerization with Sig1R. AF710B may have a wider therapeutic potential vs.a plethora of experimental treatments in AD and other protein-aggregation related diseases. High-order social interactions in groups of mice Forkosh O. 1*, Shemesh Y. 1, Sztainberg Y. 1, Shlapobersky T. 1, Chen A. 1, Schneidman E. 1 1 Weizmann Institute of Science Social behavior in mammals is often studied in pairs under artificial conditions, yet groups may rely on more complicated social structures. Here, we use a novel system for tracking multiple animals in a rich environment to characterize the nature of group behavior and interactions, and show strongly correlated group behavior in mice. We have found that the minimal models that rely only on individual traits and pairwise correlations between animals are not enough to capture group behavior, but that models that include third-order interactions give a very accurate description of the group. These models allow us to infer social interaction maps for individual groups. Using this approach, we show that environmental complexity during adolescence affects the collective group behavior of adult mice, in particular altering the role of high-order structure. Our results provide new experimental and mathematical frameworks for studying group behavior and social interactions. Epigenetics of neurodegeneration: efficacy of S-adenosylmethionine in a mouse model of Alzheimer's Disease Fuso A.* Dept. of Psychology, Sect. of Neuroscience – Sapienza Univ. of Rome Via dei Marsi,– Roma – Italy Background: Increasing evidences indicate that a number of human diseases with multifactorial origin may have epigenetic bases; among these, aging-related and neurodegenerative diseases are the most investigated. The interest in the epigenetics of neurodegenerative diseases was boosted in the recent years because of the evidence that epigenetic mechanisms could be

triggered by environmental factors. In particular, changes in DNA methylation (one of the main epigenetic changes) can be caused by alterations in dietary status influencing health and lifespan. The main pathway linking nutrition to DNA methylation involves the one-carbon metabolism, leading to the formation of S-adenosylmethionine (SAM), the main donor of methyl groups. B vitamins are key nutrients able to modify one-carbon metabolism homeostasis and methylation potential and are associated with healthy and pathological aging and with neurodegenerative diseases.The present research is aimed at investigating the role of DNA methylation in a mouse model of Alzheimer’s Disease (AD). Results: We demonstrated that B-vitamin deficiency alters one-carbon metabolism and DNA methylation in a model of AD mice. We also showed that these alterations were associated to PSEN1 gene demethylation and overexpression, amyloid overproduction and increased plaque deposition. Exogenous SAM was able to counterbalance the detrimental effects of B-vitamin deficiency in AD mice; as a consequence, a number of Alzheimer-like features were reduced or prevented. In SAM-treated mice, we observed the restoring of normal PSEN1 expression, amyloid processing and deposition, Tau phosphorylation and, finally, an improvement in spatial memory. Conclusions: These data evidence the role of one-carbon metabolism in AD onset and progression and highlight molecular mechanisms causally connecting epigenetic modifications to AD. Finally, these data provide a rationale for the possible use of SAM for the treatment of AD. Neuroscience of knowledge: from face perception to person recognition Freiwald, W. 1* 1 The Rockefeller Univ. Recent years have seen great progress in understanding theneural mechanisms of object recognition. Focusing on one particular objectcategory, faces, my own research has focused on identifying the neural networksand neural mechanisms of face processing, primarily in macaque monkeys. Weidentified six modules in the temporal lobe responding selectively to faces.These modules are selectively coupled to form the nodes of a face processingnetwork. With each of the network nodes, faces are represented differently. Inmy talk, I will present the key insights into object recognition mechanismsthis research provided. This face processing network is located within thevisual object-recognition portion of the temporal lobe. At the top of theface-processing hierarchy, we found a face area with cells that respond highlyselectively to one or a few individuals – even when these individuals had neverbeen seen in real life before. This property contrasts sharply with those foundin the human hippocampus (Quiroga, Reddy, Kreiman, Koch & Fried "Invariantvisual

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representation by single neurons in the human brain" Nature (2006)435:1102-1107) that respond selectively to familiar concepts, includingfamiliar individuals. This discovery together with that of the face processinghierarchy allows us to reveal the circuits and mechanisms that relay theperception of a face to the activation of knowledge about a person we know,e.g., when we recognize a friend on the other side of the street. In the secondin part of my talk I will present this idea and the research effort of aninternational team of researchers including Haim Sompolinsky, Rodrigo QuianQuiroga, Davide Zoccolan, Mathew Diamond, and myself that aims to elucidate themore general question: what are the neural representations of knowledge and howare they used in perception and memory? Human Frontier Science Program, The New York Stem Cell Foundation Amyloid beta regulates homodimerization of Amyloid Precursor Protein at hippocampal synapses Frere S. 1, Shapira I. 1, Fogel H. 1, Slutsky I. 1,2* 1 Dept. of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv Univ. 2 Sagol School of Neuroscience, Tel Aviv Univ. Amyloid beta (Aβ), the product of Amyloid Precursor Protein (APP) sequential β-,γ- cleavages, is thought to be the principal factor in the etiology of Alzheimer's disease. Indeed, Aβ is involved in the synaptic dysfunctions that might underline the cognitive deficits characteristic of the disease. Nevertheless, mild Aβ elevation also enhances synaptic neurotransmission (Abramov et al., Nat. Neur., 2009) but its mechanism is still unknown. The hypothesis that APP is the receptor for Aβmediated regulation of the release probability has been assessed using 2photon FLIM-FRET microscopy techniques in neurons expressing APP-mEGFP and APP-mCherry as donor/acceptor couple. We found that APP exists as a homodimer in presynaptic boutons of neurons in culture. Using a lentiviral strategy, expression of tagged APPs in the granular cells of the dentate gyrus allows us to demonstrate that APP exists also as a homodimer at mossy fiber synapses. We finally showed that Aβ promotes APP dimerization at synaptic boutons in both preparations. With FLIM-FRET methods, we could precise that the observed increase of APP interactions occurs upon a conformation change of APP homodimers while the number of interacting proteins was unaffected by Aβ. Our results indicate that extracellular Aβ promotes presynaptic APP/APP interactions in native synapse, which opens new perspectives in the role of APP/Aβ signaling at hippocampal synapses and its imbalance that might be important in the onset of Alzheimer's disease. SF thanks the Tel Aviv Univ. Center for Nanoscience and Nanotechnology for his fellowship

The neural signature of spatial uncertainty Freud E. 1,2*, Rosenthal G. 3,2, Ganel T. 1,2, Avidan G. 1,2 1 Dept. of Psychology Ben-Gurion Univ. of the Negev, Beer Sheva, Israel. 2Zlotowski Center for Neuroscience, BenGurion Univ. of the Negev, Beer Sheva, Israel. 3Dept. of Cognition and Brain, Ben-Gurion Univ. of the Negev, Beer Sheva, Israel. Background: Object recognition and particularly the processing of spatial information are mediated by a specialized neural network. Here, using fMRI we tested how this network processes objects that violate fundamental rules of spatial 3D organization (i.e. impossible objects). Participants observed possible and impossible objects and preformed one-back perceptual classification. Results: We found enhanced functional connectivity between object-selective regions for impossible objects compared to possible ones. This finding was replicated even when stimuli were presented very briefly to limit the processing of objects impossibility. Interestingly, the extent of this distinction was correlated with participants' general spatial ability. Contrary, the conventional univariate analysis revealed stronger activation for impossible objects only for long exposure duration and was not correlated with participants' general spatial ability. Conclusions: These results suggest that the visual system is highly susceptible to the objects' 3D structural information and that this sensitivity is automatic and can precede conscious experience. Critically, such sensitivity is captured mainly at the level of functional connectivity between object selective regions thus stressing the role of inter-regional synchronization in the representation of the visual environment. Processing information during a lexical decision task as an indication of brain region synchronization: Differences between dyslexic and regular readers Frid A. 1,2*, Breznitz Z. 1 1 Edmond J. Safra Brain Research Center for the Study of Learning Disabilities, Univ. of Haifa 2 Software Engineering, ORT Braude College of Engineering, Karmiel, Israel Background: Dyslexia is a learning disability that impairs a person's ability to decode words accurately and fluently. This deficit can manifest itself in the language-related domain as difficulties in phonological and orthographic working memory, brain systems asynchrony, poor executive function skills and/or poor rapid naming processing. In our previous study, we reported about the existence of differences in brain regions activation and connectivity during an auditory, short, non-linguistic, simple, sub-phonetic choices reaction time task, of typical and dyslexic readers. As it was suggested, lower levels of connectivity indicated asynchrony of the brain regions. In this study, the brain activity and connectivity between brain regions was studied within each group and between dyslexics and typical readers

J Mol Neurosci

using analysis from ongoing, 64 channel EEG recordings with Event Related Potentials (ERP) methodology during a Lexical Decision (LD) task. This task incorporated a mixture of words and pseudo-words that were presented visually to the subjects. The analysis of the data included a novel analysis method of ERP signals for Regions of Interest (ROI) identification based on a Wavelet transform followed by a feature selection procedure. Results: Data indicated that most of the differences during the LD task between the typical and dyslexic readers were found in the left anterior, left posterior and right posterior ROIs, which may indicate that the connectivity between these regions was significantly lower among the dyslexics. In addition using these ROIs led to a classification success rate of 80%. Conclusions: These findings are aligned with the findings of the previous study, present a new way of analyzing ERP data that included the analysis of brain regions connectivity which indicates a connection between the dyslexia phenomena and the theory of asynchrony. This study was supported by the Edmond J. Safra Philanthropic Foundation The time course of ocular parameters in ADHD during a continuous performance task (CPT) and the effect of medication Fried M. 1*, Bonneh Y. 2, Sterkin A. 1, Polat U. 1 1 Faculty of Medicine, Tel-Aviv Univ., Goldschleger Eye Research Institute, Sheba Medical Center 2 Dept. of Human Biology, Univ. of Haifa Background: Last year (ISFN 2012), we showed that ADHD subjects fail to suppress microsaccades and eye blinks while anticipating a visual stimulus. Here we investigated the timecourse of these ocular parameters along sessions and the effect of medication on it. Methods: 22 subjects diagnosed with ADHD and 22 control subjects performed 2 sessions of t.o.v.a. while their eye movements were tracked. ADHD subjects performed the second session after taking medication (MPH). We measured the average rates of eye blinks and microsaccades during the entire trial duration (2 seconds) and during the peri-stimulus interval (-100 to 150 milliseconds around stimulus onset) and investigated their time course along the 20 min sessions. Results: Microsaccade and blink rates increased monotonically over time during the session for both groups, and more so in the peri-stimulus interval. This increase was significantly faster and reached higher levels in the un-medicated ADHD group. With medication, the level and time-course of the microsaccade rate fully normalized to control level, regardless of the time interval (peri or post stimulus) within trials. Conclusions: ADHD subjects fail to maintain sufficient level of arousal during a simple and prolonged task, which limits their ability to dynamically allocate attention during anticipated stimuli and suppress involuntary eye movements. This impairment

normalizes with medication and its oculomotor quantification over time could potentially be used for differential diagnosis. Computerized sampling and analysis of early neuromotor development of premature infants Friedman H. 1*, Bar-Yosef O. 2, Gordon G. 3, Forkosh O. 3, Schneidman E., 3 1 Dept. of nursing, Faculty of Social Welfare & Health Sciences, Univ. of Haifa, Israel 2 Pediatric Neurology Institute, Edmond & Lily Safra Children’s Hospital, Sheba MC, Israel 3 Dept. of Neurobiology, Weizmann Institute of Science, Rehovot, Israel Background: Assessment of infant's development using the quality of spontaneous random movements has been shown to be sensitive and predictive for detection of Cerebral Palsy, Minor Neurological Dysfunction, Autism and other neurodevelopment impairments. The current clinical methods grade the quality of infant's early motor function according to specific characteristics of spontaneous motor patterns that were identified and characterized by observational studies. Our goals are to automatically track and characterize the kinematic features of young infant's movements according to a wide range of parameters, and to compare the kinematic parameters of infants born in-term to infants born premature. Results: 20 infants (10 born in-term and 10 born preterm), are video recorded (3D Kinect system) once a month. Automatic analysis of kinematics of spontaneous motor patterns is conducted by a novel tracking algorithm based on the digital output of 3D Kinect. Quality of infant's movements is graded by clinical criteria such as symmetry, fluency, complexity and more. Preliminary results show reliability of computerized sampling to track features of spontaneous motor patterns and accurate analysis of movements' kinematics. Conclusions: Motion capture systems are a very accurate method for the diagnosis of abnormal movement patterns. Identification of specific normal and abnormal motor patterns can be further used for the prediction of abnormal neurological development. Early computerized identification of early neuromotor signs of neurodevelopment impairments in young infants at risk will support initiation of early treatment and may minimize their motor and neurological deficit. # equally contributing. A Scent of Tranquility Frumin I. 1*, Endevelt-Shapira Y. 1, Eisen A. 1, Sobel N. 1 1 Dept. of Neurobiology, Weizmann Institute of Science There is ample evidence suggesting the existence of human chemosignalling. Works by McClintock pointed out to menstrual synchrony mediated by sweat, works in our lab showed the existence of a chemosignal in human emotional tears that reduces sexual arousal, and Chen discovered that humans can smell fear and change physiological functions accordingly. We

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set to find out if we can deduce the existence of yet another chemosignal, related to states of relaxation and tranquility, similarly but opposite to the effect Chen found.As known human chemosignals are excreted in axillary secretions, we collected volatiles from this area, and subjected it to a Dynamic Headspace – Gas Chromatography – Mass Spectrometry analysis (DHS-GCMS). This very sensitive method allowed the discovery and identification of volatile content of samples in a very sensitive manner. Using an intra-person design, to minimize individual differences, sweat volatiles were collected insitu in both axillae, using adsorption tubes and pumps. Samples were collected immediately before and after a 15-minutes mediation session, on several consecutives days on the same hour of day. In hope to find a single or a number of molecules changing between conditions. Initial results suggest two differences between the conditions – an increase of the content of nonanal (C9-aldehyde), concomitant with a decrease of the content of 6-methyl-5-Hepten-2-one. Analysis of the differential composition and collection of additional repetitions are still underway. As humans are social animals, such putative signals have a potentially important role in conveying non-verbal information, communicating the sense of danger as well as the sense of relaxation and bonding. To further corroborate this initial findings, we intend to present the volatiles to subjects and monitor their physiology and responses. A neural-network model of intentions within free-choice and instructed conditions Furstenberg A. 1*, Deouell LY. 2,1,Sompolinsky H. 3,1 1 Edmond and Lily Safra Center for Brain Sciences, The Hebrew Univ. of Jerusalem 2Psychology Dept., The Hebrew Univ. 3 Racah Institute of Physics, The Hebrew Univ In order to understand proximal intentions, the preparation to act 'now', as well as the more complex process of 'change of intention', we employed a masked priming paradigm. Subjects pressed a right or left button following either an instructive visible arrow cue or a visible neutral 'free-choice' cue, both preceded by a masked arrow prime. EEG measurements, through Lateralized Readiness Potentials (LRP), revealed a neural signature of 'change of intention' in both the instructed and the free-choice decisions. In order to explain the neural dynamics underlying the decision mechanism and the phenomenon of 'change of intention', and to account for the behavioral and LRP results, we have studied a large-scale neural-network model that describes the signal transformation across sensory, working memory, decision-making, motor, and context modules. A key element is the interplay between perceptual information and internal noise in shaping the decision and action. The model successfully accounts for the main features of the behavioral and neural data, including reaction time, error rates, LRP dynamics, and change of intention signals. The model is consistent with the hypothesis that

decisions in instructed and free-choice actions have the same basic ingredients, and represent a continuum of varying degree of balance between internal signals from perceptual or 'higher level' inputs and random internal neural noise. Experimental predictions of the model are discussed. Inheritance of maternal stress-induced RNA editing changes in rats Zaidan H. 1, Golumbic Y.N. 1, Gaisler-Salomon I. 1,2* 1 Psychology, Univ. of Haifa 2 Psychiatry, Columbia Univ., NY We have previously shown that in rats, stress to the dam well before she becomes pregnant (prereproductive stress, PRS) impacts her future offspring's social and emotional behavior in a sex-specific manner. Stress also affects A-to-I RNA editing, an epigenetic process that entails site-specific modification in pre-mRNA and is catalyzed by members of the Adenosine Deaminase Acting on RNA (ADAR) enzyme family, particularly at the 5-HT2c receptor site. We asked whether stressinduced changes in RNA editing can be transmitted across generations. To this end, we examined alterations in adenosine to inosine (A-to-I) RNA editing in the amygdala of PRS and control dams, as well as in their F1 and F2 offspring at birth and in adulthood. We found alterations in RNA editing at the A and B site in PRS dams, and at birth, in their F1 male offspring. Changes in ADAR1 and ADAR2 mRNA expression levels were similarly found in PRS dams and F1 females at birth. In adult male grandchildren (F2) of PRS grandmothers, ADAR expression increased when primed by stress. We also found that PRS offspring, both F1 and F2, showed sex-specific behavioral changes. In sum, stress led to changes in RNA editing at the 5HT2cR, and this effect was transmitted across generations. These changes may be related to the alterations in the behavior of progeny of stressed females. Supported by an Israel Science Foundation (ISF) grant to IGS. Procedural memory consolidation in the elderly: effects of timing of training and quality of post training sleep on memory trace representation Gal C 1,2,3* 1 Korman M 2 Karni A 3 Dept. of Neurobiology Univ. of Haifa Background: There is accumulating evidence for a reduction in the ability of elderly individuals to acquire new motor skills and generate effective long-term procedural memory. Here we addressed two questions, using the Finger Tapping Sequence Learning task paradigm with four experimental groups (elderly\young adults morning\evening): What is the time course of sequence memory consolidation in the elderly as compared to young adults? Is the time course sensitive to the timing of training - morning vs. evening? Post-training sleep was measured by actigraphs.

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Results: There were differences in total sleep time and sleep latency between young and elderly groups, no significant differences were found between evening and morning. Young adult groups showed robust delayed gains at 24 hours post training that persisted at 1 week retest. In contrast, the elderly did not show any delayed gains. Moreover, dissociation between the two elderly groups was found according to the timing of training: evening elderly group showed stabilization of gains at 24 hours post training that persisted at 1 week retest, while morning elderly group deteriorated at 24 hours test as compared to end of training, suggesting that no effective stabilization occurred post-training. Conclusions-1: Aging may significantly modify susceptibility of the memory system to maintain and consolidate memory trace for a novel sequence of movements. Sleep quality may account for these differences. 2. The time of training in the elderly may affect the overall long term effect of training. Nonspecific interference experienced during the day by subjects trained in the morning, without the protective effect of sleep,may be critical in the elderly. In contrast to evening trainees that may effectively exploit the protective effect of post training sleep on the recently acquired procedural memory. A Novel neural crest-like stem cell population isolated from human oral mucosa for the treatment of neural disorders Ganz J. 1, Arie I. 2, Ben Zur T. 1, Barhum Y. 1, Pitaru S. 2, Offen D. 1* 1 Neuroscience laboratory, Felsenstein Medical Research Center - Tel Aviv Univ. 2 School of Dental Medicine, Faculty of Medicine - TAU Recently and as a novel discovery, we reported the isolation of a unique stem cell population, with a primitive neural crest phenotype, from the lamina propria of the adult human oral mucosa, termed hOMSC. These cells express constitutively robust levels of embryonic and neural crest stem cells markers and differentiate into cell lineages of the three germ layers in vitro and into ectodermal and mesodermal-derived tissues in vivo. Our objective aimed at testing the propensity of hOMSC to differentiate into neural lineages and to assess their functional capacity in vivo. hOMSC exhibit a high propensity to differentiate into astrocyte-like cells (hOMSC-NS) as evidenced by the typical astrocyte morphology and marker expression GFAP, S100β and EAAT1, as well as increase in of neurotrophic factors secretion, GDNF, BDNF, IGF-1 and VEGF. Conditioned medium of hOMSC-NS protected motorneurons in vitro from hypoxic and oxidative stressinduced cell death, and when transplanted at sites of sciatic nerve injury in rats, significantly improved rat motor function. Notably, hOMSC also exhibited the ability to differentiate into dopaminergic-like neurons (hOMSC-DA) as evidenced by down regulation of the ESC markers, up-regulation of

dopaminergic markers TH, NURR1, PITX3, LMX1A and the increase of regulated dopamine secretion. Transplantation of hOMSC-DA into the striatum of hemi-Parkinsonian rats resulted in significant improvement of their behavioral deficits, as evidenced by apomorphine-induced rotations, cylinder and rotorod test. Functional results were positively correlated with the identification of hOMSC-DA with TH expression in the implanted striatum two month following transplantation. We show for the first time the substantial propensity of hOMSC to differentiate into neurotrophic factors-secreting astrocyte-like cells and DA-like neurons in vitro, and the capacity of these cell lines to improve function of the diseased CNS and PNS in rat models. Dependence of memory consolidation on synaptic consolidation in the cortico-hippocampal network Gao X. 1, Castro-Gomez S. 1, Graf S. 1, Kuhl D. 1, Ohana O. 1* 1 Inst. for Molecular and Cellular Cognition, ZMNH, Univ. Medical Center Hamburg-Eppendorf, Germany Background: Interactions between the hippocampus and the cortex are essential for the formation and consolidation of spatial and episodic-like memories. Synaptic plasticity in these regions is considered necessary for building the networks that code for specific memories. However, so far it is not known if cortical and hippocampal synaptic plasticity consolidates in a similar or dissimilar manner and if continuous re-consolidation in the hippocampus is essential for long-term memory even when cortical representations already exist. Our previous work shows that Arc/ Arg3.1 is necessary for consolidation of long term memory and of plasticity. We use local ablation of Arc/ Arg3.1 in the hippocampus or cortex in combination with behavioral assessments to investigate their involvement in long term memory consolidation. Results: We employed rAAV-CaMKIIα-Cre viral vector transfections together with Arc/Arg3.1flox/flox transgenic mice to specifically ablate Arc/Arg3.1 in either the hippocampus or the neocortex. We found that rAAVCaMKIIα-Cre mediated Arc/Arg3.1 ablation starts at 3 days and is complete within 7 days after the injection. Mice were tested in an open field arena and elevated plus maze one week after the injections. No significant changes in mobility and exploration behavior of the injected mice were observed. We are currently examining the impact of Arc/Arg3.1 ablation in the hippocampus on fear memory consolidation. Conclusions: Rapid and efficient ablation of Arc/Arg3.1 can be obtained by local injections of rAAV-CaMKIIα-Cre in Arc/ Arg3.1flox/flox mice. This ablation does not affect exploratory behavior or general anxiety level. Support is provided by DFG–SFB 936 "MultiSite Communication in the Brain"

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Endogenous activation of IGF-1 receptor modulates synaptic transmission and plasticity in hippocampal synapses Gazit N.1,2, Slutsky I.1,2* 1 Dept. of Physiology and Pharmacology, Sackler Faculty of Medicine, TAU, 2 Sagol School of Neuroscience, TAU Insulin-like growth factor 1 receptor (IGF-1R), controls longevity in a wide range of species. Although IGF-1Rs are widely expressed in various brain regions, its role in synaptic and cognitive function is controversial. While some studies have shown that reduction in the IGF-IR expression levels prevents synapse loss and memory decline in Alzheimer's disease model mice, other studies have suggested improvement of cognitive function and by IGF-1 injections. In order to understand the mechanisms underlying regulation of memory function by IGF-IR, we first aimed on understanding its physiological function in neural circuits. Utilizing FM-based imaging of synaptic vesicle recycling, electrophysiology and FRET spectroscopy in cultured hippocampal neurons and in CA3-CA1 connections of acute hippocampal slices, we explored how tonic IGF-1R activity regulates synaptic transmission and plasticity. Our results show that pharmacological inhibition of endogenous IGF-1R activity strongly reduces synaptic release probability and basal excitatory synaptic transmission, resulting in increased short-term synaptic facilitation. These results indicate that activation of IGF-1Rs by endogenous IGF-1 is involved in normal regulation of presynaptic activity in hippocampal neurons. We will discuss future directions and the relevance of our findings to understanding initiation of synaptic dysfunctions at the early stages of Alzheimer's disease. Switching between sensory modalities and flight directions alters 3-D spatial codes in bat hippocampus Geva-Sagiv M. 1,2*, Weiss S. 1,3, Las L. 1, Ulanovsky N. 1 1 Dept. of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel 2Interdisciplinary Center for Neural Computation, The Hebrew Univ. of Jerusalem 3 MIT-Israel student exchange program (MISTI) How are inputs from different sensory systems embedded in the hippocampal spatial representation? Here we set out to dissociate the effects of using two long-range sensory systems – vision and echolocation – on hippocampal neural activity in a unique animal model, the Egyptian fruit bat. We trained bats to fly back and forth along a 3-D "linear flight track" using vision without sonar – in a lit environment, or using sonar without vision – in the dark. We conducted simultaneous tetrode-based recordings of multiple cells in flying bats, from hippocampal area CA1 and the Subiculum. We are now in the process of characterizing the differences in the neural codes for space of individual cells, and in the ensemble activity,

based on the two sensory systems. Preliminary results from these tetrode-based recordings showed clear threedimensional (3-D) place fields along this linear-flight setup, both in the light and in the dark. Some cells showed clearly reproducible 3-D place fields between two consecutive flight sessions in light conditions, while exhibiting consistent remapping when switching from light to dark conditions (which reverted when switching back to the light condition). This 3-D flight setup also allows the exploration of the selectivity of place-cell firing to flight directionality. Previous studies in rats have examined CA1 neuronal directionality – that is, the tendency of neurons to fire differently in different running directions – mostly in rats that locomoted along constrained and reproducible 1-D paths. Our results show that many place-cells exhibit directionality also in bats that fly along a linear, 1-D track embedded in 3-D space. Further, our behavioral task resulted in different levels of heterogeneity in different sessions – and preliminary analyses indicate that the more stereotypical and reproducible behaviors, lead to higher directional selectivity of place-cells. Alzheimer Disease therapy: moving from A-beta to TAU Giacobini E. D e p t . o f In t e r n a l M e d i c i n e , R e h a b i l i t a t i on an d Geriatrics.Univ. of Geneva Faculty of Medicine and Geneva Univ. Hospitals. Geneva, Switzerland Disease-modifying treatment for Alzheimer’s disease (AD) has focused mainly on beta-amyloid (a-beta) reduction. Four major strategies have been tested: prevent or reduce its formation, remove existing deposits using active or passive immunization, prevent or reduce its aggregation, enhance its clearance. Some compounds have succeeded in decreasing brain amyloid but none has produced clinically significant results. Several methodological issues can explain this failure but a main reason could be that the amyloid cascade hypothesis does not fully integrate a large body of data relevant to the emergence of clinical AD. Most important is the fact that amyloid deposition is not strongly correlated with cognition in multivariate analyses, contrary to neuronal and synaptic loss, and tangles and hyperphosphorylated tau pathology which are closely associated with memory deficits. Targeting tau pathology may thus be more effective clinically. Potential therapeutic compounds include kinase inhibitors, phosphatase activators, phospho-tau antiaggregants and microtubule stabilizers. Also, numerous immunization studies in animal models indicate that it is possible to reduce intracellular levels of tau and PTau with an improvement in performance. Although, the potential risk of tau immunotherapy in humans should not be underestimated. Several tau-related vaccines are presently in advanced preclinical stage and will soon enter clinical trial

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Population responses in V1 encode different figures by response amplitude Gilad A. 1*, Slovin H. 1 1 The Gonda Multidisciplinary Brain Research Center, BarIlan Univ., Ramat Gan, Israel The visual system simultaneously segregates between several objects presented in a visual scene. The neural code for labeling different objects or figures is not known. To study this question we trained two monkeys to discriminate whether two elongated bars are either separate thus generating two different figures, or connected thus generating a single figure. Using voltagesensitive dyes we simultaneously imaged V1population responses evoked by the two bars, while keeping their local properties similar among the two conditions. In the separate condition, unlike the connected condition, the population response of one bar is enhanced, while the other is simultaneously suppressed. This divergent pattern was developed around 200 ms post stimulus onset, evident in single trials, and correlated with the stimulus separation saliency and behavioral report. We suggest that V1 is involved in the labeling of each figure by different neuronal response amplitude, which can mediate their segregation and perception. Differentiating sensory goals from motor actions in the human brain Krasovsky A. 1, Gilron R.* 2,3 , Yeshurun Y. 1,2 , Mukamel R.2,3 1 School of Computer Science, TAU 2 Sagol School of Neuroscience, TAU 3 School of Psychological Sciences, TAU To achieve a certain sensory outcome, multiple actions can be executed. For example, in order to draw a circle one can perform a clockwise or counter-clockwise pen trace. Thus the same sensory goal can be achieved by different motor actions. Using fMRI, we examined the neural networks that dissociate sensory goals from motor actions. Subjects controlled a figure on the screen by performing pen traces on an MR compatible digital tablet using their right hand. In order to move the figure in a certain direction (e.g. horizontal) they had to perform either congruent (horizontal) or incongruent (vertical) pen movements on different trials. This design allowed us to dissociate sensory goals (moving the figure in a certain direction) from the underlying motor actions (horizontal/vertical pen traces). Using multi-voxel pattern analysis (MVPA) and a whole brain searchlight strategy, we found that activity patterns in left(contralateral) motor and parietal cortex, and also right (ipsilateral) motor cortex significantlydiscriminated direction of pen traces regardless of intended figure movement. Furthermore, activity patterns in right superior parietal lobule and pre-motor cortex, and also left fronto-polar cortex significantly discriminated sensory

goals (horizontal vs. vertical figure movement) regardless of underlying pen traces. Together, these results highlight the role of ipsi-lateral motor cortex in coding movement directions, and point to a network of brain regions involved in high order goal representation that is dissociated from specific motor plans. Neurotherapeutic effect of cord blood derived CD45+ hematopoietic cells in mice brain after trauma Arien-Zakay H.1, Gincberg G.1, Nagler A.2, Cohen G.1, LirazZaltsman S.1, Trembovler V.1, Alexandrovich A.G.1, Galski H.2, Shohami E.1 and Lazarovici P.1* 1 School of Pharmacy Institute for Drug Research, The Hebrew Univ. of Jerusalem, Jerusalem; 2 Division of Hematology, Chaim Sheba Medical Center, Tel-Hashomer Traumatic brain injury (TBI) causes disability and death. Cell therapy by human umbilical cord blood (HUCB) transplantation has shown promising results in animal models of TBI and is under evaluation in several clinical trials. HUCB contains different stem cell populations, but only mesenchymal stem cells were evaluated for therapy of TBI. Here we confirm and further extend the characterization of the neurotherapeutic effect of HUCB-derived mononuclear cells and demonstrate for the first time, that HUCB-derived CD45 positive (CD45+) cell subset reduced the neurobehavioral deficits which typically occur in a mouse model of closed head injury. Using magnetic sorting, a CD45+ cell population was obtained which was characterized by expression of CD45 and CD11b (96-99%). Intravenous transplantation of these cells 1 day post-trauma resulted with a significant therapeutic effect observed up to 35 days as evaluated by neurological score reflecting neurobehavioral improvement. This therapeutic effect was in a direct correlation with the decreased lesion volume. Treatment of the cells with anti-CD45 antibody decreased the beneficial neurotherapeutic effect of the cells. CD45+ cells were detected by immunohistochemistry at the site of brain injury 1.5-2 h after transplantation. Preliminary experiments suggest attenuation of astrogliosis and microglia activation by decreased immunoreactivity of glial fibrillary acidic protein (GFAP) and allograft inflammatory factor 1 (AIF1/Iba1), at the site of brain injury, 20 days after CD45+ cells transplantation. These findings indicate the neurotherapeutic potential of HUCB-derived CD45+ cell population in a mice model of brain trauma and propose their use in new clinical settings. ** PL holds the Jacob Gitlin Chair in Physiology at Hebrew Univ. and is affiliated and acknowledges the support by the David R. Bloom Center for Pharmacy, the Dr. Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at The Hebrew Univ. of Jerusalem and the Israel Ministry of Science and Technology, Israel; First two authors equally contributed.

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Gene therapy in a toxin-induced mouse model of multiple system atrophy Glat M 1*, Ben-Zur T 2, Barhum Y 2, Benkler C 2, Offen D 3 1 Sagol School of Neuroscience, Tel Aviv Univ. 2 Felsenstein Medical Research Center 3Neuroscience laboratory, Head. Felsenstein Medical Research Center Background: Multiple System Atrophy (MSA) is a sporadic neurodegenerative disorder found in 4 people per 100,000 individuals with a mean survival of 7-9 years after the diagnosis. The clinical features of MSA include autonomic failures combined with Parkinsonism (MSA-P subtype) in 80% of cases, or cerebellar ataxia (MSA-C subtype) in 20% of cases. Pathologically, MSA is characterized by glial cytoplasmic inclusions (GCIs), gliosis, and striatonigral and olivopontocerebellar degeneration. Studies in animal models of MSA and MSA patients have identified several factors that may contribute to the neurodegeneration, such as inflammation, oxidative stress, and mitochondrial dysfunction. These factors are assumed to be linked to alterations in glutamate homeostasis, as observed in the CSF of MSA patients. To examine whether changes in glutamate homeostasis impacts the disease, we used 3-nitropropionic acid (3-NP) to generate a mouse model of striatonigral degeneration in order to evaluate the therapeutic effect of a mixture of three genes (NRF2, EAAT2, GDH2) involved in glutamate homeostasis and oxidative stress. Results: Following intrastriatal injection of 3-NP in C57 black mice we observed amphetamine and apomorphine induced ipsilateral rotations as well as contralateral motor deficiency. Mice that were injected intrastriataly with a mixture of NRF2, EAAT2 and GDH2 prior to 3-NP injections, showed improvement in motor function and in apomorphine induced ipsilateral rotations, but not in amphetamine induced ipsilateral rotations. Conclusions: Our findings suggest that the our novel genetic treatment combining NRF2, EAAT2 and GDH2 genes, protects cells from excitotoxicity. Our preliminary results may provide a novel potential therapeutic approach for MSA. Alertness affect subitizing but not counting: subitizing is a global process Gliksman Y. 1*, Henik A. 1 Dept. of Psychology, Ben Gurion Univ. of the Negav, Beer Sheva Background: Are subitizing and serial counting involve separate or overlapping processes? The current study was based on several recent findings: 1. Right-TPJ (Temporo-Parietal Junction) is related to both global processing and alertness. 2. Alertness enhanced global processing. 3. Right-TPJ was found to be activated when participate are engaged in enumeration in the subitizing range and inhibited in estimation

range. An important question is whether subitizing is a global process? How is it affected by alertness? Results: In two experiments, we found that in random arrangement of dots, alerting-cue modulated reaction times only in the subitizing range. In addition, we found that for canonical arrangement, namely, when global processing is encouraged, alerting-cue modulated performance in the counting range as well. Conclusions: We suggest that subitizing is a global process, but it is based on a separate mechanism than counting. Our results connect between the fields of attention and numerical cognition and are important as a possible clinical tool. A novel method for electrical stimulation-driven ion imaging: a model for studying DNA nano-devices which can respond to transmitter release Goldstein R. 1, Katz B. 1, Binshtok A. 1* 1 Medical Neurobiology, Hebrew Univ. Recently, DNA based nano-devices, termed "DNA nanorobots", capable of exposing biologically functional peptides as a response to specific cellular signals, were fabricated. These nano-devices are constructed from a capsule and aptamer locks. The aptamer locks are designed to displace when binding to a molecule of choice, resulting in the opening of the capsule and exposure of its content. Hence, these devices can be used as "logically-gated" pharmacological delivery systems. It has been demonstrated that DNA nanorobots can detect specific surface epitopes, enabling the recognition and targeting of specific cell types within a heterogeneous population. In the present study we sought to explore whether DNA-nanorobots can respond to secreted biological signals. As a first step towards this goal, we have designed DNA nanorobots, which can respond to dopamine and as a response expose peptidic ion channel blockers. In order to trigger dopamine release, we electrically stimulated PC12 cells that are known to release dopamine in response to depolarization, which results from the opening of voltage gated L-type calcium channels and subsequent Ca2+ entry. We plate PC12 cells on a transparent and conductive Iodine Tin Oxide (ITO) coated glass and loaded them with Fura2-AM, in order to be able to simultaneously monitor changes in intracellular Ca2+ concentration. We show that electrical stimulation induces a transient Ca2+ increase. The transient increase in intracellular Ca2+ was inhibited by Nimodipine, a blocker of L-type calcium channels. This novel technique allows activation of a population of dissociated excitable cells, while monitoring the desired biological activity using physiological and optical methods under condition which do not permit perfusion or change of bath solutions. Deutsch-Israelische Projektkooperation (DIP) – GermanIsraeli Project Cooperation

J Mol Neurosci

Therapeutic potential of combining novel multi-target neuroprotective compounds with a fortified high calorie/energy diet in a mouse model of Amyotrophic Lateral Sclerosis Golko S. 1, Weinreb O. 1, Mandel S. 1, Amit T. 1, Youdim M.B.H. 1* 1 Eve Topf Center of Excellence, Technion- Faculty of Medicine, Haifa Background: Given the multiplicity of pathological mechanisms implicated in amyotrophic lateral sclerosis (ALS), the management of the disease nowadays is based on the recognition of the importance of multidisciplinary care, including simultaneous manipulation of multiple brain targets and metabolic/energetic parameters to address the diverse pathology aspects of the disease. Recently, we demonstrated that the multi-target, neuroprotective, brain permeable, iron chelator monoamine oxidase inhibitor, M30 conferred a significant improvement in survival time and motor performance of SOD1-G93A mutant transgenic ALS (mSOD1) mice. The current study examined the possibility of strengthening the basal energy status of mSOD1 mice, by combined treatment of M30 or M30 derivative, and a high calorie/energy supplemented diet (CED). Results: We demonstrated that M30 and M30 derivative (0.5 and 2.5 mg/kg, p.o. 2-3 times weekly) +CED cocktail treatment, starting at pre- and post-symptomatic stages of the disease, significantly delayed the onset of motor dysfunction and showed a superiority in extending the lifespan of mSOD1 mice, compared to the effects of each individual components, suggesting a synergism between the drugs and the CED. In addition, the drug +CED treatment exerted significant changes in the expression levels of genes related to energy homeostasis and lipid and glucose metabolism, in the gastrocnemius (GNS) muscle of mSOD1 mice, compared to each of the individual treatments. Furthermore, M30 derivative +CED combined treatment significantly attenuated neuromuscular junction denervation in the GNS muscle of mSOD1 mice. Conclusion: Our findings provide significant evidence that our multifunctional iron chelating drugs, M30 and M30 derivative may exert re-innervation of muscle fibers and thus, can be used for designing a multiple-target therapeutic protocol for clinical trials in ALS. Electrophysiological analysis of a cocaine-responsive neuronal ensemble in the nucleus accumbens Goll Y. 1,2, Citri A. 1,2* 1 The Edmond & Lily Safra Center for Brain Sciences, the Hebrew Univ. of Jerusalem 2Dept. of Biological Chemistry, Institute of Life Sciences, the Hebrew Univ. of Jerusalem The nucleus accumbens (NAc) is a central integrator of reward signaling in addiction. Multiple inputs converge within

the NAc to optimize adaptive motivate behavior, and the strength of these inputs is modulated by cocaine experience. The NAc is part of the ventral striatum and is anatomically and functionally divided into core and shell. The synaptic changes in the NAc are regarded as the locus of memory of cocaine experience. However, in the absence of a strategy to enrich for cocaine-responsive population, background neurons may mask fine changes in the plasticity induced by cocaine experience. Profiling of cocaine-induced transcription in the NAc identified a robust induction of an immediate-early transcription factor. We premise that this unique cocaine-induced expression defines a neuronal ensemble involved in mediating the response to cocaine within the NAc. We therefore developed a conditional approach for labeling the cocaineresponsive neuronal ensemble in the NAc. Our hypothesis is that definable neural subcircuits within the NAc and its synaptic inputs are involved in encoding cocaine experience. By molecular and electrophysiology analysis of the cocaineresponsive neural ensemble, we expect to reveal synaptic correlates of cocaine experience and define the role of the neuronal ensemble in the development of addiction related behaviors. Defining the functional neural circuit underling behavior and its plasticity will contribute to revealing mechanisms encoding reward. Whisker stiffness determines its bending properties and information transfer during object localization tasks Golomb D. 1*, Hires A. 2, Svoboda K. 2 1 Physiology and Cell Biology, Ben-Gurion Univ., Be'er-Sheva 84105 Israel 2 Janelia Farm, HHMI Ashburn, VA U.S.A Rodents can estimate object radial distance using a single whisker. The forces, moments and deflection at the whisker base, where mechanoreceptors of trigeminal ganglion neurons are located, are determined by the modifications of whisker profile in response to bending. We compute whisker profiles during contact using the two-dimensional quasi-static approximation, and compare them with video recordings of whiskers rotated by a galvo against a cylindrical pole. A stable contacting state exists when the whisker push angle towards the pole is not too large. It disappears beyond a critical angle and the whisker slips off. Slip-off occurs when for conical, but not for cylindrical, whisker. Comparison between modeling results with homogeneous Young's Modulus and experiments shows that the bending of the theoretical whisker is smaller than that of the experimental whisker for proximal object locations, and is larger for distal locations. This discrepancy is resolved assuming a non-monotonous dependence of effective Young's modulus on the whisker arc length. The quasi-static approximation fits experimental data even if the whisker plane is not perpendicular to the pole. Whisker profiles during contact for High (19 Hz) and low

J Mol Neurosci

rotation frequency are similar, and inertial effects are not observed experimentally. Vibrations occur after the whisker detaches from the object. This work shows how whisker stiffness controls its bending properties: the conical structure is necessary for encoding object distance by slip-off events, the quasi-static description describes bending properties during whisking well if non-homogeneities in the effective Young's modulus are considered. Radial distance is encoded by quasi-static forces, slip-offs and vibrations after detach. HHMI Neural variability in visual, auditory and somatosensory systems in Attention Deficit Hyperactivity Disorder (ADHD) Gonen-Yaacovi, G. 1*, Haar, S. 1, Arazi, A. 1, Dinstein, I 1 1 Dept. of Psychology, Ben-Gurion Univ. of the Negev, BeerSheva, Israel. Background: Attention Deficit Hyperactivity Disorder (ADHD) is a developmental condition characterised with increased intra-individual reaction time variability. Abnormally large trial-by-trial behavioral variability may be generated by a general increase in trial-by-trial neural response variability (i.e., increased neural "noise"). To test this hypothesis we used EEG to measure neural response variability across multiple trials containing identical visual, auditory or somatosensory stimuli in ADHD subjects and matched controls. Method: Participants were presented with visual (checkerboard), auditory (pure tones), and somatosensory (vibrating stimulus) stimuli using an event related potential (ERP) experimental design. ERP components were identified and their amplitude and trial-by-trial variability were compared across groups. In addition all subjects completed an IQ test and three cognitive assessments of attention, working memory, and response inhibition. Results: Trial-by-trial variance was larger in the ADHD group compared with the controls across all three sensory domains. This difference in variance was present for both the early and the late ERP components in each sensory modality. Finally, higher variance in the ADHD group was also found on "catch" trials where no stimulus was presented (i.e. larger variance in ongoing brain activity). Conclusions: The results suggest that individuals with ADHD exhibit abnormally high levels of neural "noise", which may embody a fundamental physiological characteristic of this disorder. Optogenetic dissection of the neuronal circuits underlying spontaneous network oscillations in the neocortex Goshen I Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew Univ.

Prevailing theory suggests that long-term memories are encoded via a two-step process requiring early involvement of the hippocampus followed by the neocortex. Contextual fear memories in rodents rely on the hippocampus immediately following training but are unaffected by hippocampal lesions or pharmacological inhibition weeks later. With fast optogenetic methods, we examined the real-time contribution of hippocampal CA1 excitatory neurons to remote memory and found that contextual fear memory recall, even weeks after training, can be reversibly abolished by temporally-precise optogenetic inhibition of CA1. When this inhibition is extended to match the typical time course of pharmacological inhibition, remote hippocampus-dependence converts to hippocampus-independence, suggesting that longterm memory retrieval normally depends on the hippocampus but can adaptively shift to alternate structures. Further revealing the plasticity of mechanisms required for memory recall, we confirm the remote-timescale importance of the anterior cingulate cortex (ACC), and implicate CA1 in ACC recruitment for remote recall. Finally, we show that CA1 is also necessary for the online maintenance of the recalled memory, and thus memories can be turned off after recall, resulting in termination of the fear response, by CA1 inactivation. Illuminating memory: An optogenetic approach to study the role of neurons and glia in memory acquisition and recall Goshen I Edmond and Lily Safra Center for Brain Sciences (ELSC), The Hebrew Univ. Cognitive function and emotional homeostasis, and the aspiration to decipher their neuronal basis have stood at the heart of neuroscience since its inception. The complexity of the circuits underlying these processes is immense, and new techniques are necessary to provide novel efficient ways to make a significant progress in brain research. Optogenetic tools enable temporally and spatially precise in-vivo activation or inactivation of genetically defined cell populations, thus enabling deconstruction of systems that were not available for research. An example for that is our work re-examining the role of the hippocampus in remote memory. In contrast to the prevailing theory suggesting that the following system consolidation the hippocampus becomes unnecessary for the recall of remote memories we found that even weeks after contextual conditioning, the contextual fear memory recall could be abolished by optogenetic inhibition of excitatory neurons in the CA1 region of the hippocampus- at times when all earlier studies had found no detectable influence of hippocampus. In exploring mechanisms, we found that loss of hippocampal involvement at remote timepoints depended on the timescale of hippocampal inhibition, since extending

J Mol Neurosci

optogenetic inhibition of hippocampus to match typical pharmacological timescales converted the remote hippocampus-dependence to remote hippocampusindependence. These findings uncover a remarkable dynamism in the mammalian memory retrieval process, in which underlying neural circuitry adaptively shifts the default structures involved in memory—normally depending upon the hippocampus even at remote timepoints, but flexibly moving to alternate mechanisms when the hippocampus is offline on the timescale of minutes. We are now examining the involvement of astrocytes in memory processes, as optogenetics allow direct astrocytic modulation, free of any direct effect on neurons.

Neuron Glia Biol 1, 193 (Aug, 2004). 10. I. Vulih-Shultzman et al. & Gozes, J Pharmacol Exp Ther 323, 438 (Nov, 2007). 11. Y. Schirer, Malishkevich et al. & Gozes, published 29 Jan 2014 | PLOS ONE 10.1371/journal.pone.0087383. Support: The AMN Foundation, CFTAU Montreal Circle of Friends and the Adams family

ADNP and neuronal plasticity – focus on microtubules Gozes I. 1,2,3* 1 Lily &Avraham Gildor Chair for the Investigation of Growth Factors; Elton Lab/Neuroendocrinology 2 Adams Super Center for Brain Studies & Sagol School of Neuroscience 3 Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv Univ., Israel

Background: Tremendous progress in studying brain function has been achieved through neuroimaging technologies. Recent advances were with the development of genetically engineered calcium, voltage-sensitive probes, and two photon imaging technologies. Nevertheless, all the available tools currently fall short in meeting one or more of the performance requirements necessary for comprehensive understanding of real-time cortical processing and principles underlying higher brain functions, leaving many outstanding questions beyond our reach. Here we describe recent advances in real-time optical imaging of spatiotemporal patterns of coherent population activity of neuronal assemblies, in-vivo, which go a long way in bridging this gap. Results: We designed and synthetized a superior organic voltage-sensitive dye (VSD)offering remarkable single trial signal-to-noise ratio with millisecond resolution. With this VSD we observed not only the input synaptic potentials but also coherent output by detecting action potentials as well. For example, we mapped 18-26 individual barrels, in-vivo and studied the spatial pattern associated with single whisker deflections at different times, confirming that barrel representations changed as a function of time. The fast lateral-spread velocity was found to be about 500μm/ms. We discovered that row E activity does not propagate to row A, and vice versa. Exploring the dynamics of on-going cortical activity reflecting the underlying connectivity in anesthetized subjects we found recurring multi-barrels patterns suggesting that there are fundamental multi barrel columns in the rat primary somatosensory cortex. Conclusion: The newly developed VSDs have made VSDI much easier and more informative. Because much of the processing in the neocortex is widely distributed over large areas and because single neurons' firing patterns are not reliable, imaging of both the input and the output of coherent population activity is necessary. Supported by the Grodetsky center fpor research of higher brain functions.

Activity-dependentneuroprotective protein (ADNP), (1) is essential for hematopoiesis in the zebrafish (2) and crucial for brain formation in the mouse (3). ADNP interacts with the SWI/SNF chromatin modeling complex (4) and regulates >400 key genes during embryonic development (5). In men, mutations in ADNP cause autism (6, 7). We further showed that at the cellular level, ADNP expression and cytoplasm/ nucleus distribution was unique in neuronal-differentiated cells compared to cardiovascular and nondifferentiated pluripotent cells (8). ADNP-immonoreactivity occasionally colocalized with microtubule (MT), (9) and ADNP RNA silencing led to a significant reduction in neurite numbers coupled to a reduction in the MT associated protein 2, in cell culture (8). In mice, ADNP partial knockout resulted in the MT-associated tau pathology and cognitive impairments, which were ameliorated by the ADNP fragment, drug candidate, NAP (10). Our recent studies suggest that ADNP interacts with proteins specifically regulating tau RNA splicing, which may be deficient infrontotemporal dementia (11), adding another dimension of interest to ADNP research and paving the path to new therapeutic targets. References: 1. M. Bassan et al. & Gozes, J Neurochem 72, 1283 (Mar, 1999). 2. E. Dresner et al., J Biol Chem 287, 40173 (Nov 23, 2012). 3. A.Pinhasov et al. & Gozes, Brain Res Dev Brain Res 144, 83 (Aug 12, 2003). 4. S. Mandel, I. Gozes, J Biol Chem 282, 34448 (Nov 23, 2007). 5. S. Mandel, G. Rechavi, I. Gozes, Dev Biol 303, 814 (Mar 15, 2007). 6. B. J. O'Roak et al., Nature 485, 246 (May 10, 2012). 7. B. J. O'Roak et al., Science 338, 1619 (Dec 21, 2012). 8. S. Mandel, I. Spivak-Pohis, I. Gozes, J Mol Neurosci 35, 127 (Jun, 2008). 9. S. Furman et al. & Gozes,

Distributed processing in rat barrel cortex revealed by improved voltage sensitive dyes detecting coherent population spikes Grinvald A. 1*, Deneux T. 1, Drangai R. 1, Hildesheim R. 1, Fekete T. 1 1 Dept. of Neurobiology, the Weizmann Institute of Science, Rehovot 76100 Israel

J Mol Neurosci

Oxygen set point regulation in the nematode Caenorhabditis elegans brain Gross. E 1,2,3*, Soltes. Z 4, Zelmanovich. V 1,2, De-Bono. M 4 1 The Hebrew Univ. of Jerusalem, Faculty of Medicine, IMRIC, Jerusalem, Israel 2Dept. of Biochemisatry and Molecular Biology 3 [email protected] 4 MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, U.K. Background: Hypoxia, caused by chronic prolonged hypoxemia, high altitude, and obstructive sleep apnea may have harmful consequences (e.g. hypertension, and neurological disorders). However, oxygen (O2) reperfusion after hypoxia may induce generation of reactive oxygen species (ROS) that can damage any biological molecule: nucleic acids, proteins, lipids, and carbohydrates. Indeed, ROS play a critical role in the pathophysiology of many human diseases such as myocardial infraction, stroke, neurodegenerative diseases and cancer. However the mechanisms involved are incompletely understood. Results: Previously we demonstrated that GLB-5 tunes the dynamic range of O2 responses close to atmospheric level in the nematode Caenorhabditis elegans. Here,we show that GLB-5 activity is essential for fast behavioral and cellularrecovery after prolonged hypoxia. In a screen for GLB-5 suppressors, weidentified PDL-1, the C. elegans homolog of mammalian PrBP/PDE6D protein,as a GLB-5 regulator. In mammals, PDE6D regulates the activity and traffic ofprenylated proteins in cells. Our results suggest that PDL-1 physically interacts with prenylated GCY-33, and GCY-35 and escorts them to the dendritic endings of URX and BAG neurons, so regulating GLB-5 activity in these neurons. Conclusions: Taken together, our findings suggest that prolonged hypoxia reconfigures the threshold for O2 responses in URX and BAG, and that GLB-5 acts torapidly retune O2 responses to normoxic level. In addition, we suggest that PDL1 regulates the traffic of GCY-33 and GCY-35 to dendritic endings, so spatially regulating O2 responses in C. elegans. The research leading to these results has received funding from the ERC Seventh Framework Programme Encapsulated human MSC secrete factors in vivo that are anti-inflammatory and promote recovery after spinal cord contusion Grumet, M 1,2,3*, Kim, J 1, Gray, A. 4, Kumar, S. 1, Babiarz, J. 1,2, Ghorbane, M. 4, Schloss, R. 4, Yarmush, M. 4 1 Keck Center for Collaborative Neuroscience, Rutgers Univ., Piscataway, NJ, USA 2Rutgers Stem Cell Research Center 3 Dept. of Cell Biology & Neuroscience 4 Biomedical Engineering, Rutgers Univ., Piscataway, NJ, USA Traumatic spinal cord injury (SCI) is followed by a period of secondary damage extending weeks to months

that results in loss of neurons, myelin, axons and oligodendrocytes from the expanded injury site. Implantation of cells including mesenchymal stromal/stem cells (MSC) promotes functional recovery after SCI in mammalian models. MSC inhibit expression of several proinflammatory cytokines in the host and upregulate antiinflammatory cytokines and growth factors that promote axon regeneration. MSC have multiple activities, many of which have been ascribed to factors they secrete while other investigators have focused on their plasticity to transdifferentiate. To focus specifically on their secreted factors, we have encapsulated human MSC (ehMSC) in alginate and examined secreted factors in vitro and in vivo. ehMSC survived for 2 months in vivo after delivery by lumbar injection in SCI rats. This minimally invasive delivery bypasses problems with other routes of MSC delivery that can vary in MSC targeting, differentiation and survival in SCI. After injection of ehMSC, we detected changes in rat gene expression by RT-PCR in tissue from the rat SCI site and in proteins in cerebrospinal fluid. The alginate capsules segregate MSC preventing direct MSC-cell contact with host immune cells. Our results suggest that factors secreted by ehMSC induce expression changes in specific genes and proteins in the SCI rat that are antiinflammatory (e.g. IL-10), and functional studies show a trend towards improved recovery. The results also indicate that ehMSC in vivo shift macrophages to a less inflammatory state (M2 vs. M1). We will also discuss ongoing studies to determine whether activation of ehMSC to secrete reduced levels of proinflammatory factors and enhanced levels of anti-inflammatory and growth factors are more potent in reducing activated macrophage inflammation in culture, and will protect tissue after SCI, resulting in improved outcomes. Supported by grants from NIH and NJCSCR. Proinflammatory cytokine tumor necrosis factor rapidly relieves voltage dependence of slow inactivation of tetrodotoxin-resistant sodium channels, leading to acute nociceptive hyperexcitability Gudes S 1,2, Binshtok A 1,2* 1 Dept. of Medical Neurobiology, IMRIC, Faculty of Medicine, The Hebrew Univ. 2ELSC, The Hebrew Univ. Background: TTX-resistant (TTX-r) sodium channels, Nav1.8 and Nav1.9, are expressed mainly by painsensing (nociceptive) neurons. These channels have been found to be the main targets for pro-inflammatory mediators, therefore, they are central to the production of hyperexcitability leading to inflammatory pain. Proinflammatory mediators, such as proinflammatory cytokines affect the quantity of TTX-r channels and modulate their gating

J Mol Neurosci

kinetics, indirectly, via activation of secondary mediators such as cyclooxygenase and nerve growth factors. This in turn leads to, delayed-onset sensitization of nociceptors. However, inflammatory pain occurs immediately. Here we have studied the mechanism underlying the acute effect of the prototypic proinflammatory cytokine TNFα on TTX-r sodium channels, neuronal excitability and pain hypersensitivity. Results: We found that TNFα leads to acute cyclooxygenaseindependent increase in pain sensitivity of adult rats in-vivo. We also found that, TNFα produces a robust increase in TTXr-dependent excitability of nociceptor-like cultured rat neurons, shortly after application. We demonstrated that TNFα acts via activation of p38 mitogen activated protein kinase (p38 MAPK), to rapidly relieve TTX-r sodium channels' resting slow inactivation. This leads to increase in TTX-resistant sodium current. Moreover, we found that pharmacological enhancement of slow inactivation reversed the TNFα-mediated enhancement of TTX-r sodium current, eliminated TNFα-mediated nociceptive hyperexcitability and selectively abolished acute TNFα-mediated pain hypersensitivity. Conclusions: Our results suggest that TNFα, rapidly activates and sensitizes nociceptive neurons, which leads to acute pain hypersensitivity, by releiving slow inactivation of TTX-r sodium channels . Pharmacological enhancement of slow inactivation, shortly after injury, could be beneficial in treating acute inflammatory pain, without affecting the inflammationdependent healing. The research leading to these results has received funding from the European Research Council ERC Distributed coding in the trigeminal system Gugig E 1, Lottem E 1, Azouz R* 1 Dept of Physiology and Cell Biology, Ben Gurion Univ. of the Negev Untangling the neural code underlying sensory perception requires the mapping of physical stimulus parameters to neuronal responses. The speed by which rodents discriminate between tactile stimuli, and neuronal response reliability in the whisker somatosensory system suggest that temporal coding might be used to encode sensory stimuli. The interaction between whiskers and object surfaces induces a complex temporal pattern of whisker vibration which may carry important tactile information. To determine the temporal kinetic features of whisker motion that are represented by first-order sensory neurons, we recorded from trigeminal ganglion neurons (TG) during stimulation with complex pattern of whisker vibration. We find that each of the different TG mechanoreceptor subtypes transmits the position, velocity and acceleration of whisker vibrations, By using, already established, mechanoelectrical model of the receptor- follicle complex

we were able to establish the mechanisms underlying the diversity of these distinct kinetic feature selectivity. To determine what the follicle tells the rest of the brain, we measure responses of numerous TG neurons to different directions. We find that direction selectivity is stimulus-dependent and that kinetic feature selectivity is direction biased. Our results suggest that TG neurons transmit a distributed representation of whisker motion, based on tactile kinetic features, which are influenced by a small set of mechanical parameters, and the direction of whisker movement. Long-term social recognition memory of rats is mediated by protein synthesis and Oxytocin - dependent LTD in the medial amygdala Gur R 1, Wagner S 1* 1 The Joseph Sagol Dept. of Neurobiology, Faculty of Natural Sciences, Univ. of Haifa, Israel The ability to remember and recognize specific individuals is fundamental to mammalian social behavior, especially for the establishment of social structures such as family, pack or clan. Most mammals largely rely on olfaction for social recognition, using the main (MOS) and accessory (AOS) olfactory systems, both projecting to the medial amygdala (MeA). Several lines of evidence indicate that the MeA is involved in social recognition memory (SRM), and that oxytocin activity in this area is crucial for this type of memory. Yet, the role of the MeA in SRM acquisition is unknown.In the presented study we first used a modified social discrimination task to demonstrate that adult male rats do show short- (30 min) as well as long-term (>24h) SRM. We then examined the dependence of SRM on protein synthesis in the MeA by local application of anisomycin during SRM acquisition. This treatment completely blocked long-term SRM, while leaving shortterm SRM intact.We then validated the susceptibility of MeA neurons to long-term synaptic plasticity using theta burst stimulation (TBS) in the AOB to induce long-term changes at the AOB-MeA synaptic pathway in vivo. Surprisingly, we found that MeA neurons underwent long-term depression (LTD) following this type of stimulation, widely used for LTP induction. Moreover, intraventricular administration of oxytocin before TBS significantly enhanced LTD induction, which was blocked by oxytocin antagonist. Conversely, oxytocin injection without TBS caused gradual increase in the synaptic strength. Finally, we examined the influence of LTD induction on long-term SRM and found that rats that received TBS just before the behavioral paradigm failed to remember the social stimulus 24 h later.Altogether, our results indicate that protein synthesis in the MeA is required for the acquisition of long-term SRM and that oxytocin-enhanced LTD in the AOB-MeA synaptic pathway is crucial for this memory.

J Mol Neurosci

Anatomical MRI findings in autism are likely to be of low clinical and scientific significance Haar S. 1,2, Berman S. 3,2, Behrmann M. 4, Dinstein I. 5,1,2* 1 Dept. of Brain and Cognitive Sciences, Ben Gurion Univ. of the Negev, Beer Sheva, Israel 2 Zlotowski Center for Neuroscience, Ben Gurion Univ. of the Negev, Beer Sheva, Israel 3 Dept. of Industrial Engineering and Management, Ben Gurion Univ. of the Negev, Beer Sheva 4 Dept. of Psychology, Carnegie Mellon Univ., Pittsburgh, PA, USA 5 Dept. of Psychology, Ben Gurion Univ. of the Negev, Beer Sheva, Israel Previous studies with small samples have reported that individuals with autism spectrum disorders (ASD) exhibit numerous anatomical brain abnormalities when compared with controls. The recent release of the Autism Brain Imaging Data Exchange (ABIDE, >1000 participants, ages 6-65) offers an important opportunity to perform more definitive large-scale comparisons between ASD and control individuals who span a wide range of IQ scores, ages, and symptom severities. Anatomical Magnetic Resonance Imaging (MRI) scans of 348 male ASD participants and an equal number of age, gender, and IQ matched controls were selected for the current study. We performed comprehensive univariate and multivariate analyses using multiple volumetric, cortical thickness, and cortical surface area measures derived for each of 150+ brain areas. Significant findings were almost entirely confined to comparisons of ASD individuals with relatively severe symptoms (Autism Diagnostic Observation Schedule, ADOS > 14) and controls. Even significant differences between groups, however, were on the order of 2-4%, while between-subject differences within each group reached 80-100% for most measures. Multivariate classification analyses yielded marginal decoding accuracies of ASD and control individuals, which significantly exceeded chance levels only when classifying ASD individuals with ADOS >14 and controls. We suggest that previous reports of anatomical differences across ASD and control groups and high decoding accuracies of ASD and control individuals may have resulted from the substantial anatomical heterogeneity across individuals and the recruitment of small samples. These sobering findings suggest that measures of brain volumes, cortical thickness, and cortical surface areas are likely to be of low clinical and scientific significance for understanding the pathophysiology of children, adolescents, and adults with ASD. GABA-related gene expression alterations the hippocampus and the amygdala in response 'controllable / uncontrollable stress' in adult Hadad O. 1,2,3*, Eilat N. 2,4, Richter Levin G. 1,2,3,4 1 Neurobiology and Etiology Dept., Univ. of Haifa, Israel 2 The Brain and Behavior Research Center, Israel 3 The Institute for the Study of Affective Neuroscience (ISAN) 4 Psychology Dept., Univ. of Haifa, Israel

Brief periods of mild stress can potentiate memory formation, whereas more severe or prolonged stress can have deleterious effects upon broad aspects of cognition (McEwen and Sapolsky, 1995). The impact of a stressful event is strongly determined by its actual or apparent controllability, i.e. the perceived ability to alter the onset, duration, intensity or pattern of an aversive experience (Maier and Seligman, 1976). These mechanisms are critical for the effect of stress on emotional states and the performance in cognitive tasks. For example, uncontrollable electric foot shocks in rodents interfere with subsequent learning of operant tasks (Overmier and Seligman, 1967; Seligman and Maier, 1967). A previous study demonstrated alterations in GABAergic interneurons' related genes in hippocampal sub-regions and in the BLA following learning the water maze task (Hadad et al., in preparation). We now investigate potential alterations of expression of these genes following exposure to two-way shuttle (TWS) avoidance task. We used the TWS avoidance task in order to achieve different levels of controllability. Rats were exposed to 6 days, 50 trials each day, of controllable stress. At the end of the TWS session rats that have learned poorly were assigned to Bad Learner/uncontrollable group and rats that exhibited high rate of avoidance were considered as Good Learners/controllable. 14 days later, rats were tested in the TWS, were examined for anxiety levels (elevated plus maze) and were tested in other learning related tasks (Fear conditioning and extinction). After the behavioral tests rats were decapitated and blood and brain areas of interest were collected for analysis of alterations in GABA-related gene expression. Preliminary data suggests differences in expression which reflect the level of controllability in the TWS task. Save the global: global signal connectivity as a tool for studying clinical populations with fMRI Hahamy-Dubossarsky A 1*, Calhoun VD 2, Pearlson G 3,4, Harel M 1, Stern N 5, Attar F 5 1 Dept. of Neurobiology, Weizmann Institute of Science, Rehovot, Israel 2 Dept. of ECE, The Univ. of New Mexico & The Mind Research Network, Albuquerque, NM, USA 3Dept.s of Psychiatry and Neurobiology, Yale Univ. School of Medicine, New Haven, Connectic 4 Olin Ctr., Institute of Living, Hartford Healthcare system, Hartford, Connecticut, USA 5 Dept. of biological services, Magnetic resonance imaging unit, Weizmann Institute of Science, The global signal is defined as the average time-course over the entire brain. It is commonly removed from resting state data, since it was presumed to reflect physiological noise. However, removal of the global signal is now under debate as this signal may reflect important neuronal components, and its removal may introduce artifacts into the data. Here we show that the functional connectivity of the global signal is of functional relevance, as it differentiates between

J Mol Neurosci

schizophrenia patients and healthy controls during rest. We therefore advise against global signal removal in schizophrenia rest data, and propose a method for mapping cases where the removal of the global signal should not be implemented in clinical data. Cognitive training improves sleep quality and cognitive function among older adults with insomnia Haimov I 1*, Shatil E 1 1 Dept. of Psychology, Yezreel Academic College, Emek Yezreel, Israel Background: Insomnia is a sleep disorder frequently observed in older persons. Along with the changes in sleep structure, ageing is also associated with cognitive impairment. In view of the findings showing that sleep during the night is critical in the consolidation of previously acquired memory traces, we hypothesized that intensive new learning experience provided by systematic cognitive training will act as a catalyst to change sleep architecture and by doing so will improve sleep quality among older adults with insomnia. Furthermore, we posited that if that learning specifically targets cognitive function, older adults with insomnia will also exhibit improved cognitive performance. Thus, the present study examined the impact of cognitive training on sleep quality and cognitive performance among older adults with insomnia. Methods: 51 older adults with insomnia were randomized into two groups: a cognitive training group and an active control group. The participants in the cognitive training group completed an 8-week cognitive training program, while the participants in the active control group completed an 8-week program involving tasks that do not engage high-level cognitive functioning. Before and after training, all participants' sleep was monitored for one week and their cognitive performance was evaluated. Results: Mixed models for repeated measures analysis showed between-group improvements for the cognitive training group on both sleep quality (sleep onset latency and sleep efficiency) and cognitive performance (avoiding distractions, working memory, visual memory, general memory and naming). Moreover, hierarchical linear regressions analysis indicated correlation between the improvement in cognitive function and those in sleep quality. Conclusions: Cognitive training may be beneficial in the initiation and maintenance of sleep among older adults with insomnia. The present study constitutes pioneering work in this field among older adults with insomnia. Nitric oxide as an intercellular messenger between neurons and glial cells in sensory ganglia: implications for chronic pain Hanani, M. *, Belzer, V. Experimental Surgery, Hadassah-Hebrew Univ. Medical Center,Mount Scopus, Jerusalem

Background: Nitric oxide (NO) is well known to be a modulator of neuronal excitability, but its role in chronic pain is controversial. Neurons in sensory ganglia release NO, and we asked how NO acts as a messenger between neurons and satellite glial cells (SGCs) in dorsal root ganglia (DRG) of mice. Results: Dye coupling between SGCs was examined by intracellular injection of Lucifer yellow (LY), and SGC activation was assessed by immunostaing for glial fibrillary acidic protein (GFAP). Electrical excitability of DRG neurons was evaluated using intracellular recording. Ten days after induction of colitis with dinitrobenzoate sulfonate (DNBS), we found that both neuronal excitability and dye coupling between SGCs in S1 DRG significantly increased. This increase was completely reversed by NO synthase (NOS) inhibitor, Nω-nitro-L-arginine methyl ester (L-NAME) and promoted by the NO donor sodium nitroprusside (SNP). Both in vivo inflammation and in vitro SNP upregulated GFAP in SGC, indicating glial activation. In addition, SNP increased both neuronal excitability and dye coupling among SGCs after a long-term (>1 h) in-vitro incubation in DRG from untreated mice. Similarly, 8-bromo-cGMP, an analogue of cGMP, increased dye coupling between SGCs. Conclusions: These findings show that the colitis-induced changes in DRG are at least partly due to increased NO production, apparently by the neurons, which acts on SGCs via the NO-cGMP pathway. The activation of SGC, in turn, contributes to augmented neuronal excitability, which is a major factor in chronic pain. Supported by ISF (311/07, 508/13), BSF (2011044), and EU 7th Program (EduGLIA) Mapping brain networks in awake mice using intrinsic functional connectivity MRI Harari E. 1, Bershadsky G. 1, Kahn I. 1* 1 Rappaport Faculty of Medicine. Technion – Israel Institute of Technology Background: Intrinsic functional connectivity MRI (fcMRI) is widely used for mapping neural networks in the human brain in health and disease. However, its precise neural origin and relation to anatomical connections and stimulus-evoked functional responses and connectivity is yet to be fully determined. A challenge in studying intrinsic functional connectivity in mice using MRI is the need to avoid the use of anesthesia which results in an attenuated fMRI signal limiting the signalto-noise at high resolution and the translation of results obtained in animals to human fMRI studies. Here, we present an experimental setup for fcMRI studies in awake mice and compare the results to known anatomical connections and stimulus-evoked functional responses and connectivity. Results: Seed-based analysis of the somatosensory network with seeds localized in the primary somatosensory cortex

J Mol Neurosci

(SI) yielded maps that included secondary somatosensory cortex, superior colliculus, primary motor cortex, caudateputamen and ventral postero-medial nucleus of the thalamus. These maps were also consistent with functional connectivity maps resulting from deflection of the mystacial vibrissae (whiskers) and prior results obtained in our lab using optogenetic drive of SI. Conclusions: Our results demonstrate close relation between intrinsic and stimulus-related functional connectivity and anatomical connections in the mouse primary somatosensory cortex. These findings are consistent with recent evidence for close agreement between anatomical connectivity, electrophysiological responses and functional connectivity in local and large-scale networks in the primate somatosensory cortex. This approach lays the foundation for longitudinal mapping of brain networks in awake mice which will enable characterization of development and plasticity in the healthy brain as well as conditions of disrupted neural development and neurodegeneration. Innovative multi functional drug approach for the treatment of TBI Harel A. 1* 1 Medicortex USA Ltd. Traumatic brain injury (TBI) is one of the main causes of mortality among military personnel, children, young adults and athletes. Background: TBI is manifested by early events and delayed secondary alterations. The latter include: mitochondrial dysfunction, lipid degradation and peroxidation and blood-brain barrier (BBB) disruption. This is followed by raised intracellular calcium influx and activation of proteases, resulting in axonal swelling, disconnection and degeneration. Pro-inflammatory factors are produced and secreted by local and infiltrated immune system cells, promoting the development of the inflammatory process. This series of events results in various neurological deficits. Over the past decade, many clinical trials testing drugs for TBI have been conducted but failed to show significance attheir primary endpoint. Since the degenerative process is mediated by multiplebiological reactions, agents that target a single pathway are ineffective.Therefore, an intervention that simultaneously targets multiple factors shouldbe more effective in halting the secondary degeneration. Medicortex USA Ltd.presents a novel family of NCEs that cross the BBB, each possessing apenetrating head with a chemical spacer and two or more of the followingproperties: binding of free metal ions, antioxidation, anti-inflammation,and/or anti-bacterial. The lead compounds will be selected according to theirsolubility, stability and toxicity. In vitro and in vivo studies will be conducted in order to explore the efficacy of the molecules as neuroprotective agents under different insults and to attenuate neural damage, utilizing animal models of cortical impact

braininjury. Conclusions :Taken together, Medicortex's multi-functional drug agents will target biochemical pathways occurring at different time points post-injury,thereby attenuating and even preventing secondary TBI-associated neurologicaldysfunction and neuronal cell death. Receptive-Field like models accurately predict individual zebrafish behavior in a group Harpaz R. 1, Schneidman E. 1* 1 Dept. of Neurobiology, Weizmann Institute of Science, Israel Understanding the ability of groups of organisms to perform synchronized and collective actions is an important challenge for the neural and behavioral sciences. We studied group behavior of adult zebrafish in a controlled laboratory environment, and used fast video recording and automatic tracking to reconstruct the trajectories of individual fish and obtain a quantitative description of their swimming behavior. To characterize collective motion in these groups, we modelled the directional response of a single individual based on a "receptive field" model of its surrounding, where the space around a specific fish was parameterized according to the distance and angle from that fish. Specifically, the velocity of a fish was predicted by the model according to the weighted sum of the velocities of the other fish in the parameterized space around that fish. The predictions of these models show very high agreement with actual fish swimming behavior at a single point in time. Extending the models to include the weighting of sensory information, in this case the distance to arena walls, further improved prediction accuracy. This approach proved to be significantly more accurate than previous theoretical assumptions regarding fish interactions (metric and topological models). Establishing accurate models of zebrafish interactions would be imperative for future studies of the neural and genetic control of group behavior and decision making. Effects of temporal interactions on perceptual learning’s dynamics and transfer Harris H 1*, Sagi D 1 1 Dept. of Neurobiology, Brain Research, The Weizmann Institute of Science, Rehovot, Israel Background: In perceptual learning (PL) repetition-based training is typically applied, resulting in improved sensitivity. Temporal correlations across trials and over different time scales are essential for PL to occur. However their contribution to learning is not clear. Here we study the effect of temporal correlation on PL using the texture-discrimination paradigm with Stimulus Onset Asynchrony (SOA) controlling observers' performance level. We focused on testing temporal interactions and their consequences on learning in either early or late phases of learning. In order to target pattern correlations

J Mol Neurosci

we interleaved 'dummy' trials, previously found to reduce inter-trials adaptive processes. To target signal-strength correlations we compared learning with SOA gradually reduced within a session (high correlation) to learning with randomized SOA (weaker correlations). Additionally, to modulate correlations at the early phase of learning we manipulated temporal correlations during a pre training phase by reducing the number of correlated trials (from 'stable' to 'minimal'). Three thresholds: initial and final training (target at 1st location) and initial transfer (target at 2nd location) were measured using random SOA for all groups. Results: (1) the 'minimal' procedure generated higher initial thresholds and was followed by location-specific learning in all conditions; (2) The 'stable' group, had a reduced learning rate with gradual SOA as compared with random SOA, but a similar transfer pattern, showing transfer in the presence of 'dummy' trials and specificity in their absence. Conclusions: Increased temporal correlations at the early phase of learning promotes efficient (better initial performance, increased learning rate) and generalizable PL, while presence of correlations at a later phase of learning slows down learning and makes it specific. Supported by the Israel Science Foundation (ISF). H.H is supported by the Azrieli Foundation. Dynamics and underlying factors of social foraging strategy choice in the Egyptian fruit bat Harten L. 1*, Navon H. 1, Yovel Y. 1 1 Dept. of Zoology, Tel-Aviv Univ., Tel-Aviv Introduction: Behavioural strategies used by animals to gain access to valued resources, often differ, with exploitation of others' behavioral efforts being particularly widespread. Barnard and Sibly (1981) coined the terms ''Producer'' and ''Scrounger'' to represent strategies that correspond to investing in making a resource available and exploiting another's effort, respectively. We examined social foraging strategies in the Egyptian fruit bat, looking into the temporal dynamics, underlying factors influencing strategy choice and flexibility. Bats are among the most social mammals, living in extremely complex social environments. Despite this however, very little is known about their social behaviour. We studied 20 individuals over a full year observing thousands of social interactions. Results: We reveal that fruit bats show a distinct tendency towards either producing or scrounging. Strategies usually corresponded to sex, with males being largely producers and females scroungers but bats proved to be flexible, shifting their foraging strategy when needed: (1) Females exhibited a rise in producing rates shortly after gestation, followed by a decrease post weaning. (2) When manipulating producer-toscrounger ratios in small groups of four bats, scroungers alone

exhibited flexibility in foraging strategy, showing a gradual increase in producing rates. In any given group of four at least two producers emerged, regardless of group member's initial strategy preference. Conclusions: Examining changes in social behavior over time and across social settings can elucidate drivers and functions of social organization. Results show for the first time that different foraging strategies, which depend on social context and physiology, exist in bats. Producer-scrounger dynamics seem to be driven by social factors in addition to nutritional demands. In accordance, scroungers tend to consistently scrounge on specific producers generating a complex social network. Activity and connectivity of C. elegans locomotion network Haspel G. 1* 1 Biological Sciences, New Jersey Institute of Technology Locomotion acts as the common output pathway for the majority of the behaviors studied in C. elegans, including foraging, escape, entry and emergence from quiescence, aspects of mating and thermo- chemo- and klinotaxis. The undulatory motor output is produced by a concise neuromuscular network consisted of 75 identifiable excitatory and inhibitory motoneurons and 75 muscle cells. However, the cellular and neuronal mechanisms that underlie the generation and propagation of undulations are still unclear. Furthermore, the synaptic connectivity data that exist for this network is partial and originates from a single animal. To overcome the gap in connectivity data, we constructed a model of the connectivity that span the length of the animal by extrapolating connectivity pattern in the existing data. Furthermore, we are currently using Serial Block-face Scanning Electron Microcopy to collect new connectivity data from multiple animals. Such data will allow not only to test the predictions made by our connectivity model and to fill in the missing gap but also to provide new insight about variability and co-variability of connectivity. To address the network activity, we use optical recording (optophysiology) and stimulation (optogenetics) via genetically encoded indicators and photoactivated channels. We used genetically encoded calcium indicators to demonstrate that some classes of motoneurons are dedicated to forward locomotion while others are dedicated to backward locomotion or both. Hence, two motoneuronal networks are overlaid, each dedicated to a direction of locomotion. We use the connectivity model to interpret these results. Connectomics: the dense reconstruction of neuronal circuits Helmstaedter M. Structure of Neocortical Circuits Group, Max Planck Institute of Neurobiology, Am Klopferspitz 18, 82152 MunichMartinsried, Germany

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The mapping of neuronal connectivity is one of the main challenges in neuroscience. Only with the knowledge of wiring diagrams is it possible to understand the computational capacities of neuronal networks, both in the sensory periphery, and especially in the mammalian cerebral cortex. Statistical circuit mapping using a combination of paired intracellular recordings and anatomical reconstructions has provided insight into the connectivity between populations of cells. To move beyond pairwise connectivity statistics, however, dense circuit mapping is required. Our methods for dense circuit mapping are based on 3-dimensional electron microscopy (EM) imaging of tissue, which allows imaging nerve tissue at nanometer-scale resolution across substantial volumes (typically hundreds of micrometers per spatial dimension) using Serial Block-Face Scanning Electron Microscopy (SBEM). The most time-consuming aspect of circuit mapping, however, is image analysis; analysis time far exceeds the time needed to acquire the data. Therefore, we developed methods to make circuit reconstruction feasible by increasing analysis speed and accuracy, using a combination of crowd sourcing and machine learning. We have applied these methods to circuits in the mouse retina, mapping the complete connectivity graph between almost a thousand neurons, and we are currently improving these methods for the application to neuronal circuits in the neocortex. References: Helmstaedter M, Briggman KL, Turaga S, Jain V, Seung HS, Denk W (2013) Connectomic reconstruction of the inner plexiform layer in the mouse retina. Nature 500:168-174 Helmstaedter M (2013) Cellular-resolution connectomics: challenges of dense neural circuit reconstruction. Nat Methods 10:501-7. Denk W, Briggman KL, Helmstaedter M (2012) Structural Neurobiology: Missing link to a mechanistic understanding of neural computation. Nat. Rev. Neuroscience 13:351-358. Briggman KL, Helmstaedter M, Denk W (2011) Wiring specificity in the direction-selectivity circuit of the retina. Nature 471:183-188. Helmstaedter M, Briggman KL, Denk W (2011) High-accuracy neurite reconstruction for high-throughput neuroanatomy. Nat Neurosci 14:1081-1088. Diffusion MRI study of cortical plasticity induced by a short linguistic task Hofstetter S 1*, Friedmann N 1,2, Assaf Y 1 1 Sagol School of Neuroscience Tel Aviv Univ. 2 School of Education Tel Aviv Univ. MRI studies of cortical plasticity showed morphometric alternation in cortical density after long term training of weeks to months. A recent DTI study found changes in diffusion indices after 2 hour training, suggesting a more rapid timescale of neuroplasticity. However, whether a short learning experience can induce microstructural changes in the neocortex is still unclear. Furthermore, in order to detect changes in the neocortex a higher scanning resolution is needed. Here we used

diffusion MRI, a sensitive method of tissue's microstructure, to study cortical plasticity. In order to attain cortical involvement we used a short language task (under 1 hour). 15 adult participants learned new words in their native language (20 unfamiliar flowers names), and were scanned before and after the task. Scanning protocol included DTI, CHARMED and SPGR. Voxel-based statistical analysis was restricted to specific regions in the left hemisphere related to the task. Subjects showed continuous improvement in the learning task, indicating an aptitude of rapidly learning a language task. Increase in MD was found in the hippocampus and STG. L1 significantly increased in the STG cluster, and RD was increased in the hippocampus. Decrease in FA was found in the fusiform gyrus and IFG. Significant increase was shown in RD in the IFG. FR decrease was also found in the same cluster as the FA though with a less restricted p values. Results show a first indication of cortical plasticity in the human brain after a short language learning task of introducing new lexical items to the lexicons. Using diffusion MRI we were able to detect changes in regions involved in language and reading. It seems that short training of less than an hour of high cognitive demand can induce microstructural changes in the cortex, suggesting a rapid time scale of neuroplasticity and providing additional evidence of the power of MRI to investigate the temporal and spatial progress of this process. dPAG priming differentially modulates plasticity in the BLA and the NAcc, under controllable and uncontrollable stressful conditions Horovitz, O. 1,2, Richter-Levin, A. 2,3, Richter-Levin, G. 1,2,3,4* 1 The Brain and Behavior Laboratory, Israel 2 The Institute for the Study of Affective Neuroscience (ISAN) 3 Neurobiology and Etiology Dept., Univ. of Haifa, Israel 4Psychology Dept., Univ. of Haifa, Israel The degree of behavioral control that an organism has over a stressor critically determines the behavioral and neurochemical consequences of that experience (Rozeske et al., 2011; Seligman and Beagley, 1975). A circuit which involves the vSub, the BLA and the NAcc, may reflect negative and positive aspects of affective experiences (Panksepp, 1998), including stressful behavioral control. Additionally, midbrain structures (i.e. dPAG) are known to have the ability of interfering or inhibiting other structures (De Oca et al., 1998). We have previously shown that simultaneous activity, plasticity and modulation of such active-defense and reward brain pathways in relation to previous dPAG priming is indeed evident (Kim et al., 2103). It was found that while vSub HFS resulted in LTP simultaneously in both the BLA and the NAcc, priming the dPAG induced differential effects on plasticity in these regions. Since 'controllability' was previously found to differentially activate negative and positive brain-related regions (e.g. BLA: Ilin and Richter-Levin, 2009; NAcc: Bland et al.,

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2003), the current study tested for possible reflection of the observed priming-induced plasticity changes in controllable and uncontrollable rats. Under vSub HFS, LTP was evident in both controllable and uncontrollable rats although controllable rats exhibited significantly higher % changes in LTP compared to uncontrollable and Naïve rats. Priming resulted in LTP only in controllable and Naïve rats, whereas uncontrollable rats failed to achieve LTP. Moreover, stimulation protocols induced plastic changes which were significantly and differently correlated with the contextual test conducted two weeks following learning in controllable and uncontrollable rats. The results demonstrate that dPAG differential modulation of plasticity in the BLA and NAcc is sensitive to the controllability level over the stressor and may contribute to the differential outcome of such stress experiences. to the HDRF Megf10-mediated clearance of apoptotic cells by astrocytes in the CNS Iram T. 1,2, Frenkel D. 1,2, El Khoury J. 3* 1 Dept. of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv Univ., Tel Aviv 2 Sagol School of Neuroscience, Tel Aviv Univ., Tel Aviv 699788, Israel 3 Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy,and Immunolog Background: Efficient phagocytic clearance of apoptotic cells in the central nervous system (CNS) is necessary to avoid toxicity and auto-immunity. Astrocytes, the most abundant cells in the brain, were shown to take part in debris clearance and tissue repair in physiological conditions, and also in several brain pathologies such as Alzheimer's disease. Extensive work has been done on the clearance of apoptotic cells in Caenorhabditis elegans and Drosophila and several receptors such as cell death abnormality protein 1(CED-1) and Draper have been identified. Multiple EGF-like domains 10 (Megf10) is a type-I receptor that consists of all the structural features of CED-1 and Draper, positioning it as a high-potential candidate for a mammalian CED-1 homologue. Astrocytes are highly enriched with the CED family phagocytic-pathways genes, especially with Megf10. We investigated whether Megf10 is an essential receptor for clearance of apoptotic cells by astrocytes during development and in the adult brain. Methods: To study the function of Megf10 as an engulfment receptor in-vivo we generated a Megf10 knockout mouse and analyzed its pathology at the behavioral, cellular and molecular level. Specifically, to better understand the importance of Megf10 in apoptotic-cells clearance we focused on post natal day-7 (PND-7), a developmental stage with high naturally occurring apoptosis in the cerebellum.

Results and Conclusions: Megf10-KO adult mice had smaller brains and demonstrated motor dysfunction in the Open Field test. Furthermore, we found that PND-7 Megf10-KO had higher levels of apoptotic cells in the cerebellum, indicating a defect in clearance of apoptotic cells. Astrocytes purified from Megf10-Het and Megf10-KO brains showed 50% reduction in apoptotic-cells phagocytosis assays compared to astrocytes from WT mice. These findings indicate that Megf10 plays an important role in astrocyte-mediated clearance of apoptotic cells in the developing cerebellum. Alzheimer's association NIRG grant Associations between cognitive flexibility and PTSD symptoms in individuals with repeated exposure to traumatic events Shapiro A.1, Keri S.2, Israeli K.1, Richter-Levin G.1, Levy-Gigi E.1,* 1 The institute for the Study of Affective Neuroscience, Univ. of Haifa, Israel 2 National Psychiatry Center, 2 Budapest, Hungary Associations Between Cognitive Flexibility and PTSD Symptoms in Individuals with Repeated Exposure to Traumatic Events Alla R. Shapiro, Szabolcs Keri2, Keren Israeli1, Gal Richter-Levin1, Einat Levy-Gigi1.2 1 The institute for the Study of Affective Neuroscience, Univ. of Haifa, Israel 2 National Psychiatry Center, Budapest, Hungary * Presenter As part of their daily occupational routine active duty firefighters in Israel attend to various emergency incidents, and thus they are repeatedly exposed to traumatic events and are in a potential risk to develop PTSD. However, while several studies involving firefighters found a positive correlation between exposure time, commonly defined as the number of years in service, and posttraumatic stress symptoms other studies failed to find such direct effects. These results suggest that although exposure time might have some role in the risk of developing PTSD there are other factors which moderate its effect. One possible moderator between exposure time and PTSD symptoms is cognitive flexibility. Previous studies in our lab showed that individuals with PTSD have impaired cognitive flexibility. More specifically, they have a deficit in the ability to appropriately update and modify their response strategies according to the contextual demands. The aim of the present study is to test whether there are connections between levels of PTSD symptoms, exposure time to trauma and cognitive flexibility. We tested 80 active duty firefighters on two cognitive tasks that measure the ability to react in accordance to the context. Participants were at different stages of their service and with various levels of exposure to traumatic events. PSTD symptoms were assessed using a structured clinical interview (SCID–NP–PTSD). We found that individuals with impaired cognitive flexibility were more prone to suffer from PTSD symptoms across time.

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Attention load during early development and its behavioral and neurobiological effects in adulthood Itay Hadas 1*, Lihi Bokovza 1, Avraham Zangen 1 1 Life Sciences Dept., Ben Gurion Univ. of the Negev, BeerSheva, Israel Attentional functions are known to change during the life of an animal, yet these changes remain poorly understood. More specifically, it is unclear whether the attentional system could be altered by an attention-straining early experiences, and ultimately impact its function in adulthood. Here we demonstrate the plastic nature of attentional functions during early development. We show that exposing rats to an attention-engaging nonecological environment during a presumed critical developmental window changes performance accuracy in attention-stringent tasks and influences the degree of neuronal plasticity of attention-related brain systems in adulthood. Specifically, we show that, rats exposed to a continuous regimen of changing and salient olfactory stimuli during early development, acquire the five choice serial reaction time task (5-CSRTT) similarly to control, yet found to be more distractible. This is correlated with nucleus accumbens, cingulate cortex and hippocampal BDNF levels (a marker for neuronal plasticity), implying a possible primary cause for attention-related disorders in humans as well. Formation of pathologic oligomers in SBMA Jochum, T. 1*, Brinkmann, F. 2, Ritz, ME 3, Bauer, M 1, Moss, DA 4, Cato, ACB 3 1 Laboratory of the Application of Synchrotron Radiation, Karlsruhe Institute of Technology 2Institute for Nanotechnology Karlsruhe Institute of Technology 3 Institute for Toxicology and Genetics Karlsruhe Institute of Technology 4 ANKA Synchrotron, Karlsruhe Institute of Technology Aggregation of the androgen receptor (AR) with a polyglutamine (polyQ) stretch amplification (>38) is thought to be toxic and the causative agent of the neurodegenerative disorder spinal and bulbar muscular atrophy (SBMA). The role of protein aggregation in this disease pathogenesis is however controversial. It is unclear whether toxicity of this expanded polyQ protein results from the presence of visible aggregates or from smaller intermediary species generated during the aggregation process. It is likely that the visible aggregates merely represent endproducts of upstream toxic events. In this study, we have used atomic force microscopy (AFM) to visualize and to analyze different nanometer scale aggregates formed by androgen receptor mutants and to relate these to the toxic effects of the receptors when expressed in the motoneurons of Drosophila. For the AFM studies, we have used a baculovirus-insect cell expression system to produce full-length AR containing polyQ stretch amplifications or distinct mutations outside the polyQ stretch. For the toxicity studies, we have scored for survival and locomotor deficits of transgenic larvae as well as morphological

defects at the neuromuscular junctions following expression of the receptors in the motoneurons of Drosophila. Our results show that all the AR mutants that are toxic in the Drosophila model form similar oligomeric structures. These are fibrils made up of oligomers that reach sizes of between 300-600nm in length. These structures are clearly different from globular aggregates mainly of 120-180nm in diameter formed by the nontoxic receptors. Melatonin, a chemical modifier that reduces toxicity, affected the nature and structure of the toxic aggregates. Thus, we have established a system for the identification of a potentially toxic component in the aggregation process. Young Investigator Network, KIT Molecular changes in a model for spontaneous fluctuations of manic-and depressive- like behavior Jukic M. 1, Avin A. 1, Bar M. 1, Baron T. 1, Zega K. 1, Novikov O. 1, Jovanovic V 1, Tarasiuk A. 1, Agam G. 2, Kofman O. 3, Brodski C. 1* 1 Dept. of Physiology and Cell Biology, Ben Gurion Univ. of the Negev, Israel 2 Dept. of Biochemistry, Ben Gurion Univ. of the Negev, Israel 3 Dept. of Psychology, Ben Gurion Univ. of the Negev, Israel The molecular mechanism underlying mood instability, uncorrelated to apparent external events, is poorly understood. Fluctuations in manic and depressive behaviors, often independent of obvious exogenous triggers; play a critical role in bipolar disorder. A major obstacle preventing progress in our understanding of this phenomenon has been the lack of appropriate animal models. Previously, we demonstrated that the transcription factor Otx2, also suggested as a susceptibility gene for bipolar disorder; orchestrates the development of monoaminergic neurons. Here, we use mouse mutants overexpressing Otx2 to study endogenous fluctuations in manic- and depressive-like behavior. We found that Otx2 mutants show spontaneously alternating periods of hyperactivity and reduced activity in their home cage. Repeated measurements in the open field demonstrated increased intra-individual fluctuations over time in locomotor activity, habituation and different risk-taking behavioral parameters in Otx2 mutants. Otx2 mutants showed increased intraindividual changes in sweet preference in sugar preference test, used as a measure for hedonic-like behavior. Lithium, carbamazepine and olanzapine, which are used in the treatment of bipolar disorder, reverse behavioral alterations. Using ELISA we found significant increases in interleukin production specifically in prefrontal cortex of mutants and not in the hippocampus or hypothalamus. In addition, we complemented these studies using quantitative real time PCR. We conclude that Otx2 is critical to maintain intra-individual behavioural stability. In addition we suggest that a dysfunction of Otx2 is involved in intra-individual behavioral fluctuations found in bipolar disorder by altering normal monoaminergic neurotransmission.

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NIPI (grant 209-11-12 to C. B.) and Ministry of Health (grant 3-7433 to C.B.) The nasal cycle: functional neural asymmetry reflected in the nose Kahana R. 1*, Eisen A. 1, Korisky U. 1, Grossman S. 1, Weissbrod A. 1, Plotkin A. 1, Serfaty C. 2,3, Soroker N. 2,3, Sobel N. 1 1 Dept. of Neurobiology, The Weizmann Institute of Science 2 Loewenstein Rehabilitation Hospital 3 Sackler Faculty of Medicine, Tel Aviv Univ. Airflow through the nasal passages is asymmetric. The dominant nostril alternates along a cycle termed the nasal cycle (NC). NC is regulated by the autonomic nervous system, through sympathetic and parasympathetic dominance. It was previously hypothesized that nasal changing airflow correlates with concomitant changes in brain hemisphere activation and function. We set out to ask whether nostril dominance is correlated with cognitive task performance. 23 healthy subjects performed verbal tasks (left-hemisphere-dependent) and spatial tasks (righthemisphere-dependent) while nasal airflow was recorded. Moreover, we asked whether brain damage is manifested in nostril dominance. Therefore we recruited two groups of post-CVA patients: 1) Patients with R. hemisphere damage, exhibiting spatial neglect symptoms and 2) Patients with L. hemisphere damage exhibiting aphasia. While healthy subjects showed an ipsi-lateral correlation between brain activity and nostril dominance (Denoted by Air Distribution Ratio R/(R+L) correlation coefficient=ADR-r)(spatial ADR-r=0.07, verbal ADR-r=-0.1, F(1,22)=5.08, p<0.04), preliminary patients' results showed a different trend: Patient with R. hemisphere damage showed a contra-lateral relation (n=1, spatial ADR-r=-0.58 t(22)=10.12, p<0.001, verbal ADR-r=0.09, t(22)=3.05 p<0.01). Patient with L. hemisphere damage showed even more intriguing results: verbal tasks, occupying the damaged hemisphere, showed contra-lateral relation (n=1, ADR-r=0.12, t(22)=2.46 p<0.05) but spatial tasks, occupying the intact hemisphere, did not differ from healthy subjects (ADR-r=0.03, t(22)=0.2 n.s.) To conclude seems that nostril dominance is correlated with brain activity in healthy subjects in an ipsi-lateral manner. i.e. nostril dominance is driven leftward during verbal tasks and rightward during spatial tasks. In addition, nostril dominance tendency during cognitive task performance may serve as an indicator of lateral brain damage. Proteome changes in host’s brain behind the parasitoid Wasp manipulation Kaiser M. 1*, Biron D. 2,3, Libersat F. 4 1 Dept. of Life Sciences, Ben Gurion Uni., Beer Sheva, Israel 2 Clermont Université, Université Blaise Pascal, ClermontFerrand, France 3 CNRS, UMR 6023, LMGE, F-63177 Aubiere, France 4 Dept. of Life Sciences, Ben Gurion Univ., Beer Sheva, Israel

Background: Cockroaches (Periplaneta americana) can fall victim to the parasitoid Jewel Wasp (Ampulex compressa) which uses them as food supply for its larva. The wasp stings the cockroach and injects a venom cocktail directly inside the CNS (central nervous system). The venom does not paralyze the cockroach. Instead, the venom alters its behavior. The cockroach is turned, metaphorically, into a submissive 'zombie': it enters a long-lasting hypokinetic state. The intoxicated cockroach follows the wasp submissively to its nest, demonstrating a completely normal walking pattern. The wasp then lays an egg on the lethargic cockroach. The larva that will hatch from the egg will have accessible fresh food needed for developing into an adult wasp. The goal of our current research is to uncover the molecular mechanism which underlies this unique parasite manipulation strategy. Results: As a first step, we examined the differential expression of the CNS proteome of P. americana for two treatments: (i) stung and (ii) not-stung (control) cockroach by A. compressa. Proteins were extracted from the two treatments and analyzed by using 1D and 2D gel electrophoresis. From those results we build a proteome profile for each treatment and compared between them. Using 1D/2D gels analysis software, we were able to identify spots which are significantly different between both groups. The proteins marked by those spots will be identified by Mass Spectrometry (MS/MS). Conclusions: Revealing the proteomics changes caused by the wasp's venom is a first step in understanding the molecular mechanism behind the host manipulation. Proteins can then be extracted and their mass and amino acid sequence can be determined via mass-spectrophotometry and aligned against available databases. Using such technique, we hope to identify the molecular targets of the venom components in the cockroach cerebral ganglia. This work is currently supported by the Israel Academy of Sciences and Humanities (1181/11). The interaction between emotional stimuli and attentional control in healthy and anxious individuals Kalanthroff E.1, Usher M 2*, Henik A.1 1 Dept. of Psychology and the Zlotowski Center for Neuroscience, Ben-Gurion Univ. of the Negev2 School of Psychology and Sagol School of Neuroscience, Tel Aviv Univ., Tel Aviv, Israel. Background: The Stroop effect consist of two conflict—the information conflict and the task conflict. It has been shown that emotional stimuli can modulate attentional processes and executive control, though the effect of irrelevant emotionalprime on both Stroop conflicts was not investigated before. The effect of task-irrelevant emotional stimuli on attentional control in the Stroop task was examined in a series of three experiments, in which Stroop stimuli were preceded by brief (neutral vs. aversive) picture primes on every trials;

J Mol Neurosci

emotional-prime was presented in one-third of the trials to reduce the ability to control over it; and with anxious individuals considering that emotional picture will cause higher load and be more difficult to control over. Results: We found that the effect of picture valence was minimal in the standard Stroop condition with primes preceding every Stroop stimulus, in our typical student participant population. However, clear emotional interference effects became evident in the same population when the picture prime was rare (unexpected) or when participants where characterized by high levels of trait anxiety. Further analysis of the interference pattern showed a slowdown mainly for congruent Stroop stimuli but not for neutral ones. Conclusions: The results indicate that our typical student participant could recruit executive control to filter out the taskirrelevant picture prime under the standard conditions but that this ability is fragile and can be abolished, either by the primecontingency (rare vs. frequent primes) or as a result of individual differences in trait anxiety. The results are consistent with the dual competition model, in that aversive stimuli interfere with pro-active task control resulting in increased task conflict.

Gross anatomy of the archer fish brain Karoubi N. 1, Segev R. 1* 1 Life Science Dept., Ben Gurion Univ. of the Negev

The Schwann cell-melanocyte choice and its regulation Kalcheim C. *, Nitzan, E. Dept. of Medical Neurobiology, IMRIC and ELSC, Hebrew Univ. of Jerusalem

Analysis of social behavior deficits in a rat model of autism spectrum disorders Kay M. 1, Wagner S. 1* 1 Neurobiology and ethology, Haifa Univ.

The Neural Crest is the major embryonic source of peripheral neurons, glia, Schwann cells and melanocytes (skin pigmentation). Skin melanocytes arise from two sources, either directly from neural crest progenitors or indirectly, from neural crest-derived Schwann cell precursors following colonization of peripheral nerves. The relationship between these two melanocyte populations and the factors controlling their specification remain poorly understood. Direct lineage tracing reveals that neural crest and Schwann cell progenitorderived melanocytes are differentially restricted to the epaxial (back) and hypaxial (abdominal and limb) body domains, respectively. Furthermore, while both populations are initially part of the lineage defined by the transcription factor FoxD3, hypaxial melanocytes lose Foxd3 at late stages upon separation from the nerve whereas we recently found that epaxial melanocytes segregate earlier from Foxd3-positive neural progenitors while still residing in the dorsal neural tube. Gain and loss of function experiments in avians and mice, respectively, reveal that Foxd3 is both sufficient and necessary for regulating the balance between melanocyte and Schwann cell development. In addition, Foxd3 is also sufficient to regulate the switch between neuronal and glial fates in sensory ganglia. Together, we propose that differential fate acquisition of neural crest-derived cells depends upon their progressive segregation from the Foxd3-positive lineage. Supported by ISF and DFG

Mammals show an extremely broad range of social systems and organizations, most of which demand the memorization and recognition of specific individuals. Social recognition memory (SRM) is also the basis for the wide range of emotional relationships humans tend to develop with parents, friends, foes, and lovers. SRM can be quantitatively assessed in rats or mice by their innate tendency to investigate novel conspecifics more persistently than familiar ones. Autism spectrum disorders (ASD) are a range of complex neurodevelopment disorders, characterized by social impairments, communication difficulties, and restricted, repetitive, and stereotyped patterns of behavior. The SHANK proteins (SHANK1-3) are scaffolding proteins that form a key structural part of the postsynaptic density of glutamatergic synapses . Recent human studies indicated that loss of one copy of SHANK3, occurring through deletion or mutation, causes a monogenic form of ASD with very high penetrance. The aim of this study is to explore the differences in behavior and neuronal activity between SHANK3-deficient rats, a first rat genetic model for ASD, and their wild-type (WT) littermates. The three genotypes (homozygotes, heterozygotes and WT) were analyzed using several tests of social behavior. We found no significant difference between the three genotypes in the social preference and short-term SRM tests. Nonetheless, we found a significant difference between SHANK3-deficient rats and their WT littermates in the long-term social memory

Archer fish feed on insects above water level that they knock down with a shot of water from their mouth. This exceptional ability is possible thanks to a sophisticate visual system. The archer fish is an excellent animal model for many questions in neuroscience since it can learn to distinguish between artificial targets presented on a computer monitor. Thus, the archer fish can provide the fish equivalent of a monkey or a human subject that can report psychophysical decisions and make controlled and complex experimental procedures possible. However little is known about the archer fish brain structure and anatomy. For this reason we produce a topological atlas of the archer fish brain and provide comparison with other teleost. This enables us to identify and analyze specific cerebral structures involved in vision and participating in decision making by the archer fish during predation.

J Mol Neurosci

test. Only WT rats showed a long-term SRM, reflected by a preference towards the novel social stimulus over the familiar one, while SHANK3-deficient rats did not show such a preference. We conclude that SHANK3 deficient rats show deficits in their long-term social memory. Further experiments are now performed using in vivo electrophysiology in order to correlate this deficiency with modified brain activity during social behavior. Amyloid-beta alters ongoing neuronal activity and excitability in frontal cortex Kellner V. 1, Menkes-Caspi N. 1, Beker S. 1, Stern E.A. 1,2* 1 Gonda Interdisciplinary Brain Research Center, Bar Ilan Univ., Ramat Gan, Israel 2M.I.N.D., Dept. of Neurology, Massachusetts General Hospital, Charlestown, MA., USA Background: The effects of amyloid-β (Aβ) on the activity of cortical neurons remain one of the unanswered questions in Alzheimer's Disease research. Recent studies using electroencephalography recordings and calcium imaging have shown neocortical and hippocampal hyperexcitability in mice overexpressing Aβ. However, the effects of Aβ on excitability of individual neurons in the early and advanced stages of the disease progression are still controversial. Here we measured the electrical properties of neurons in frontal cortex of APP/PS1dE9 transgenic mice. We used in vivo intracellular recording to measure the ongoing and evoked activity of pyramidal neurons and to distinguish between the effects of Aβ on intrinsic electrical properties of the neurons from those due to changes in network synaptic effects. Results and Conclusions: Evoked excitability was altered in young and old transgenic mice in a divergent manner. The young transgenic mice displayed hypoexcitability, while the old transgenic mice displayed hyperexcitability. Our results suggest that this is due to changes in intrinsic properties of the neurons in these groups. During ongoing activity, both transgenic groups showed signs of hyperexcitability, as evident by changes in firing patterns but not in firing rates. In old transgenic mice we found alterations in the duty cycle of the membrane potential. Neurons from this group had shorter Up state durations and increased failed attempts to transition to the Up state. We suggest that the effect of Aβ on ongoing activity of neurons arises from intrinsic as well as synaptic mechanisms. Funding was provided by the Legacy Heritage Bio-Medical Program of the ISF (688/10). Controlling Network Responsiveness: Constraints and Tradeoffs Keren H. 1, Marom S. 1* 1 Network Biology Laboratories, Technion – Israel Institute of Technology

Adaptive control of evoked neural activity is a long standing challenge in neuroscience, from both basic and applied science perspectives. In this work, we demonstrate the capacity to control the responsiveness of neural networks over many hours. A closed-loop circuit is constructed by implementing a generalized PID (Proportional-Integral-Derivative) algorithm that stabilizes responsiveness by realtime adjustment of stimulation input. By controlling network responsiveness for many hours, we were able to identify constraints and tradeoffs involved. The general picture that emerges is that restricting inherent response variability results in destabilization of lower, maybe underlying, network processes. The European Union Seventh Framework Program FP7 under grant agreement 269459 EEG correlates of motor learning Kerzhner M. 1, Demchenko I. 2,3, Pratt H. 4,5, Zacksenhouse M. 2,3* 1 Motorika Inc. 2 Brain-Computer Interfaces for Rehabilitation Lab. 3 Faculty of Mechanical Engineering, Technion, Israel 4 Evoked Related Potentials Lab. 5 Faculty of Medicine, Technion, Israel Background: Brain recovery following injury share similar processing with motor learning, gearingthe plastic changes towards maximizing behavioral relevant utility functions. EEGmeasurements can contribute to our understanding of neural processes underlyingmotor learning due to their excellent temporal resolution, allowing electrical brainactivity to be visualized as it is occurring. In this study we aim to identifyand characterize EEG-based markers that indicate different stages of motorlearning, while performing a motor task consisting of a sequence of four planarmovements. We hypothesize that skill acquisition will result in more efficientmotor preparation and sensory processing, which will be evidenced by experience-dependent modulation of sensory-motor cortical activity. Results: EEG signals were recorded from 10 healthy subjects, each performing 5 practice sessions of a reaching motor task. The motor task involved passing through a sequence of 4 targets, in which the last three were highly co-linear. Theeffect of practice on Movement Related Potentials (MRP) and Lateral ReadinessPotentials (LRP) at the beginning of each motor sequence and at each target alongthe movement-sequence will be presented. In particular, the effect of practice on the MRP and LRP at the third target, which is close to the line connecting the second and the final targets, will be compared to the effects at other targets, to assess co-articulation. Conclusions: The effect of practice on the MRPs and LRPs will be related to known motor learning processes such as co-

J Mol Neurosci

articulation and global planning. We thank Motorika for providing the Reo-Go for conducting the experiments.

Can EEG be used to train for modulation of activity in sub cortical areas? Keynan N. J. 1,2, Jakont G. 1,2, Gilam G. 1,2, Cohen A. 1,2, Shany O. 1,2, Meir-Hasson Y. 3, Fruchter E. 4, Intratur N. 3, Hendler T. 1,5,6,7* 1 Functional Brain Center, Wohl Institute for Advanced Imaging, Tel-Aviv Sourasky Medical Center. 2 School of Psychological Sciences Tel-Aviv Univ. 3 Blavatnik school of computer sciences, tel aviv Univ. 4 Mental Health Dept. IDF Medical Corps 5 School of Psychological Sciences, Tel-Aviv Univ. 6 Sagol School of Neuroscience, Tel-Aviv Univ. 7 Sackler Faculty of Medicine, Tel-Aviv Univ. Background: Training subjects to modulate sub-cortical areas such as the amygdala via real time (rt) fMRI NeuroFeedback (NF) has been found beneficial in the relief of stress and depressive symptoms. However the application rtfMRI has been limited by its low accessibility for bed-side use. It is from this motivation that we have developed an EEG probe of limbic activity: "the amygdala electrical fingerprint" (EFP). Development of the EFP was done using simultaneous EEGfMRI recordings and advanced machine-learning computational methods. At the current research we have tested the effect of NF guided by an fMRI-amygdala driven EFP on subject's ability to down regulate their amygdala activity. Subjects were tested at 3 different time points (TP): At TP1 subject's baseline ability to down regulate amygdala activity was measured by a single trail of rtfMRI NF. At TP2 the test group received online audio feedback on their rtEFP signal and were asked to reduce its volume. The control group received a sham feedback in otherwise similar protocol. At TP3 subjects ability to down regulate amygdala activity was measured again using rt-fMRI NF directly guided by the amygadala. We expected that the test relative to shame group will show greater amygdala deactivation during the rtfMRI in TP3, thus showing transfer of the training ability. Results: At TP1 no significant differences were found between the groups. At the EEG NF training period (TP2), the test group had a significantly higher success rate than the sham group. At the post training test (TP3) the test group was significantly more successful than the sham group at reducing amygdala activity. Conclusions: In this research we were able to train subjects to self-regulate activity in deep brain areas using a unique oneelectrode EEG probe that has been driven from simultaneous fMRI. This novel approach opens up the possibility for lowcost, bed-side tools for mechanism-driven diagnosis and treatment of brain disorders.

Mild neonatal stress and MTHFR deficiency suppress histone methylation and behaviors associated with stress in mice Kezurer N. 1,2, Golan H. 3,4* 1 Physiology, Health Sciences, BGU 2 Zlotowski Center for Neuroscience, BGU 3 Physiology, Faculty of Health Sciences, BGU 4 Zlotowski Center for Neurosciences, BGU Early life stress is shown to have life-span outcome on human and animal behavior, increasing the risk for psychopathology. Here, we examined the hypothesis that Methylenetetrahydrofolate reductase (MTHFR) deficiency increases the susceptibility of the developing brain to mild neonatal stress (NS), affect histone H3 lysine methylation and alter behaviors associated with stress in the adult mice. Behavioral phenotyping of Wt and MTHFR-deficient mice, provide evidences that the effect of mild NS may be amplified by deficient MTHFR genotype. Distinct patterns of behavior and gene methylation were altered in male and female. Alterations in H3 lysine methylation were as following: NS and MTHFR+/- genotype reduced H3K9me2 by 30% compared to WT (p<0.01) in females. In contrary, in the MTHFR+/- mice, NS elevated the levels of H3K9me2 by 33% (p<0.05). On the other hand, in males NS elevated H3K9me2 by 92% in WT (p=0.07) and further elevation was obtained in the MTHFR+/- (98%, p<0.05). Suppression of H3K27me2 by NS and MTHFR+/genotype in female but not in male, were similar to those obtained in the H3K9me2; 32% and 24% in NS and MTHFR+/-, respectively (p<0.01 and p<0.001). For this site NS had no effect in MTHFR +/- females. Exploration in the elevated plus-maze was similarly altered in male and females. MTHFR+/- genotype reduced the time spent in the closed arms by 42% and 36%, respectively (p<0.05). Stress related parameters were significantly sensitive to genotype in female, where 67% of the MTHFR+/- urinated during the test, as opposed to 47% of Wt. NS suppressed this response, remarkably in Wt (22% of mice urinating), and slightly in MTHFR+/females. Although the number of urinating female was not changes by NS in the MTHFR+/-, it elevated corticosterone by 80%. Overall, our results support an interaction between mild NS, MTHFR genotype and sex which involve differential silencing of DNA associated H3 methylation. When first language is not first: an fMRI investigation of the neural basis of diglossia in Arabic Khateb A 1,2,3*, Nevat M 3, Prior A 3 1 The Unit for the study of Arabic, Faculty of Education, Univ. of Haifa 2 Dept of Learning Disabilities, Faculty of Education, Univ. of Haifa 3 Edmond J. Safra Brain Research Center for the Study of Learning Disabilities The Arabic language used for everyday conversation ("spoken Arabic", SA) differs markedly from the written language

J Mol Neurosci

("literary Arabic", LA). The difference between them raises questions regarding their respective cognitive status. Behavioral studies with auditory stimuli suggested that SA behaves as a first language (L1) and LA as a second language (L2). In this experiment, native speakers of Arabic, who have also learned Hebrew, performed a semantic categorization task on visually presented stimuli in LA, SA, and Hebrew. Brain activity was measured using fMRI. Performance in LA was higher than in SA and Hebrew (with two latter not differing). fMRI responses differed between SA and LA, but also between SA and Hebrew. Contrary to the observations in the auditory modality, these findings suggested that LA behaved as L1 and SA as an L2. Further research is needed to confirm the modality-dependence of the cognitive status of the two varieties of Arabic Research supported by the Israeli National Science Foundation (Grant no’ 623/11) Structure and repetition assist vocabulary acquisition Kimel E 1*, Ahissar M. 1,2,3 1 Edmond and Lily Safra Center for Brain Sciences, Hebrew Univ. of Jerusalem, Israel 2Dept. of Psychology, Hebrew Univ. of Jerusalem, Israel 3 Dept. of Cognitive Sciences, Hebrew Univ. of Jerusalem, Israel How do we acquire new vocabulary? Previous work showed that words with internal structure in Hebrew are processed differently than those without internal structure. One of this work goals is to investigate whether it is possible to utilize a familiar structure for new words learning as opposed to remembering the whole phonological sequence. Another goal is to see whether it is more effective for the acquisition process to repeat the same sentence or introduce a variety of sentences with the target word. The Hebrew verb system, being highly ordered, allows us to examine those questions. In a 9-days auditory vocabulary acquisition experiment, subjects listened to sentences containing an unfamiliar verb. This verb was either a nonexistent word without any specific form ("nonword") or a word that had the form of a Hebrew verb ("binyan") with a nonexistent root ("pseudo-word"). Our results indicate that words with familiar internal structure ("binyan") are learned faster and their integration into the mental lexicon is stronger - the chance to recall a pseudo-word in the end of the experiment is significantly higher than recalling a non-word. Presenting the word in the same sentence throughout the experiment is found to be more effective for learning than presentation in varying sentences. Microglia and other tissue resident macrophages in tissue maintenance: phagocytic activity and autism Kipnis J. Dept. of Neuroscience Center for Brain Immunology and Glia (BIG), Univ. of Virginia, Charlottesville, VA, USA, 22908.

Tissue homeostasis is achieved when a state of equilibrium is reached between two major processes: clearance of dying cells and generation of new ones. Numerous diseases are accompanied by an increase in death processes and a decrease in regenerative capacity, resulting in deterioration and malfunction of the tissue. Dead cells must be cleared to make room for new cells and to remove toxic compounds that the dying cells produce. The effect of impaired phagocytic activity of brain professional phagocytes (microglia) and other tissue resident macrophages will be discussed here in the context of Rett syndrome and its potential implication to a wide variety of animal models for autism. We propose the microglia, in general, and phagocytic activity, in particular, as new targets for future therapeutic intervention for autism spectrum disorders. Molecules and mechanisms that control neuronal wiring in the spinal cord Hadas Y. 1, Avraham O. 1, Falk H. 1, Cohen O. 1, Shreiber E 1, Klar A. 1* 1 Dept. of Medical Neurobiology, IMRIC, Hebrew Univ.Hadassah Medical School, Jerusalem, Israel Motor tasks demand the integrated activity of a diverse set of neural circuits. In vertebrates, the executive element of motor control has been assigned to neural circuits located within the spinal cord. At the core of the spinal motor system are sets of local interneurons (INs) that are webbed in neuronal circuits capable of controlling the activity and output of spinal motor neurons. Interneurons differ from each other by their type of afferent input, cell body positioning along the body axis, axonal trajectory and their axonal targets. A specific axonal pathway of a neuron, governed by a transcriptional code, is manifested by the expression of receptors for guidance molecules that discern the guidance cues en route and at their putative target. Studies aimed toward decoding the wiring of spinal neuronal circuits will be presented. Specifically: 1) defining the axonal trajectories of spinal IN and their neuronal circuit; 2) elucidating the transcriptional code that governs the axonal patterning of INs; 3) characterizing neuronal receptors for positional guidance cues that control axonal choice along the embryonic spinal cord axes. The neural basis of creative thinking and originality among musicians: an fMRI experiment Kleinmintz, O. 1, Abecassis, D. 2, Shamay-Tsoory, S.G. 1* 1 Psychology, Univ. of Haifa 2 Graduate School of Creative Arts Therapies, Univ. of Haifa The relationship between creativity and musical expertise is relatively unknown. Using the framework of the twofold model according to which creativity is comprised of a recursive process of idea generation and idea evaluation, the current study sought to investigate the neural underpinning to creativity among musicians. It was hypothesized that stricter

J Mol Neurosci

evaluation is related to lower creativity, which is associated with lower activation in the evaluation neural network (e.g. left inferior frontal gyrus[IFG]) and higher activation in generation neural network (e.g. right hemisphere). Specifically, training and expertise in improvisation was hypothesized to have a 'releasing effect' on the evaluation system that leads to higher divergent thinking scores. To examine these hypotheses, three groups were scanned while performing a divergent thinking task: musicians with training in improvisation, musicians without training in improvisation and non-musicians. The pre-scan behavioral results show that the improvisation group had higher fluency and originality scores as compared to the other two groups. Additionally, among the musicians, different measures of musical expertise and training, with emphasis on improvisation, seems to mediate the relationship between evaluation of creativity and originality scores. Furthermore, the neuroimaging findings indicate that the left IFG is associated with evaluation of creative output, while generation is characterized by lower activation of these leftward evaluative regions. The results suggest that training in improvisation may have a 'releasing effect' on creativity. It is possible that training in improvisation diminishes the activity of the evaluation system (IFG) which is associated with higher creativity. Neural signatures of processing faces and objects as manifested in steady-state visual evoked potentials Kliger, L. 1*, Deouell, L. Y. 2,3, Bentin, S. 2,4 1 Dept. of Cognitive Sciences, Hebrew Univ., Jerusalem, Israel 2 Dept. of Psychology, Hebrew Univ., Jerusalem, Israel 3 Edmond and Lily Safra Center for Brain Sciences, Hebrew Univ., Jerusalem, Israel 4 The Interdisciplinary Center for Neural Computation, Hebrew Univ., Jerusalem, Israel Background: Scalp event-related potentials, derived from EEG, proved to be a useful tool in the study of face processing. By virtue of temporal tagging, steady-state visualevoked-potentials (SSVEPs) may provide a more sensitive alternative and allow the simultaneous extraction of specific responses to multiple objects. Here we provide a proof of concept for using SSVEPs to study the processing of faces and other objects. Results: Fourteen participants viewed faces or watches flickering at 4 or 5 Hz. At central display conditions, we observed higher power at the relevant frequency for faces compared to watches at parietal sites, while the opposite pattern was observed at occipital sites. The results suggested preferred rates of stimulation for each type of stimuli. Conclusions: SSVEPs may be used as a fast and simple tool for studies of face perception and other complex visual stimuli, although close attention should be paid to the parameters used in the experiment.

Dual array EEG-fMRI for optimal separation between brain signal and artifact Klovatch-Podlipsky I 1*, Medvedovsky M 1,2, Gazit T 1, Tsirelson B 3, Fahoum F 4, Kipervasser S5,6, Ben-Zeev B 7,8, Neufeld M 6,5, Fried I 1,9,10, Hendler T 11,8 1 Functional Brain Center, Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center 2 Helsinki Univ. Central Hospital, Helsinki, Finland 3 School of mathematics, Tel Aviv Univ. 4 EEG and Epilepsy Unit, Dept. of Neurology 5 EEG and Epilepsy Unit, Dept. of Neurology, Tel Aviv Sourasky Medical Center 6 3Sackler School of Medicine, Tel Aviv Univ. 7 Sheba Medical Center, Ramat-Gan 8 Sackler School of Medicine, Tel Aviv Univ. 9 Dept. of Neurosurgery, David Geffen School of Medicine,Univ. of California, Los Angeles 10 7Functional Neurosurgery Unit, Tel-Aviv Medical Center 11 Brain Center, Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center Background: EEG recorded simultaneously with fMRI is often contaminated by artifact elicited by movement inside the magnetic field. We herby present a dual array MR compatible EEG– a device and analysis method, aimed to allow optimal signal to noise ratio. Methods: The application of the dual array EEG measures is demonstrated on data of epilepsy patients whose EEG was recorded simultaneously with fMRI. The dual array was implemented with two sets of EEG electrodes organized into intersecting bundles. The EEG was recorded using a referential montage and later converted to virtual bipolar measurements along and across bundles. Independent component analysis (ICA) was applied to the data. The ICA components were classified according to degree of correlation between ICA coefficients spatial distribution along bundles vs. across bundles. Components with low correlation were removed from the data while other components were transformed back to channel space. Results: Using the proposed novel device and analysis, movement artifacts were suppressed in all cases compared to standard pre processing steps. Furthermore this method allowed clear visualization of epileptiform spikes, sharp waves and seizures. Conclusions: the presented new device and method is useful for brain signal and movement artifact separation in EEG recorded inside MR scanner. The device and method significantly improved signal to noise ratio and detectability of epileptic spikes. The building blocks of curved trajectories: studying the effect of shortened preparation time on movement planning and execution Kohen D. 1*, Karklinsky M. 1, Flash T. 1, Shmuelof L. 1,2 1 Dept. of Computer Science and Applied Mathematics, Weizmann Institute of Science 2Dept. of Brain and Cognitive Science, Ben Gurion Univ.

J Mol Neurosci

The timed response (TR) reaching task was designed to study the independent control of movement direction and amplitude by examining the effect of shortening movement preparation on the performed trajectories (Henning et al. 1988). Nevertheless, in curved trajectories direction and magnitude are intertwined and controlled variables are likely to differ. Fifteen subjects made reaching movements to 4 targets presented 15 cm from the origin, while avoiding obstacles presented halfway between the start and end-point targets. Subjects initiated the obstacle avoidance movements in synchrony with a predicted auditory cue. Targets were presented at two different time points before the auditory cue (25 and 350 ms), imposing short and long preparation time conditions. While subjects successfully reached the targets in both conditions, movements in the short preparation condition showed increased initial directional variability, suggesting that execution variability is sensitive to preparation time. Additionally, the distribution of initial directions in the short condition across targets was narrower and showed less target sensitivity, suggesting the existence of an initial target-insensitive default plan in the short condition. We applied segmentation methods to capture preparation time effects throughout the trajectories and found that all movements were composed of a long parabolic segment followed and/or preceded by a straight segment. The quality of the parabolic fit was lower for the short condition, providing further evidence for the effect of preparation time on execution variability. Additionally, the average focal length parameter for the short condition parabolas was smaller, indicating that these parabolas were less shallow. Overall, shortening the preparation time for curved trajectories results in the selection of similar geometrical components but with different spatial shapes and with more variable execution. This work was supported by the EU Commission, 7th Framework Programme: EC FP7-ICT-248311 AMARSi Differential effects of sustained attention on early ERP components among adults with and without ADHD Kolodny T. 1*, Luria R. 2,3, Shalev L. 4,3 1 Dept. of Cognitive Sciences, the Hebrew Univ. of Jerusalem 2 School of Psychological sciences, Tel Aviv Univ. 3 Sagol School of Neuroscience, Tel Aviv Univ. 4 School of Education, Tel Aviv Univ. Sustained attention and response inhibition are key attention functions, found to be deficient in individuals with attentiondeficit/hyperactivity disorder (ADHD). In the current study we investigated the neural mechanisms underlying these functions in order to identify neurophysiological markers of impaired functioning in ADHD. Adults with ADHD and control participants performed a conjunctive continuous performance task (CCPT) with a manipulation of target frequency: low target frequency stretches the demand for sustained attention, whereas high target frequency challenges response inhibition

ability. EEG data was collected during the performance of the task. Higher error rates and higher variability of RTs were obtained among ADHD participants in both variants of the task, as expected. The ERP components P1 and N1, reflecting early perceptual processing, were modulated by the target frequency manipulation. Interestingly, this modulation differed substantially between the control and the ADHD groups, suggesting different perceptual processing associated with sustained attention at the neural level. Differential regulation of BDNF expression in cortical neurons by class-selective histone deacetylase inhibitors Koppel I. 1*, Timmusk T. 1 1 Dept. of Gene Technology, Tallinn Univ. of Technology Histone deacetylase (HDAC) inhibitors show promise as therapeutics for neurodegenerative and psychiatric disorders. Brain-derived neurotrophic factor (BDNF) is considered a candidate mediator of the beneficial therapeutic effects of these drugs, but the mechanism of BDNF induction is not well understood. Here, we analyzed the effects of class I and class II selective HDAC inhibitors on BDNF expression in rat primary neurons. We found that inhibition of class II HDACs resulted in rapid upregulation of BDNF mRNA, while class I HDAC inhibition produced a delayed BDNF induction. These results suggest that class II HDACs may act as direct regulators of BDNF expression, whereas the induction of BDNF expression by class I HDAC inhibitors is at least partly mediated by indirect effects. This hypothesis found support with the following observations: 1) BDNF promoter IV-luciferase activity was repressed by HDAC4 and HDAC5 (class II HDACs highly expressed in neurons) and induced by a class II selective HDAC inhibitor MC1568; 2) HDAC inhibitor SAHA rapidly induced histone acetylation at BDNF promoters I and IV, but induction of BDNF mRNA markedly lagged behind promoter acetylation; 3) delayed (24h), but not early (3h) BDNF induction by HDAC inhibitors was sensitive to protein synthesis inhibition. In addition, we show a critical role for the cAMP/Ca2+ response element (CRE) in induction of BDNF promoter IV by HDAC inhibitors of different selectivity. In contrast, MEF2-binding CaRE1 element was not necessary for promoter IV induction by HDAC inhibition. Finally, we show that similarly to BDNF, the studied HDAC inhibitors differentially induced expression of neuronal activity-regulated genes c-fos and Arc. Acute and chronic effects of ethanol on network activity of cultured hippocampal neurons Korkotian E. 1*, Odegova T.F. 2, Bombela T.V. 3, Biton E. 1, Segal M. 1 1 Neurobiology, The Weizmann Institute 2 Microbiolody, Perm State Pharmaceutical Academy3 Pharmacognosy and Botany, Perm State Pharmaceutical Academy

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Ethanol can alter spontaneous activity of central neurons through multiple chemical pathways. Both synaptic and non-synaptic effects of ethanol (EtOH) at different concentrations and time courses have been described. The GABAergic synapse is one of the main targets, as it becomes over- activated by EtOH. This pathway is mostly responsible for depression of overall activity in multiple regions of the brain exposed to relatively high doses of alcohol. Still, activation of GABAergic system cannot explain the facilitation observed in neuronal networks under lower doses of EtOH. We have examined the acute effects of low doses of EtOH on dissociated cultures of rat hippocampus. In an earlier study we found that EtOH activates small potassium (SK) channels, which lead to facilitation of the network in a selective manner. In the present study we examined the age-dependent sensitivity of cultured hippocampal neurons to EtOH during both acute and chronic treatment. Particularly, young cultures (4-8 days after plating) expressed significant excitability increase already in the presence of low EtOH concentrations (0.10.25%) while higher dozes (1-1.5%) could effectively inhibit their firing. In contrast, more adult cultures (about 3-4 weeks old) were much less sensitive to the lower doses of EtOH, undergoing facilitation only in the presence of 0.5-1% alcohol and requiring at least 3% or higher dose exposure to be significantly inhibited. Unlike acute application, the chronic (2-5 days) treatment of cultures with relatively low (0.25%) EtOH could completely block the network firing. This effect was age-independent and could be blocked by SK antagonist apamin (40 nM). These results suggest the involvement of SK channels in the chronic effect of EtOH on hippocampal neurons in culture. This work was supported by Grant from The Ministry of Education and Science of The Perm Krai, Russia Motor learning consolidation gains in the elderly are under expressed unless a nap is afforded Korman M 1*, Dagan Y 2, Karni A 3 1 Occupational Therapy Dept., Univ. of Haifa 2 Medical Sciences Dept., Univ. of Haifa 3 Neurobiology and Ethology Dept., Univ. of Haifa Background: Two behavioral phenomena characterize human motor memory consolidation: diminishing susceptibility to interference by a subsequent experience and the emergence of delayed, offline gains in performance. In young adults sleep independent reduction in interference is followed by the sleepdependent expression of offline gains. Moreover, daytime sleep condenses the time course of motor memory consolidation. Here, using the finger opposition sequence–learning task, we show that in older adults robust within session learning is preserved while consolidation processes are distinctly modified. Results: Interference experienced at 2 h following the initial training prevented the expression of delayed gains at 22 h post-training, as also the mere passage of time, suggesting that there is unspecific interference experienced during awake

period post-training. However, a 90-min nap, immediately post-training, resulted in robust delayed gains expressed overnight, probably to reduced susceptibility to unspecific interference. When intended interference training was provided at 2 h post-training, a nap did not counteract interference. Conclusions: The process of procedural memory consolidation generally becomes less effective with aging; however it is still sensitive to both sleep and interference in the time-window of several hours post-training. Natural unspecific interference processes were found to be related to the low effectiveness of learning compared to the young adults. Delayed overnight gains in performance, however, could be realized under condition of nap provision timed immediately post-training and no exposure to intentional interference. These findings offer some promise for improved management of ageing by offering methods by which motor skill learning can be enhanced, e.g., day sleep, provided immediately after training, may enhance consolidation and raise the long-term effectiveness of the training experience. The role of Corticotropin-releasing hormone signaling in the extinction of conditioned fear across development Kritman M. 1, Richter-Levin G. 1, Maroun M. 1* 1 Sagol Dept. of Neurobiology, Faculty of Natural Sciences, Univ. of Haifa Background: Impairments in extinction of fear conditioning underlie maladaptive behavior and the emergence of anxiety disorders. The processes underling the acquisition of conditioned fear and its subsequent extinction are dependent on interactions of various areas in the brain. While the acquisition of fear conditioning is mainly dependent on the amygdala, the ventro-medial prefrontal cortex (vmPFC) plays a crucial role in the consolidation of extinction.The mechanisms of extinction in the postweanling (P19-P30) and adult (
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Conclusions: CRH is differentially expressed in the BLA of the postweanling as compared to that adults and it has differential involvement in fear extinction across development. Glial phagocytosis affects neurodegeneration in adult Drosophila brain Mishnayevski K 1, Levy-Adam F 1, Kurant E 1* 1 Dept. of Anatomy and Cell Biology, The Rappaport Family Institute, Technion Human neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer disease and others are characterized by a progressive neuronal loss often resulting in memory and cognitive decline, motor dysfunction, and premature death. Drosophila models of a number of neurodegenerative disorders have proved useful, including a PD model generated by ectopic expression of human α-synuclein in flies, which results in dopaminergic neurodegeneration and locomotor deficits. Drosophila glia, similarly to microglia and astrocytes in mammals, are competent to perform immune-related functions and notably phagocytosis, which consists of clearance of apoptotic neurons and pruned or degenerated axons in the developing and mature nervous system. These functions are mediated by a number of proteins including two transmembrane phagocytic receptors: Draper (DRPR) and Six Microns Under (SIMU). In this study, we are elucidating the link between glial phagocytosis and neuronal cell death in the adult brain, by altering the expression of these two phagocytic receptors and generating superphagocytic glia or glia with compromised phagocytic function in normal flies and in the Drosophila α-synuclein model. Our results have shown that superphagocytic glia, which are created by ectopic expression of SIMU phagocytic receptor specifically in glia, but not in neurons, of adult flies, caused neuronal loss in transgenic fly brains. This neurodegeneration was accompanied by a decrease in the fly lifespan and locomotor abilities. Moreover, we found that compromised glial phagocytosis affects PD progression. Our in vivo work suggests that glial phagocytosis can influence neuronal cell death and this finding may open new directions for treatment of neurodegenerative disorders. Neuroprotection conferred by human PLacental eXpanded (PLX) mesenchymal stromal cell to rat PC12 sympathetic neurons exposed to oxygen-glucose-deprivation (OGD) Lahiani A.1, Arien-Zakay H.1, Cohen G.1, Zahavi-Goldstein E.2, Abraham E.2, Wadmany M.2, Netzer N.2, Grynspan F.2, Yavin E.3 and Lazarovici P.1* 1 School of Pharmacy Institute for Drug Research, The Hebrew Univ. of Jerusalem, Jerusalem, 2Pluristem Therapeutics Ltd., Haifa, 3Dept. of Neurobiology, Weizmann Institute of Science, Rehovot

Stroke afflicts a large segment of population and is a leading cause of death in the western world. Stroke develops when a part of the brain is deprived of oxygen and glucose. Recently, mesenchymal stem cells have been suggested as a therapeutic approach for stroke, due to their ability to secrete a large number of protective anti-inflammatory cytokines and growth factors. Here we investigate the neuroprotective effect of PLX cells (expressing mesenchymal markers but lacking expression of hematopoietic, endothelial and trophoblastic-specific cell markers), on differentiated pheochromocytoma PC12 cells, in an OGD ischemic model. At first, we determined the optimal conditions for neuroprotection, by exposing undifferentiated or nerve growth factordifferentiated PC12 cells to hypoglycemic and hypoxic conditions followed by reoxygenation in a trans-well system with PLX cells. Under optimal conditions, 2x105 PLX cells conferred 30% neuroprotection towards PC12 cells exposed to ischemic insult. PC12 necrotic cell death, evaluated by lactate dehydrogenase release, was reduced by PLX cells in a dosedependent manner. Interestingly, the neuroprotective effects of PLX cells was also promoted by conditioning media of cells exposed to OGD insult and was similar to those achieved by the antioxidant 4-Hydroxy-2,2,6,6-tetramethylpiperidine-Noxyl. Since neuroprotection is one of the prominent functions of the interleukin (IL)-6-type cytokine family and VEGF is an angiogenic factor known to confer neuroprotection, we measured their secretion from PLX cells under ischemic conditions. We found that IL-6 and VEGF secretion was higher, compared to normoxia. Furthermore, exogenous supplementation of human recombinant IL-6 and VEGF to ischemic PC12 cells conferred neuroprotection, reminiscent of PLX cells neuroprotective effect. Therefore, PLX inducedneuroprotection on PC12 neurons exposed to ischemic conditions may partly be explained by IL-6 and VEGF secretion. *PL holds the Jacob Gitlin Chair in Physiology at Hebrew Univ. and is affiliated and acknowledges the support by the David R. Bloom Center for Pharmacy, the Dr. Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at The Hebrew Univ. of Jerusalem and the Israeli Ministry of Industry and Trade, MAGNETON program for the financial support. Effects of oxytocin in the basolateral amygdala and medial prefrontal cortex on fear extinction: developmental differences Lahoud.N 1, Maroun.M 1* 1 Sagol Dept. of Neurobiology, Faculty of Natural Sciences, Univ. of Haifa Background: The basolateral amygdala (BLA) and infralimbic subregion of the medial prefrontal cortex (IL-mPFC) circuit has a crucial role in extinction of fear. The oxytocinergic system promotes social behavior and reduces

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anxiety. The interaction of the IL-mPFC- BLA circuit in extinction provides a unique experimental setting to examine the effects of oxytocin on extinction of fear. We have recently reported that when oxytocinergic system in adult rats is manipulated in either the IL-mPFC or the BLA, it is associated with complex effects on extinction, depending on the site of injection and the drug used (Lahoud and Maroun, 2013). Specifically, microinfusion of oxytocin in the IL-mPFC was associated with enhanced extinction. In the BLA, whereas microinfusion of TGOT, selective agonist, did not affect subsequent extinction, synthetic oxytocin microinfusion resulted in impaired extinction. There is a recent interest in the neural mechanisms that mediate fear and extinction across the development. In the present study, we aimed to address whether manipulations of oxytocin exert similar effects in the postweanling rat (PW). Results: Our results show that microinfusion of TGOT or the synthetic oxytocin in the PW IL-mPFC did not affect extinction of fear. In contrast, microinfusions of either TGOT or oxytocin in the BLA after the retrieval of fear resulted in impaired extinction. Conclusions: These results show (1) manipulation of the oxytocin system does not necessarily result in enhanced extinction and reduction of fear and (2) differential effects of oxytocin in the PW animal as compared to the adult animal. In conclusion, the data of the present study join recent reports which show that oxytocin manipulations exert complex effects on the regulation of fear depending on the brain structure and the drug used. The developmental differences should be taken while considering oxytocin- based therapies in treatment of anxiety disorders in adults and youngsters. Developing methods for multi-channel neural recording and stimulation in freely flying bats Las L. 1, Eliav T. 1, Saraf-Sinik I. 1, Vecht J. 2, Ulanovsky N. 1* 1 Dept. of Neurobiology, Weizmann Institute of Science, Rehovot, Israel 2 Deuteron Technologies Ltd., Jerusalem, Israel A major goal of behavioral neuroscience and neuroethology is to elucidate the neural basis of behavior and cognition in naturally-behaving animals. This requires the development of methodologies that will allow conducting neural recordings from freely moving animals in complex naturalistic laboratory settings – and ultimately also in the wild. We were recently able to use a wireless neural-telemetry system to record from three-dimensional (3D) place cells in the hippocampus of flying bats, as they foraged on an artificial tree in the laboratory (Yartsev and Ulanovsky, Science 2013). Here we report on our progress in developing a new system, which will meet the following functional specifications: (i) High channel count: 16 channels (and 64 channels in the future) of continuous

high-bandwidth spike and LFP recordings, for at least 2 hours. (ii) Neural data stored on board the device – which provides a substantial improvement over systems that are based on RF transmission of data, because on-board storage does not suffer from RF-transmission-related noises, and it is also unlimited in distance. (iii) On-line monitoring of a subset of the recording channels. (iv) 7 channels of wirelessly-controlled electrical micro-stimulation of up to 7 independent brain sites. (v) Synchronization to additional data-loggers, such as camera video-trackers, GPS, and 9-axis accelerometers – for measuring the animal's position, head-direction and other movement data. (vi) Highly miniaturized and very lightweight, allowing the device to be mounted on the head of a flying bat. Initial testing of the wireless micro-stimulation system was conducted by successfully training bats on 3 different behavioral tasks, using microstimulation of the medial forebrain bundle (MFB) as reward, including on two tasks in feelyflying bats. We will report here on these and further experimental tests of the system. VLO5, A snake venom disintegrin toxin inhibited nerve growth factor induced, A9B1 Integrin mediated progression of glioblastoma Lazarovici P. School of Pharmacy Institute for Drug Research, Faculty of Medicine,The Hebrew Univ. of Jerusalem Background: Malignant gliomas are not curable because the tumor cells invade the surrounding brain tissue without a clear tumor-brain boarder line, making complete neurosurgery resection impossible. Therapy aimed at inhibition of invasion is crucial not only for prevention of brain tumor spreading, but also for selectively blocking migrating cells that may be more resistant to chemotherapy and radiation. Recently, investigations have shown that the snake venom non-RGD disintegrin VLO5, specifically interacting with a9b1 integrins on the surface of glioma cells by an MLD-motif inhibited glioma cell adhesion. Results: We describe the effect of VLO5 on the interaction of alpha9beta1 integrin with nerve growth factor (NGF), which is important in glioblastoma progression and brain invasion. We report that the level of expression of a9b1 on astrocytomas is correlated with increased grade of this brain tumor and is highest on glioblastoma, whereas normal astrocytes do not express this integrin. NGF significantly stimulated promigratory and pro-proliferative activities of glioblastoma cells through direct interaction with a9b1 integrin by activation of Erk1/2 phosphorylation. The level of NGF increased approximately threefold in the most malignant glioma tissue when compared with normal brain. VLO5 treatment or a9b1 integrin gene silencing, inhibited NGF-induced proliferation of LN229 cell line to the level shown by LN18 cells. VLO5 at

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high doses caused a9b1-dependent apoptosis.This disintegrin significantly inhibited tumor growth induced by implantation of LN229 cells to the chorioallantoic membrane (CAM) of quail embryoonic model. Conclusions: a9b1 integrin appears to be an interesting target for blocking the progression of malignant gliomas.VLO5 disintegrin or derived cyclic peptide are proposed for the treatment of malignant gliomas. P.L. holds Jacob Gitlin Chair in Physiology Peripheral neurons differentiated from Familial Dysautonomia human embryonic stem cells as an experimental model for studying the role of IKAP in the disease Lefler S. 1, Cohen A.M 2, Kantor G. 1, Razin A. 3, Reubinoff B. 2, Weil M. 1* 1 Dept. of Cell Research and Immunology, Tel-Aviv Univ., Ramat-Aviv, Israel. 2Dept. of Gynecology, Hadassah Univ. Hospital, Jerusalem, Israel. 3 Dept. of Developmental Biology and Cancer Research, Institute of Medical Research Israel-Canada Familial Dysautonomia is an autosomal recessive congenital neuropathy that affects the peripheral nervous system (PNS). The splicing mutation in the IKBKAP gene in FD patients was found to be responsible for the developmental defects in the sensory and autonomic PNS. The cellular function of IKAP, the product of IKBKAP gene, is still highly debated; ranging from histone acetylation to cell cytoskeleton regulation. Human embryonic stem cells (hESC) have the potential to differentiate into PNS neurons, which makes them a suitable candidate for peripheral neuropathies research. We found that IKAP is highly expressed in PNS-derived hESC neurons, mainly in neurites as granular vesicle-like structures. These structures, co-localized with the SV2/Rab3a-positive synaptic vesicles. In parallel, we differentiate a unique hESC line derived from FD human preimplanted embryos which was generated by the Benjamin Reubinoff's laboratory at Hadassah, Jerusalem. We were able to produce neurons with similar morphologies as the WT ones with typical mRNA IKBKAP FD mis-splicing phenotype. Microarray cDNA gene expression chip analysis showed significant differences in gene expression, mainly related to neuronal function, synaptogenesis and cellular adhesion. By comparing the cDNA expression data-set obtained from our WT and FD neurons to similar data obtained from WT and FD aborted fetus brains, we confirm the similarity in gene expression of our hESC FD neuronal model. We used the plant cytokine Kinetin and found a 6-fold increase in the correctspliced IKAP in FD-derived neurons accompanied by upregulation in several genes that we found to be downregulated in untreated FD neurons. This novel experimental system of FD hESC-derived PNS neurons described here for the first time is expected to contribute greatly to the study of FD disorder,

would allow us the benefits of studying IKAP at its neuronal vesicle-associated context and will help us discover new therapeutics to aide FD patients. This work was supported by the research consortium (FD hope, FD foundation Inc., FD Israel foundatio Exploiting the angioneural crosstalk for repairing spinal cord injury Lelkes P.I. 1,2, Perets A. 2, Saglam A. 2, Cohen G. 3, Fischer I. 4, and Lazarovici P. 3. 1 Dept. Bioengineering Temple Univ. and Temple Institute for Regenerative Medicine and Engineering (TIME), Philadelphia, PA USA 2 School of Biomedical Engineering, Drexel Univ., Philadelphia, PA USA 3 Institute for Drug Research, School of Pharmacy, The Hebrew Univ. of Jerusalem, Jerusalem, IL 4 Dept. of Anatomy and Neurobiology, Drexel Univ. College of Medicine, Philadelphia PA USA The aim of our work is to exploit the developmental crosstalk between the vascular and the neuronal system to enhance directed neuritogenesis in uniaxial guidance scaffolds for the repair of spinal cord injury. In this study, we describe a novel method for angioneural regenerative engineering, i.e., for generating biodegradable scaffolds, produced by a combination of controlled freezing (freeze-casting) and lyophilization, which contain longitudinally oriented channels, and provide uniaxial directionality to support and guide neuritogenesis from neuronal cells in the presence of endothelial cells. The optimized scaffolds, composed of 2.5 % gelatin and 1 % genipin crosslinked, were characterized by an elastic modulus of ~51 kPa and longitudinal channels of ~50 μm diameter. The scaffolds support the growth of endothelial cells, undifferentiated or NGF-differentiated PC12 cells, and primary cultures of fetal chick forebrain neurons. The angioneural crosstalk, as generated by first forming endothelial cell monolayers in the scaffolds followed by injection of neuronal cells, leads to the outgrowth of long aligned neurites in the PC12/endothelial cell co-cultures also in the absence of exogenously added nerve growth factor. Neuritogenesis was not observed in the scaffolds in the absence of the endothelial cells. This methodology is a promising approach for neural tissue engineering and may be applicable for regenerative spinal cord injury repair Detection of neuronal sprouting during the development of neuropathic pain Tsuriel S.* 1, Leibovich H. 1, Peretz L., Binshtok A. 1* 1 Dept. of Medical Neurobiology Institute for Medical Research Israel Canada Faculty of Medicine Detection of neuronal sprouting during the development of neuropathic pain. Neuropathic pain, results from a lesion or disease of the somatosensory system ". According to current

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statistics, a large percentage of the adult population suffer from this kind of pain. In an attempt to understand the mechanisim underlying neuropathic pain, several models have been developed and among the more useful is the Spread Nerve Injury (SNI) model. In this model the nerves innervating the middle paw area are dissected, while the nerves innervating the paw on both ends remain intact. This partial nerve lesion results in paw allodynia even in the de-innervated areas. Although SNI, as well as other neuropathic pain models, have been studied, the nerve rearrangement pattern which parallels the developing pain remain unexplored. The objective in the current study is to anatomically characterize the peripheral nerve rearrangements that follows nerve injury that correlate with the developing pain. To this end, we injected Wheat germ agglutinin (WGA) conjugated to 4 different fluorophores in 4 different areas of the paw. In this way each part of the paw was labeled with a unique (WGA conjugate) color, the dye was uptake by neurons ends innervating the paw and retrogradely transported to the neuron's somata. Day later the somata within the dorsal root ganglia (DRG) that innervate these areas become labeled. Imaging these DRG allows us to anatomically correlate the cell population that innervates those areas under normal conditions, and to describe the nerves rearrangement process after the nerve lesion with the developing pain. A comprehensive description and analysis of this process will give profound understanding of the mechanisms involved in development of neuropathic pain in conjunction to neuronal rearrangements of nociceptor and other sensory type neurons. This will ultimately lead to advance in development of treatments towards this as now untreatable debilitating condition. Perceptual learning reduce the size of the human perceptive field Lev M. 1,2*, Yehezkel O., Sterkin A., Polat U. 1 Faculty of Medicne, Tel-Aviv Univ. 2 Goldschelger Eye Research, Sheba Medical Center, Tel-Hashomer Visual masking refers to impaired performance on a target stimulus.Crowding refers to an impaired ability to recognize objects in clutter. Presbyopia (aging eye), the visual input to the brain, is limited by the degraded optics of the eye, creating a bottleneck for the near visual information in the visual cortex. Consequently, presbyopes have difficulty in near reading and exhibit an increased crowding effect. Parafoveal vision is also characterized by increased crowding and masking effects. Both crowding and masking effects result in visual suppression from the flankers when they overlap the perceptive field (PF) and decrease with increasing distance between the PF and the flankers. Hence, it is not clear whether they share similar mechanisms. Here we tested whether both crowding and masking are correlated and can be reduced by perceptual training. We also tested whether the effect can be accounted for by the PF size. We used our method for

estimating the PF's size (Lev & Polat, 2011) and determined the magnitude of the crowding and masking inside and outside the PF in the fovea and parafovea. We tested crowding and masking using two groups of subjects: (1) those with normal vision in their fovea and parafovea and (2) those with uncorrected presbyopia. Subjects were trained on contrast detection of Gabor targets under collinear facilitation and backward masking conditions. We found that crowding was correlated with the masking conditions. The masking and crowding effects were correlated with the size of the PF; subjects that exhibit stronger masking exhibit a corresponding stronger crowding effect. The spatial range of the crowding and masking effects was related to the size of the PF for each subject. Perceptual training decrease both crowding and masking effects. The results suggest that masking and crowding share common underlying mechanisms and that both depend on the size of the PF. Suported by grant from Israeli Science Foundation (ISF) Octopus crawling involves a unique strategy for arms coordination Levy G. 1,2,3*, Hochner B. 1,3 1 Dept. of Neurobiology, Silberman Life Sciences Institute, Hebrew Univ. of Jerusalem 2 The Edmond & Lily Safra Center for Brain Sciences, Hebrew Univ. of Jerusalem 3 The Interdisciplinary Center for Neural Computation, Hebrew Univ. of Jerusalem Octopus body, with flexible arms, each with an enormous number of degrees of freedom (DOFs), is highly complicated to control. The octopus simplifies the control by using stereotypical motor programs that reduce the number of DOFs to just few. Here we present a first analysis of crawling in the octopus, focusing on the complex task of coordinating the arms. Octopuses were video recorded from below while they were crawling in shallow water. Points of interest, like the mouth and specific suckers were labeled on the video images. Distances between points were measured and velocities were calculated. Octopuses crawl in any direction relative to their body coordinates, creating the thrust force solely by elongating a proximal segment of the arms to push the body in a stereotypical fashion. One to four arms push simultaneously, producing virtually equal forces opposite to their position around the body. During crawling, an octopus can rotate about its body or change the facing direction independently, as there is no correlation between these two types of maneuvers. Starkly contrasting to common patterns of animal locomotion, there is no evidence for a stereotypical rhythmical pattern of arm recruitment. Control thus appears to be decentralized: the arms push the body autonomically driven by a motor program in the arm motor system that resembles the motor programs in crawling of other soft bodied animals, such as inchworm and leech. However uniquely to the octopus, the coordination

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between the pushing arms is centrally controlled by two independent mechanisms, one controlling body rotation, and the other controlling crawling direction. Remarkably, the pattern of arm activation could not be attributed to a central pattern generator (CPG). Our findings reveal another special organization of motor control that is most likely evolved in the octopus embodiment (Hochner 2012; 2013) to simplify the control in a complex body lacking constraints of a rigid skeleton. European Commission EP7 projects OCTOPUS and STIFFFLOP Motor skill acquisition in ADHD: training in the evening results in more effective consolidation and better retention than training in the morning Levy I. 1, Korman M. 2, Karni A. 1,3* 1 The lab of Human Brain & Learning, E.J. Safra Brain Research Center and the Dept. of Learning D 2 Dept. of Occupational Therapy, Faculty of Social Welfare & Health Sciences, Univ. of Haif 3 The Sagol Dept. of Neurobiology & Ethology and Dept. of Human Biology, Univ. of Haifa Background: The learning and practice of a given sequence of movements can produce robust procedural memory for the learned sequence. The acquisition of this memory develops in two phases that are largely dependent on the amount of practice and the time elapsed from practice: I. gains in speed that emerge concurrently with training, and ii. Additional gains in speed and accuracy that evolve (hours to days) following the termination of practice. The delayed gains in task performance are considered a manifestation of procedural memory consolidation processes, and result in long-lasting retention of the task. Both timing of training and circadian type are known to play a role in the development of the off-line performance gains. Furthermore, adults with ADHD are more evening oriented than adults without ADHD. How this affects the time-course of skill acquisition is largely unknown. Results: All four groups showed robust within-session gains and well-retained the practiced sequence of finger movements. However, participants with ADHD training at evening time showed significantly higher delayed gains than the morning-trained ADHD participants. No significant differences were found between the performance of the eveningtrained ADHD group and the morning and evening trained control groups. Conclusion: Young female adults with ADHD, who are more likely to be evening oriented, express more robust offline, consolidation phase, gains in the performance of a newly learned sequence of movements if trained in the evening. Morning-trained young adults with ADHD may show the smallest offline performance gains and thus less than optimal procedural knowledge.

Neuronal Gateways to Conscious Word Perception Levy J. 1* Goldstein A. 1,2 1 The Gonda Multidisciplinary Brain Research Center, BarIlan Univ. 2 Dept. of Psychology, Bar-Ilan Univ. Background: It is commonly assumed that word perception operates in an all-or-none manner. However, we have recently presented behavioral and neural evidence for the dissociation between partial (orthography) and full (semantics) perception by maintaining short-lived exposure and manipulating masking levels. Results: Here, we further investigated the existence of four putatively intermediate levels of perception: visual, orthographic, partial semantic and full semantic. In order to predetermine the four corresponding bottom-up stimulation parameters, an off-line staircase procedure operated on masking luminance while maintaining identical word stimulation. Online oscillatory brain activity was monitored with magnetoencephalography while participants performed a passive viewing task. Conclusions: Time-frequency and beamforming analyses reveal a recently emerging view of the complex role that various neuronal oscillations play during piecemeal reading perception. Moreover, they provide electrophysiological evidence for the prominent role of the VWFA as a mediator of conscious word perception. Association among clinical response, hippocampal volume, FKBP5 gene expression and cognitive flexibility in individuals with posttraumatic stress disorder receiving cognitive behavioral therapy Levy-Gigi E. 1*, Keri, S.. 2 1 The institute for the Study of Affective Neuroscience, Univ. of Haifa, Israel 2 The National Psychiatry and Addiction Center, Budapest, Hungary Background: Posttraumatic stress disorder (PTSD) is characterized by a reduced expression of FKBP5, a key modulator of the glucocorticoid receptor. Smaller hippocampal volume has also been documented in PTSD. In this study we explored FKBP5 gene expression, brain structure and cognitive flexibility in patients with PTSD before and after cognitive behavioral therapy (CBT) Methods: We measured peripheral FKBP5 RNA, volumes of the hippocampus, amygdala, and medial orbitofrontal cortex and cognitive flexibility in 39 patients with PTSD before and after CBT. The control subjects were 31 trauma-exposed individuals without PTSD who were also assessed twice. Results: At baseline, patients with PTSD showed lower FKBP5 gene expression and smaller hippocampal and medial orbitofrontal cortex, but not amygdala, volumes relative to control subjects. At follow-up, we found significantly

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increased FKBP5 expression and increased hippocampal volume in patients with PTSD. At follow-up, patients did not differ from control subjects in hippocampal volume. Improvement in PTSD symptoms was predicted by increased FKBP5 expression and increased hippocampal volume, but the primary predictor was FKBP5 expression. There was a positive correlation between the performance on a partial reversal task which tests cognitive flexibility and treatment responsiveness. Conclusions- Clinical improvement in individuals with PTSD was associated with increased expression of FKBP5, increased hippocampal volume and better cognitive flexibility. The three variables were positively correlated. Threat bias mediates the relation between hippocampus and anxiety Lin T.1,2*, Vaisvaser S.1,3, Fruchter E.4, Admon R.1, Wald I.2, Pine D.S.5, Bar-Haim Y.2, Hendler T.1,2,3 1 Functional Brain Center, Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center 2School of Psychological Sciences, Tel-Aviv Univ.3Dept. of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv Univ. 4Division of Mental Health, Medical Corps, IDF 5Mood&Anxiety Disorders Program, Intramural Research Program, The Institute of Mental Health Background: Individuals differ in processing threat by either allocating attention toward (i.e. vigilance) or away (i.e. avoidance) from it. These threat biases have been related to anxiety, yet their contribution to the known relation between anxiety and limbic and prefrontal (amygdala, hippocampus, ACC) activation has not been underpinned. To examine this, 55 combat soldiers underwent fMRI with dot-probe task with angry faces and were later allocated to avoidance (n=25) and vigilance (n=30) groups. Results: We found that only among high-anxious individuals, avoidance compared to vigilance showed increased hippocampus activity to angry faces as well as less post trauma symptoms. Mediation analysis further revealed that in high anxious individuals threat bias of avoidance mediated the relation between enhanced hippocampus activity and decreased PTSD symptoms. Importantly, we also found that the ACC acts on the hippocampus to influence threat bias. Conclusions: Our results point to the significant role of the hippocampus in determining PTSD symptoms through threat bias. Furthermore, this study reveals the role of the ACC in regulating these biases through the hippocampus, thus possibly protecting from traumatic stress vulnerability. These findings point to the importance of considering threat bias when investigating anxiety brain markers, and indicate the ACC and hippocampus as potential targets for neuromodulation interventions.

D-cycloserine improves cognitive deficits in a mouse model of global neuroinflammation with a wide treatment window - a novel treatment approach Liraz-Zaltsman S. 1,2, Alexandrovich AG. 3, Yaka R. 3, Shohami E. 3*, Biegon A. 4,2 1 The Hebrew Univ. Dept. of pharmacology, Jerusalem, Israel 2 The Joseph Sagol Neuroscience Center, Sheba Medical Center, Israel 3The Hebrew Univ. Dept. of pharmacology, Jerusalem, Israel 4 Brookhaven National Lab. USA Background: Neuroinflammation is believed to play a major role in several acute-onset human neuropathologies as well as chronic conditions. Most of these pathologies are usually associated with short and long term cognitive disabilities, in particular memory loss of varying intensities. Despite enormous progress and research in that field, atpresent, there is no pharmacological intervention known to prevent or ameliorate cognitive deficits following a neuroinflammatory insult. The goals of this study were to examine therapeutic approaches that will allow the translation of the results to humansubjects. To this end we used an in-vivo model, in which mice were subjected to global neuroinflammation by LPS injection into the cisterna magna. Results: Using a model of global, non-invasive and pure LPSinduced neuroinflammation we found regional sensitivity of brain regions associated with cognitive processes accompanied by long lasting cognitive deficits. The cognitive deficits were found in an extensive battery of well-established behavioral tests as well as impaired long term potentiation(LTP) in the CA1 field of the hippocampus. We tested the effects of treatment by the NMDA partial co-agonist-d-cycloserine (DCS) given once, at 24 h post LPS injection. We found that a single dose of DCS significantly improved the long lasting cognitive deficits and restored the magnitude of impaired LTP. Moreover, DCS treatment of LPS mice led to a significant reduction of regional neuroinflammation and to changes in NMDAR density and function. Conclusions: These results demonstrate a novel approach to the recovery of inflammation-induced cognitive deficits in a clinically-relevant model of global neuroinflammation using a therapeutic modality which activates the hypo-activated NMDA receptor ion channels. Since DCS is approved for human use, this approach can be readily translated to clinical application of DCS in humans with inflammation-induced cognitive decline. Prediction of Parkinson's disease and epilepsy related genes from high resolution spatial gene expression images Liscovitch N. 1*, Chechik G. 1 1 Gonda Multidisciplinary Brain Research Center, Bar Ilan Univ. Identifying genes that are involved in neurological disorders is an essential step in understanding cellular pathways that are

J Mol Neurosci

impaired in the diseased brain and in developing new therapeutic strategies. For some diseases, disease-related genes can be identified by finding genes that are co-localized with known disorder-related genes. Finding these similar genes is usually achieved using high-throughput methods that average expression in a tissue. Unfortunately, this approach faces problems when considering neural diseases, since the global expression in a brain tissue mixes a multitude of cell types. Here we use a genomic dataset of mouse neural in situ hybridization (ISH) images to characterize the spatial expression patterns of known genes involved in epilepsy and Parkinson's disease (PD). The ISH images show mRNA expression at a cellular resolution and contain spatial information that goes beyond coarse expression levels, capturing finer properties such as cell shapes or expression gradients. We used stateof-the-art methods from computer vision to learn detectors for epilepsy and PD related genes based on spatial expression patterns of known disease-related genes. The detectors achieve 79% accuracy for PD and 73% accuracy for epilepsy, on a set of held-out labeled data. We applied the trained classifiers to the entire mouse genome and predict dozens of new candidate genes for epilepsy and PD. For example, a top epilepsy prediction is Tph2 (tryptophan hydrozylase). This gene is important in the biosynthesis of serotonin, which has been hypothesized to be involved in epilepsy. We also find that PD genes are widely expressed in the brain, while epilepsy genes show much more localized patterns, notably in the periaquaductal grey, a region that has been shown to be associated with the induction of audiogenic seizures in epilepsy-prone rats. Anti-apoE4 immunotherapy: A novel approach to the treatment of Alzheimer's disease Luz I 1*, Liraz O 1, Smolar A 1, Frenkel M 1, Ophir G 1, Smorodinsky N 2, Michaelson DM 1 1 The Sagol School of Neuroscience, Tel-Aviv Univ. 2 Cell Research and Immunology Dept. Tel-Aviv Univ. Introduction: The pathological phenotype of apolipoprotein E4 (apoE4), the most prevalent Alzheimer's disease (AD) genetic risk factor, evolves years before AD is diagnosed. Consistently, pathological phenotypes are observed in apoE4-targeted replacement (TR) mice at a young age. This study examined the extent to which anti-apoE4 mAbs can counteract the apoE4 phenotypes. Results: The anti-apoE4 mAbs were injected to apoE3 and apoE4-TR mice via a preventive paradigm (10 weekly i.p injections, starting post-weaning) and a treatment paradigm (3 weekly i.p injections, 4 months old mice). Examination of naïve 4 months old apoE4 mice revealed distinct hippocampal pathologies, including tau hyperphosphorylation, Aβ neuronal accumulation, synaptic impairments, decreased levels of

apoE receptor 2 (apoER2), as well as behavioral deficits. Of these parameters, the apoE4-driven accumulation of hyperphosphorylated tau and the decreased apoER2 levels were abolished by the anti-apoE4 mAbs in both the preventive and treatment paradigms. In contrast, the apoE4 accumulation of Aβ was not affected by either treatment. Behavioral studies, thus far performed only in the preventive paradigm, revealed that the anti-apoE4 mAbs counteract the cognitive deficits of the apoE4 mice. The extent to which the preventive and treatment paradigms increase the levels of brain IgG and the mechanisms underlying the protective effect of the anti-apoE4 mAbs will be discussed. Conclusion: Injected Anti-apoE4 mAbs counteract key pathological effects of apoE4 in TR mice. This suggests a novel therapeutic approach for treatment of apoE4 carriers in AD and in other acute and chronic diseases. Thrombin regulation of synaptic transmission in the hippocampus. Maggio N. 1,2*, Chapman J 1,3, Segal M. 4 1 Dept. of Neurology, The Chaim Sheba Medical Center at Tel HaShomer, Israel 2 Talpiot Medical Leadership Program, The Chaim Sheba Medical Center at Tel HaShomer 3Dept. of Neurology, Physiology, Pharmacology, Sackler School of Medicine, Tel Aviv Univ. 4 Dept. of Neurobiology, The Weizmann Institute of Science Background: Thrombin, a serine protease involved in the coagulation cascade has been recently shown to affect neuronal function following blood-brain barrier breakdown. Several lines of evidence have shown that thrombin may exist in the brain parenchyma under normal physiological conditions, yet its role in normal brain functions and synaptic transmission has not been established. In an attempt to shed light on the physiological vs. pathophysiological functions of thrombin and Protease Activated Receptor 1 (PAR1) in the brain, we studied the effects of thrombin and a PAR1 agonist on synaptic transmission and neuronal excitability in hippocampal slices. Results: Different concentrations of thrombin affect LTP through different molecular routes converging on PAR1. While high concentrations of thrombin induce slow onset NMDA-dependent LTP, lower concentration enhance stimulus induced LTP through a mechanism dependent on calcium stores. In addition, high thrombin concentrations affect neuronal excitability and lower the threshold for seizures, through an NMDA- independent mechanism. Conclusions: These findings reveal novel insights by which PAR1 may regulate neuronal transmission in the hippocampus and provide additional insights into the role of this receptor in normal and pathological conditions.

J Mol Neurosci

The nature of visual object representation in the human cortex Malach R. Neurobiology, Weizmann Institute of Science The discovery of object-related representations in the human cortex- located in the Lateral Occipital Complex (LOC), has initiated a wide ranging research effort aimed at delineating the exact functional characteristics, anatomical specificity and relationship to human perceptual awareness of this intriguing cortical region. Here I will review major findings related to the LOC, highlighting its high order placement within a global hierarchy leading from a tight link to the optical properties of retinal stimulation in early visual cortex and terminating in abstract conceptual representations in entorhinal cortex. Thus, functionally, LOC responses show significant holistic-configural properties of visual objects. Dynamically, they manifest rapid, non-linear activations ("ignitions")- that are tightly linked to object perception and show a clear dissociation from the lowlevel optical properties of the retinal stimulation. Finally, the similarity between patterns of neuronal responses ("neuronal proximity") to different exemplars reflects their perceptual similarity. These results place LOC as a major candidate for the neuronal correlate of perceptual awarenes of visual objects in the human brain. The effect of ACE inhibitors on microglial inflammation Mali E. 1, Torika N. 1, Apte R 2, Fleisher-Berkovich S. 1* 1 Dept. of Clinical Biochemistry and Pharmacology, BenGurion Univ. of the Negev, Beer Sheva, Isr 2 Shraga Segal Dept. of Microbiology and Immunology, Ben-Gurion Univ. of the Negev, Beer She Background: Microglia, are an important mediators in neuroinflammation. Upon activation microglia release factors such as cytokines and reactive oxygen species e.g nitric oxide (NO). NO is a free radical that is generated by NO synthases (NOS), and involves in neurotoxic process that may lead to neurodegeneration. Angiotensin-converting enzyme (ACE) is a major part of the brain renin-angiotensin system (RAS). There is contradicting evidence regarding the role of ACE inhibitors (ACEI), an anti-hypertensive drugs, in preventing cognitive decline and neuroinflammation in Alzheimer's disease (AD). Here we examined the effects of brain-penetrating ACEI, perindopril and captopril, on basal and lipopolysaccharide (LPS)-stimulated synthesis of NO and Tumor necrosis factor alpha (TNF-α) production. We also examined the expression and transcription of inducible NOS (iNOS) and the transcription of TNF-α in BV2 microglia. Results: Exposure of the cells to perindopril results in a dosedependent decrease in basal and LPS-stimulated synthesis of

NO and in basal synthesis of TNF-α. However, in stimulated cells, perindopril increased production of TNF-α. Exposure of the stimulated cells to captopril resulted in a dual effect regarding the release of NO and TNF-α and the expression of iNOS. Captopril concentration of 0.1mM increased NO and TNF-α synthesis and iNOS expression and at concentration of 3mM caused the opposite outcome compared to LPS-treated cells. Ang II nor selective antagonists of BK altered NO and TNF-α observed levels upon ACEI treatment. Conclusions: These results suggest that perindopril and captopril has an anti-inflammatory effect in BV2 microglia that is not mediated through BK nor Ang II. This may suggests that brain penetrating ACEI can serve as neuroprotecting agents neuroinflammation. This research was supported by the ISF (grant No. 101/11). Restoration of sight with photovoltaic retinal prosthesis: evaluation in-vivo Mandel Y 1,2*, Lorach H 1, Goetz G 1,3, Lavinsky D 4, Huie P 1,4, Mathieson K 5, Wang L 3, Lei X3, Kamins T 3, Manivanh R 4, Harris J 3, Palanker D 1,4 1 Hansen Experimental Physics Laboratory, Stanford Univ., Stanford, CA, 94305, USA 2The Mina & Everard Goodman Faculty of Life Sciences, Bar Ilan Univ., Israel. 3Dept. of Electrical Engineering, Stanford Univ., Stanford, CA, 94305, USA 4Dept. of Ophthalmology, Stanford Univ., Stanford, CA, 94305, USA 5 Institute of Photonics, Univ. of Strathclyde, Glasgow, Scotland, G4 0NW Background: In the photovoltaic approach to retinal prosthesis the camera-captured images are projected onto the retina using pulsed near-infrared (NIR) light. Each pixel in the subretinal implant converts pulsed light into local electric current to stimulate the nearby inner retinal neurons. This study characterized the cortical responses to photovoltaic stimulation and compared them with visual evoked potentials elicited by visible light. Methods: Subretinal photodiode arrays with pixel sizes of 70 and 140um were implanted in the subretinal space of rats with normal (Wild type, WT) and degenerate (Royal College of Surgeons, RCS) retina. Cortical responses (Visual Evoked Potentials, VEP) to pulsed NIR (915nm) and visible (635nm) light stimulation were recorded over a 6 month follow-up period. Stimuli were modulated by pulse duration, peak irradiance and repetition rate. Results: Stimulation thresholds with 10 ms pulses were, on average 0.5mW/mm2 for 70um pixels and 0.25 mW/mm2 for 140um pixels. Latency of the visible light-induced VEP decreased with increasing irradiance, unlike the latency of electrically-induced VEP (eVEP), which was significantly shorter, and did not vary with NIR light irradiance. In both, WT and RCS rats the eVEP amplitude increased with peak irradiance and pulse duration, and decreased with increasing frequency in the range of 2-20Hz, similar to the visible light

J Mol Neurosci

response. However, from 20 to 40Hz the VEP continued to decrease, while the eVEP did not change as much. Conclusions: Robust cortical responses to photovoltaic subretinal stimulation and similarity of the eVEP modulation by NIR irradiance, pulse duration and frequency to VEP modulation by visible light suggest similarity in processing of the retinal responses elicited by both types of stimuli at the visual cortex. The small size and lack of wires makes photovoltaic arrays easy to implant and well tolerated in the subretinal space. Photovoltaic retinal prostheses offer a promising approach to restoration of sight in patients blinded by retinal degenerative diseases. Cortical plasticity following perceptual learning Maor I. 1,2,3, Mizrahi A. 1,2,3* 1 Dept. of Neurobiology, The Hebrew Univ. of Jerusalem, Jerusalem, Israel 2 The Edmond and Lily Safra Center for Brain Sciences, The Hebrew Univ. of Jerusalem 3 Interdisciplinary Center for Neural Computation, Hebrew Univ. of Jerusalem Perceptual learning is a cognitive phenomenon whereby perceptual capabilities improve with training. The neural substrate of perceptual learning is not well understood but probably involves multiple brain regions, one of which is the neocortex. Our work focuses on how learned information is encoded at the functional level by individual cortical neurons. Our model is the primary auditory cortex (A1) of the mouse. We study how different subpopulations of neurons in A1, e.g. inhibitory neurons and excitatory pyramidal cells, encode the learned information. First, to study perceptual learning in mice, we developed an automated assay in a learning chamber that we named "the Educage". The Educage is designed to train groups of mice (up to 6 mice simultaneously) on a two-tone 'go no-go' discrimination task. Once the procedure is learned, task difficulty is gradually increased by decreasing the difference between the two tones. Using this procedure, mice became experts in this task and reached their perceptual limits within thousands of trials. Second, to study the physiological correlates of learning in A1, we used in vivo two photon targeted patch clamp to asses basic response properties of inhibitory and excitatory neurons of layer 2/3. As inhibitory neurons, we targeted Parvalbumin positive (PV+) interneurons, the largest inhibitory subpopulation of the cortex. We used transgenic mice expressing TdTomato in PV neurons and used unlabeled neurons as controls (PV−). We compared the frequency receptive fields and other response properties (e.g. response latency, spontaneous and evoked firing rate) of PV+ and PV− neurons in A1 of expert and naïve mice. To date, the data we collected already

reveals that PV+ and PV- neurons changed in unique ways following learning. We suggest that specific modifications in inhibitory circuits within layer 2/3 of A1 contribute to auditory perceptual learning. Linking nigrostriatal dopaminergic plasticity to neurogenesis, inflammation and Wnt/beta-catenin signaling : therapeutical implications for Parkinson's Disease Marchetti B 1,2*, L'Episcopo F 1,2, Tirolo C 2, Testa N 2, Caniglia S 2, Serapide M.F. 1 Dept. of Clin. Mol. Biomedicine, Pharmacol. Section, Univ. of Catania medical School, Italy 2OASI Scientific Institute for Res. and Care (IRCCS) Neuropharmacol. Section; Troina (EN), Italy Background: Inflammation and oxidative stress are the hallmarks ofaging and neurodegenerative diseases including Parkinson's disease, (PD) a commonneurodegenerative disorder, characterized by progressive loss of dopaminergic(DAergic) neuronal cell bodies in the subtantia nigra pars compacta (SNpc) andgliosis. In particular, the aging process isassociated to a gradual decline of DAergicneuron plasticity, dysfunctional glia-neuron crosstalk and limited neurogenicpotential. The Wingless-type MMTV integration site (Wnt) signalingcascade has emerged as an essential system regulating multiple processes indeveloping and adult tissues. Particularly, dysregulation of Wnt signalingin major neurodegenerative disorders has recently emerged. Results: Here,we highlight dysfunctional "Wnt/β-cateninneuroimmunedialogue" with age in the MPTP(1-methyl-4phenyl-1,2,3,6-tetrahydropyridine) mouse model of PD, by presenting both in vivo and vitro evidencesdocumenting that aging andinflammation/oxidativestress stronglyantagonize Wnt/β-catenin signaling in DAergic neurons and subventricular zone, onemajor niche for adult neurogenesis, with consequences for DAergicneuroprotection/repair. We report dysregulation of the crosstalk between Wnt/β-catenin signaling and critical inflammatory/anti-inflammatory and pivotal survivalpathways, including the Nuclear factorE2related factor 2 (Nrf2)-hemeoxygenase(Hmox)and phosphatidylinositol3-kinase (PI3K)/Akt. Importantly, pharmac olo gical activatio n/antagonism studies, in vivo and in vitro, suggest the potential for aged SVZ manipulation associated to DAergic functional recovery Conclusions: Together,these findings delineate a novelmechanism driving reduced SVZ plasticity linked to the limited DAergicself-repair capacity observed with age. These findings hold promise for the development of targeted therapies focusing on modulationof Wnt/β-catenin signaling to enhanceendogenous neurogenesis and neuronal outcome in PD.

J Mol Neurosci

The effect of basic emotions on directed forgetting – an fMRI study Marchewka A. 1*, Jednorog K 2, Michałowski J 3, Riegel M 1, Nowicka A. 4 1 Laboratory of Brain Imaging, Neurobiology Center, Nencki Institute of Experimental Biology, Poland 2 Laboratory of Psychophysiology,Nencki Institute of Experimental Biology, Poland 3Univ. of Warsaw, Poland 4 Laboratory of Psychophysiology, Nencki Institute of Experimental Biology, Poland Background: Memory for emotional information, especially when it is negatively charged, is usually better and more vivid, while forgetting of such information is difficult and requires considerable effort. Here, for the first time, we investigated whether memory enhancement is influenced by the discrete category of basic negative emotions. For this aim we used directed forgetting item-method paradigm with pictures evoking 3 different basic categories of negative emotions: disgust, fear and sadness as well as neutral ones. Images were taken from databases available for neuroscience community: Nencki Affective Picture System, Geneva Affective Picture Database and International Affective Picture System. Initial subdivision for categories was confirmed by the participants' ratings. Explicit instruction either to remember (R) or to forget (F) was given after each image presentation. Results: Behaviorally, there was a significant directed forgetting effect and an increased recognition rate for emotion evoking compared to neutral images. Furthermore, there was a significant effect of discrete emotion category. For both R and F instruction, pictures evoking disgust were better remembered and more difficult to be forgotten than all other categories of pictures, whereas images evoking fear produced higher number of false alarms. On the neuronal level we observed corresponding stronger effect of F instruction for disgust. Conclusions: The preliminary findings of our study suggest that discrete emotional categories differentiate both processes of forgetting and remembering. Is it regret I see in your brain? looking for the electrophysiological correlates of regret Marciano Romm D. 1,2*, Deouell L. 1,3, Bentin, S. 1,3 1 Dept. of Psychology, Hebrew Univ. 2 The Center for the Study of Rationality, Hebrew Univ. 3 ELSC, Hebrew Univ. Background: Regret is defined as the negative emotion we experience when we realize or imagine that our present situation could have been better had we chosen differently in the past. This definition implies that the alternative outcome, that is, the unselected option in a decision-making task, somehow influences the evaluation of the chosen outcome, even though it is economically neutral. It also implies that this influence should differ whether an individual was responsible for the choice that was made. In this study we tested whether the

feedback-related negativity (FRN), an early event-related potential associated with outcome evaluation, is sensitive to regret. We used a simple computerized decision-making task in which participants were shown two cards. Each card could hide a green coin (gain) or a red coin (loss). In half of the trials participants were asked to choose one card, and on half of the trials the software randomly picked one card. The alternative outcome was always presented before the chosen outcome. We hypothesized that the FRN elicited by the chosen outcome would be influenced by the valence of the alternative outcome. We also hypothesized that this effect of the alternative outcome on the FRN would be modulated by the sense of responsibility of the participants in the decision-making process. Results: The results confirmed both hypotheses. The FRN elicited by the chosen outcome was influenced by the valence of the alternative outcome, and this effect disappeared when the computer, and not the participants, was responsible for the choice made. Conclusion: Taken together, these two findings indicate that the FRN might be sensitive to regret, and shed light on the temporal dynamics of regret. In future research the FRN might be used as an objective measure of regret as it provides an insight on the emotional state of participants without requiring them to actively report it. POMC CPG methylation is associated with high fat diet induced perinatal programming of weight gain Marco A 1,2, Kisliouk T 3, Tabachnik T 1,2, Lavi Y 1,2, Eliyahu L 1,2, Meiri N 3, Weller A 4,2* 1 Faculty of Life Sciences, Bar-Ilan Univ. 2 Gonda Brain Research Center, Bar-Ilan Univ. 3 Institute of Animal Science, ARO, The Volcani Center 4 Dept. of Psychology, Bar Ilan Univ. Background: The neuropeptide POMC is a major regulator of food intake and body weight (BW). We studied an epigenetic mechanism affecting hypothalamic arcuate nucleus expression of Pomc, examining its role in nutritional environmental influences during early development. Methods: Rats received either high fat (HFD) or standard diet (C) from weaning to adulthood. In separate groups, females received these diets throughout pregnancy and lactation ("Dams"). Results: HFD fed male and female rats were significantly heavier than C, with higher plasma leptin levels but no changes in Arc mRNA expression levels of Pomc. The Pomc promoter area in HFD rats was found to be hypermethylated. As expected, in males, the HF diet resulted in up-regulation of the transcription factor Sp1, essential for Pomc expression. Furthermore, Sp1 binding to the hypermethylated Pomc promoter was significantly reduced. Despite significant weight differences between the diet groups during pregnancy and postpartum, at 3-weeks lactation HFD treated dams presented a sharper decrease in BW. As a result, both maternal groups

J Mol Neurosci

presented similar BW, leptin levels, Pomc mRNA expression and methylation pattern on the Pomc promoter. Compared to the HFD virgin female group, HFD dams (after 3-weeks of lactation) presented significantly lower leptin and similar mRNA Pomc levels. In addition, hypermethylation on the Pomc promoter, observed in the HFDtreated virgins, was absent in lactating rats. Nevertheless, the female offspring of the HFD-treated dams, on day 22, presented significantly increased BW, leptin, hypermethylation of the Pomc promoter and of H3K9 compared to the C offspring. Conclusions: Hypermethylation on Pomc gene promoter may emerge at post-lactation periods and interfere with transcription factor binding. This may be one of the "programming" mechanisms that underlie the detrimental effects of HFD exposure during development, increasing the individual's risk of developing obesity. [Support: ISF]. Dorsal vs. ventral hippocampus: space vs emotion or degree of sensitivity to change? Markus E 1*, Swanson A 1, Schmidt B 2, Satvat E, Marrone D 3 1 Univ. of Connecticut 2 Univ. of Minnesota 3 Wilfrid Laurier Univ. Background: The link between the hippocampus and episodic memory is well known. The hippocampus however, is not a homogenous structure. Determining the manner in which different regions work in parallel and/or interact will provide a better understanding of how information is processed within this system. Based on connectivity and results of lesion studies it has been proposed that the dorsal hippocampus processes spatial while the ventral hippocampus emotional information. Given the importance of the hippocampus in navigation we provided an "episodic event" where animals maintained a fixed trajectory and motor behavior under two different "cognitive" conditions. One manipulation was a change in task strategy the other caused a change in emotional context. Results: Using immediate early genes to identify individual cells that differentiated between our task manipulations, we found heterogeneity both along the longitudinal axis (dorsal/septal vs. ventral/temporal) and among sub-regions of the hippocampus (DG, CA1, CA3). Similarly local field potential recordings show differences in theta frequency, a correlation with running speed, and differences in power and coherence along the longitudinal axis. Conclusions: These data support and extend upon previous reports of regional differences in the hippocampal system. Our data indicate that both the dorsal and ventral regions of the hippocampus are involved in processing a navigation task. Furthermore it seems that the dorsal hippocampus is more

sensitive to change, regardless of it being spatial or emotional in nature. NIH to EJM; NSERC & OMHF to DFM A data-driven approach for characterizing human brain networks that are involved in response to stress Maron-Katz A. 1,2,3*, Vaisvaser S. 1,2,4, Lin T. 1,5, Bar-Haim Y. 5, Shamir R. 3, Hendler T. 1,2 1 Functional Brain Center, Wohl Institute for Advanced Imaging, Tel Aviv Sourasky Medical Center 2 School of Psychological Sciences, Faculty of Medicine, Tel Aviv Univ. 3 Blavatnik School of Computer Science, Tel-Aviv Univ. 4 Sagol School of Neuroscience, Tel Aviv Univ. 5 School of Psychological Sciences, Tel Aviv Univ., Tel Aviv, Israel Exposure to acute stress has been shown to induce various short term physiological and neural changes. Several studies have used fMRI to examine changes in neural functional connectivity (FC) following exposure to stress. However, to date this has been done by focusing on a specific region of interest (seed-based). The usage of seed based analysis was, in part, due to the statistical limitation of whole-brain FC analysis, which involves a large number of comparisons. Here we used a data-driven approach in order to examine FC changes induced by acute social stress during fMRI scanning. To overcome the statistical limitation we adopted a parcellation scheme, thus reducing the dimensionality of the problem. We applied this approach on resting state fMRI data recorded from 57 healthy male subjects before and after performing a social stress inducing task. We conducted the analysis both across all subjects and after partitioning subjects into two groups based on the change in their subjective stress ratings. FC patterns before and after stress were calculated using Pearson correlation and Fisher transformed to better fit a normal distribution. Values were compared using a onesample t-test, and p-values were FDR corrected (FDR<=0.05). We identified a large number (490) of significant FC changes, of which 190 get stronger. Interestingly, while most of the connections that were strengthened link cortical regions with subcortical regions, over 90% of the connections that got weaker link cortical regions to other cortical regions. A comparison of FC changes between two subject groups based on changes in subjective stress ratings, revealed a single connection, which links the right amygdala to the right precuneus. Results indicate a large scale phenomena of FC changes following exposure to acute stress. In addition, they demonstrate how dimensionality reduction can contribute to our ability to analyze fMRI data, and facilitate the discovery of novel unpredicted findings. Supported in part by the Ministry of Science and Technology, Israel and US Dept. of Defense.

J Mol Neurosci

Novel tubulin and tau neuroprotective fragments sharing structural and functional similarities with the drug candidate NAP (davuentide) Maryanovsky E. 1, Iram T. 1, Schirer Y. 1, Giladi E. 1, FurmanAssaf S. 1, Gozes I. 2,3,4,1* 1 Dept. of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, TAU Univ. 2 The Adams Super Center for Brain Studies and Sagol School of Neuroscience 3 The Lily and Avraham Gildor Chair for the Investigation of Growth Factors 4The Elton Laboratory for Neuroendocrinology NAP (NAPVSIPQ, davunetide) is a microtubule stabilizing peptide drug candidate. Here, we set out to identify NAP-like peptides that provide neuroprotection. NAP-like peptides were derived using publically available search engines, which identified sequence homologies in the microtubule subunit tubulin and in the microtubule associated protein, tau. NATLSIHQ (NAT), and STPTAIPQ were derived from tubulin and TAPVPMPD (TAP), was derived from tau. All peptides provided neuroprotection against the Alzheimer's disease (AD) toxin, the beta amyloid 1-42 peptide, although NAT and TAP were much more potent than STPTAIPQ. NAT also protected astrocytes, while STPTAIPQ was active only at micromolar concentrations. Protection was also measured against zinc intoxication in a pheochrmocytoma (PC12), neuronal-like differentiation model. Because NAT and TAP were much more potent than STPTAIPQ in neuroprotection, those peptides were also tested for inhibition of tau-like aggregation (the second protein hallmark pathology of AD). Both NAT and TAP inhibited tau-like aggregation, with NAT being active over a very broad concentration range. NAT also protected in vivo in a frontotemporal dementia (FTD) transgenic mouse model (TauTg), when tested at the age of ~10 months. Results showed significantly decreased levels of the NAP parent protein, activity-dependent neuroprotective protein (ADNP) in the cerebral cortex of the Tau-Tg which was increased back to normal levels by NAT treatment. This was coupled to protection of Brain-Body weight ratio in the compromised Tau-Tg. With AD being the major tauopathy and with tau taking part in FTD, novel NAP derivatives that reduce tauopathy and provide neuroprotection, are of basic and clinical interest. Support: The AMN Foundation, CFTAU Montreal Circle of Friends and the Adams family. NEAT, a comprehensive multi-channel neural activity analysis toolbox Mayblum T. 1, Luz T. 1, Naor O. 1,2, Shoham S. 1* 1 Faculty of Biomedical Engineering, the Technion - I.I.T., Haifa, Israel 2 The Interdisciplinary Centre for Neural Computation, The Hebrew Univ. of Jerusalem Background: Many neuro-engineering and neuroscience research applications make use of multi-channel recording

devices, such as multi-electrode arrays (MEAs), as a common method for monitoring neural population activity at a singleunit level. Given the large amounts of data, advanced tools for processing and conducting elaborate analysis are becoming essential. Our work meets this need by introducing such a tool, supporting up to 256 channels of neural activity recordings. Implementation: We have developed a toolbox for display and analysis of multi-channel neural activity in online and offline work modes. The toolbox provides the user with various features, including several raw data representations and common analysis methods, such as PSTH and raster graphs. Furthermore, we incorporated advanced spike sorting algorithms and receptive fields mapping, combined with newly developed noise removal procedures. The toolbox is being used extensively during experiments involving stimulation of isolated mouse retinas, where the responses are recorded using a 256 MEA. It proves to be useful for online analysis, instantly displaying results of analyzed responses in a multi-channel view. Offline analysis of data from multiple experiments exhibits added value, improving spike sorting results and allowing a more profound analysis. Conclusion: We have developed a toolbox for display and analysis of recorded 256-channels neural activity. Our toolbox provides the user with various common methods, which combined with advanced spike sorting algorithms, enable elaborate analysis of neural responses. The toolbox proved to be useful during lab research, and attracted interest from several other labs. Being open-source and complying with standard neuroscience community file formats, it will be available for generic use with various experimental and recording setups. Brain molecular targets of the multifunctional iron chelating drug, M30 in type 2 diabetes mellitus mice models Mechlovich D. 1, Amit T. 1, Mandel S. 1, Bar-Am O. 1, Youdim M.B.H. 1, Weinreb O. 1* 1 Eve Topf Center of Neurodegenerative Diseases Research, Faculty of Medicine, Technion, Haifa, Israel Background: Insulin resistance, or hyperinsulinaemia and impaired glucose tolerance associated with insulin resistance were demonstrated to enhance the progression of neurodegeneration responsible for the symptoms of cognitive decline and dementia. The concept of complex etiology in neurodegenerative diseases led our group to develop a number of multifunctional, nontoxic, brain permeable compounds with iron chelation and anti-apoptotic properties. One leading multitarget compound, M30 possesses the neuroprotective Npropargyl moiety of the anti-Parkinsonian, monoamine oxidase (MAO)-B inhibitor, rasagiline (Azilect®) and the antioxidant-iron chelating moiety of the 8-hydroxyquinoline derivative, VK28. In the present study, we evaluated the effect of the drug on brain molecular mechanisms in type 2 diabetes

J Mol Neurosci

mellitus (T2DM) experimental models (high fat diet (HFD) and ob/ob Tg mice). Results: Our results demonstrated that M30 increased cerebral levels of insulin/InsR and phosphor-glycogen synthase kinase-3β in HFD mice, as compared to vehicle-treated HFD mice. In both T2DM mice models, M30 treatment produced a significant up-regulation of cerebral hypoxia-inducible factor (HIF)-1α protein levels and induced the expression of HIF-1targets genes involved in neuroprotection and glycolysis (glucose transporter-1 and -3, enolase-1, and aldolase). Additionally, M30 caused a significant inhibition of both MAO-A and B activities in the cerebellum. In accordance, M30 administration significantly reduced brain levels of the metabolites of dopamine and increased the levels of serotonin and noradrenaline. Conclusions: Our data demonstrated that in the brain of HFD and ob/ob Tg mice, M30 exhibits various beneficial regulatory effects, which might be attributed to the multi-modal design paradigm of our drug. It is suggested that all these favorable regulatory effects may act synergistically with other molecular mechanisms to prevent or delay neurodegenerative processes in T2DM. Epigenetic regulatory mechanisms of thermal stress response development Meiri N. 1*, Kisliouk T. 1, Yossifoff M. 1, Cramer T. 1 1 Institute of Animal Science, ARO, TheVolcani Center, Bet Dagan, 50250, Israel Background: Thermal stress during the critical postnatal sensory developmental period determines a delicate balance of a probably adjustable stress response set-point. The adjustment of the thermal-response is determined by hypothalamic neuronal network remodeling which might be accompanied by alteration in the repertoire of expressed proteins and in variation in neuronal hypothalamic cell populations. Here we describe epigenetic changes associated with heat stress response in chicks during thermal control establishment and as a consequence during heat challenge later in life. Results: We have found that heat stress during the critical period of thermal control establishment in 3-days-old chicks renders habituated or sensitized response, which is dependent on the ambient temperature and at least partially regulated by CRH. Moreover, we demonstrated three different levels of epigenetic regulation underlying heat stress resilience, focusing on neurotropic activity in the anterior hypothalamus (BDNF-R-Ras3 signal transduction pathway) and neurogenesis: 1. Alterations of histone H3 post translation modifications at lysine 9 (H3K9) and lysine 27 (H3K27) at the promoters of BDNF and eiF2B; 2. Alterations of CpG methylation at the BDNF promoter interfering CREB binding to the DNA; 3. The role of microRNA, miR-138 specifically, in thermal control establishment and hypothalamic

neurogenesis via its inhibitory effect on H3K27 specific methyltransferase (EZH2) and reelin, respectively. Conclusion: These data demonstrate a multilevel epigenetic regulatory mechanism of response to stress, which can be fine-tuned during the critical sensory developmental period. BARD, ISF, The chief scientist of the Israeli ministry of agriculture The ability of the 4 – 6 y.o. children to recognize and express emotions and the brain maturation Mekler A.A. 1*, Vishnevetskaya E.V. 2 1 The Bonch-Bruevich Saint-Petersburg State Univ. of Telecommunications, Russia, [email protected] 2 South-Ural State Univ., Cheliabinsk, Russia Background: The emotional development of an infant is a factor which determines his further psychological status in childhood as well as in further adult life. Thus the study of emotional development on the early stages of ontogenesis and the underlying neurophysiological processes is of a special interest. The meaning of the emotional intelligence concept may slightly vary in different theories, but in most contexts it includes the subjects' ability to recognize, express and control his emotions as well as emotions of other people. We consider the abilities to recognize and express emotions as an emotional competence (EC). The present study is an attempt to find relations between the EC and the brain development. The latter was evaluated via the electroencephalography methods. Anohin et. al. (1996) and Polonnikov et. al. (2003) showed that the EEG complexity increases with aging. Our studies revealed the same. The EEG complexity in all mentioned studies was evaluated by the correlation dimension of the EEG reconstructed attractor or the EEG curve fractal dimension. Results: We studied the EC of children of 4 – 6 y.o. We used the D2 value as a brain maturation indicator. The EC of the children was evaluated using specially developed test. Statistical analysis showed that there is direct relation between the children's ability to recognize emotions (leads C3 and T3) and the ability to express emotions (Fz, C3, P3 and O1) Conclusions: Our study showed that EC of 4 – 6 y.o. children is related with the brain maturation of the left hemisphere zones. One can make a somewhat «oldfasioned» conclusion that this means relation of EC and the speech zones development. We suppose that in spite of discussiblness of the speech function localization there is a relation between the EC and the brain systems involved in the social communication functions, that is quite reasonable from the theoretical point of view.

J Mol Neurosci

Identification of the genes for the glioblastoma subtyping by Kohonen self-organizing maps Knyazeva I.S. 1, Mekler A.A. 2*, Dmitrenko V.V. 3, Iershov A.V. 3, Kavsan V.M. 3 1 Central Astronomical Observatory of the RAS at Pulkovo, Saint-Petersburg, Russia 2 The Bonch-Bruevich SaintPetersburg State Univ. of Telecommunications, Russia, [email protected] 3 Institute of Molecular Biology and Genetics of NASU, Kiev, Ukraine Background: Molecular classification of glioblastoma may result in development of new targeted therapies. Gene expression data of glioblastoma samples available in Gene Expression Omnibus (GEO) Database were analyzed with the aim of the identification of glioblastoma molecular subtypes. Entropy analysis and Kohonen self-organizing maps (SOMs) were used for the selection of the most informative genes, whose expression levels are applicable to distinguish the glioblastoma molecular variants. Results: GEO database contains the data concerning the expression of 12480 genes in 144 glioblastoma samples. Main task of the study was to select a subset of features that will give a well-defined clusterization of glioblastoma samples analyzed. Such features were selected in several steps. Entropy analysis was used at the first because it helps us to find the most varying features and increases in this way chances to find subgroups. 474 genes with highest entropy of their expression levels in glioblastomas were selected. On the next step we trained the SOM by all possible pairs of genes mapping each time the data onto it. For every pair of genes a quantization error (QE) was calculated. Then we took those pairs, for which QE is less than 0.04. Then we calculated for each gene of this set, how many pairs contain it. We set a threshold as 30 times and found that 26 genes are in more than 30 pairs. This is the sign that these genes may split selection into several subclasses. We trained SOM and applied to it Kmeans method using different number of clusters and calculating each time the Davies–Bouldin index. The best clusterization was when number of clusters was four. Conclusions: Obtained results showed that glioblastomas may be divided at least into four molecular subtypes and further studies should give more information on these subtypes. Study was supported by the RFBR grant #12-04-90434-Укр_а and Ukrainian NAS grant #07-0412 Locus K: novel denomination for cuneate subnuclear regions in the human dorsal column nuclei with neurochemical, cyto- and myeloarchitectural features of the protopathic sensory nuclei Melis T. 1, Boi M. 1, Poddighe L. 1, Picci C. 1, Serra M.P. 1, Quartu M. 1, Del Fiacco M. 1* 1 Dept. of Biomedical Sciences, Section of Cytomorphology, Univ. of Cagliari, Italy

Background: We have shown that, in the human newborn and adult medulla oblongata, the territory of the cuneate nucleus and fascicle hosts discrete gray matter subregions whose neurochemical features are remarkably similar to those of the second order sensory nuclei that relay protopathic stimuli, including pain (Del Fiacco et al., Brain Struct. Funct. 2013). Those areas appear distinct from the known subdivisions of the dorsal column nuclear complex described by early and recent literature. Here, we provide a further histochemical and a histological characterization of those subregions and propose a denomination for them. Results: Immunoreactivity to the transient receptor potential vanilloid type 1 receptor (TRPV1), absent in the main nucleus, occurs in the cuneate subregions as well as in the superficial layers of the spinal trigeminal nucleus, caudal part (Sp5C). Computerized analysis of cell size and density shows that, in adult tissue, the mean cell diameter of Nissl stained neurons ranges 6-32 (mean 15) mm in the main cuneate nucleus, and 5-18 (mean 9) mm in both the TRPV1-immunoreactive cuneate subregions and Sp5C substantia gelatinosa. In the same three regions, the mean cell density values amount to 159/ mm2, 872/mm2, and 560/mm2, respectively. Differences in cell size and density among the three regions are statistically significant. Luxol fast and Black Gold kit II staining shows that myelinated fibres, abundant in the main cuneate nucleus, are scarce in both the discrete cuneate subregions and Sp5C substantia gelatinosa. Conclusions: Immunoreactivity to TRPV1 and cyto- and myeloarchitectural analysis uphold the parallel neurochemical and structural setting for the distinct cuneate subregions and Sp5C in the human medulla oblongata. Our data support the concept that those cuneate subregions represent a special component of the human dorsal column nuclei and, from the ancient name of our town, Karalis, we propose to name it Locus K. A role for midbrain 2-arachidonoylglycerol signalling in increased consumption of and preference for ethanol in Sardinian alcohol-preferring rats Melis, M 1*, Colombo, G 2, Pistis, M 1 1 Dept. Biomedical Sciences, Univ. of Cagliari, Italy 2 Institute of Neuroscience, CNR, Italy Background: Sardinian alcohol-preferring (sP) or -non preferring (sNP) rats are one of the few pairs of lines of rats selectively bred for their voluntary alcohol preference or aversion, respectively. The ventral tegmental area (VTA) dopamine (DA) neurons have long been implicated in many drugrelated behaviors, including alcohol self-administration. Indeed, the VTA is a key component of brain reward circuitry. Endocannabinoids (eCBs), retrograde signaling molecules at many synapses in the brain, regulate reward seeking by modulating DA signaling, and interact with alcohol to produce its

J Mol Neurosci

reinforcing effects. Here we took advantage of significant differences in alcohol self-administration displayed by sP and sNP rats, and investigated VTA DA cell synaptic properties ex vivo. Results: sP rats showed a decreased probability of GABA release at two discrete sets of inhibitory synapses onto VTA DA neurons. Because eCBs activating presynaptic cannabinoid-type 1 (CB1) receptors inhibit neurotransmitter release, we studied an endocannabinoid-mediated form of short term synaptic plasticity, that is depolarization-induced suppression of inhibition (DSI). sP rats express different DSI at both synapses onto VTA DA neurons. Both DSI are mediated by 2-arachidonoylglycerol (2-AG), which activates CB1 receptors. However, two discrete DSI do not depend upon differences in CB1 number and/or function, but rather to a tonic 2-AG signalling. Conclusions: 2-AG by tonically depressing inhibitory synapses might indirectly alter DA neuron functional state, and enhance the responsiveness of reward pathway to phasic DA. Our results suggest that differences in molecular architecture of 2-AG signaling might contribute to regulate responses to aversive intrinsic properties to alcohol, thus resulting in faster acquisition/initiation of alcohol drinking that may be associated to alcohol preference. Role of notch in neural structural plasticity Memo M.*1, Bonini S.A.1, Ferrari-Toninelli G.1 1 Dept. of Molecular and Translational Medicine, Univ. of Brescia, Viale Europa 11, 25123 Brescia, Italy Background: Functional and structural plasticity, often referred to as “neuroplasticity”, is a fundamental property of the brain involving chemical, electrical, molecular and cellular responses and leading to reorganization of connections within a brain region and/or between brain regions. Notch signalling pathway has been mainly recognized as one of the main contributors in regulating neural development and has been proposed as a key mediator in neuroplasticity. We further supported this concept, demonstrating that Notch plays a role in determination of the only possible “cell fate” decisions in post-mitotic mature neurons: synaptic remodelling or neurite extension/retraction. Results: Primary cortical neurons and differentiated human SH-SY5Y neuroblastoma cells were analyzed in terms of neuron morphology and functionality. In primary cortical neurons, we demonstrated that Notch pathway activation causes a decrease in neurite branching and a loss of varicosities, with consequent reduction in release of neurotransmitter. Furthermore, in dysfunctional neurons that present an hyper-activation of the Notch pathway, neuronal morphological effects were reversed after treatment with the γ-secretase inhibitor DAPT or Notch RNA interference.

Conclusions: Potentially, a better understanding of the molecular events participating in neuroplasticity may prove relevant information for innovative therapeutic approaches in a variety of neurological disorders, including Alzheimer’s disease (AD). On these basis, we propose a Notch signalling finetuned manipulation as a novel approach to modulate neuronal cytoskeleton plasticity in order to prevent dysfunctional structural plasticity in neurodegenerative diseases. Parole chiave: neurite remodelling, neuroplasticity, Notch pathway, cytoskeletal protection, dysfunctional neurons, Alzheimer’s disease Motivational cues enhance mental action in the human brain Mendelsohn A. 1*, Pine A. 2, Schiller D. 1 1 Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York 2Neurobiology, Weizmann Institute of Science Background: Desires, urges, and wishes pertinent to obtaining rewards are key components in maintaining goaldirected behavior. These mental processes can turn disruptive, such that individuals become subject to intrusive and unwanted thoughts about obtaining desired rewards. Moreover, intrusive thoughts regarding reward seeking are predictive of substance abuse relapse and binge eating, and are strongly encouraged by the presence of environmental cues associated with these rewards. Using real-time fMRI to reward goal-specific brain activation, we investigated how cues imbued with motivational salience affect motor imagery networks preceding action. Results: The concomitant presentation of reward-related cues during motor imagery enhanced neural responses in motivational centers (ventral caudate and amygdala), and exerted a motivational effect in imagery brain networks. Moreover, functional connectivity between ventral caudate and motor cortex was heightened during imagery in the presence of the reward-related cue. Conclusions: The concurrent activation of "value" and "action" networks illuminate the neural process that links motivational cues to desires and urges to obtain goals, shedding light on the neural means by which environmental cues may bring about unwilling thoughts that support maladaptive behaviors such as relapse to substance abuse. ApoE4 directed therapy of Alzheimer's disease targeting both gain of toxicity and loss of function Michaelson D.M. 1*, Boehm-Cagan A. 1, Luz I. 1 1 Dept. of Neurobiology, Sagol School of Neurosciences, Tel Aviv Univ. Israel 69978 Background: The pathological effects of apoE4, the most prevalent genetic risk factor of Alzheimer's disease (AD), can be due to loss of a structural feature which the

J Mol Neurosci

"good"apoE3 allele(s) possesses and/or to gain of structural feature specific to apoE4. We will presently examine the extent to which such mechanisms mediate the effects of apoE4. The contribution of the gain of structural effects of apoE4 will be assessed by investigation of the extent to which the pathological effects of apoE4 can be counteracted by i.c.v. injection of anti-apoE4 mAbs. The possible role of loss of structure related mechanisms will be assessed by measurements of the extent to which correction of the impaired lipidation of apoE4 utilizing the RXR-agonist Bexarotene can reverse its pathological effects. Results: We have recently shown utilizing apoE3- and apoE4targeted replacement mice that apoE4 triggers cognitive impairments. This is associated with the accumulation of Aβ42 and of hyperphosphorylated tau in hippocampal neurons and down regulation the levels of the presynaptic glutamate transporter Vglut1 and of the apoE receptor apoER2. Both i.c.v injections of anti-apoE4 mAb and oral application of Bexarotene reversed the cognitive impairments of the apoE4 mice and abolished their tau hyperphosphorylation. In contrast Bexarotene, but not the anti-apoE4 mAb, counteracted the effects of apoE4 on Aβ42 and Vglut whereas the antiapoE4 mAbs, but not Bexarotene, counteracted the effects of apoE4 on the apoE receptor apoER2. Conclusion: Taken together the findings show that the pathological effects of apoE4 are mediated by both loss and gain of structural features and that apoE4 directed therapy should target both the gain and loss of structural features of apoE4. Navigation in the labyrinth of epileptogensis – from vessels via glia to hyperexcitable neuronal network Milikovsky D.Z. 1, Levy N. 1,2, Wood L. 3, Weissberg I. 1, Baranuskas G. 1, Vinogradov E. 2, Kamintsky L. 1, Abutbul S. 2, Fleidervish I. 1, Kaufer D. 3, Monsonego A. 2, Friedman A. 1* 1 The Dept. of Physiology & Cell Biology and Cognitive & Brain Sciences 2 Shraga Segal Dept. of Microbiology Immunology and Genetics, Zlotowski Center for Neuroscience, BGU 3 Dept. of Integrative Biology and Helen Wills Neuroscience Institute, Univ. of California, Berkeley Background: Epilepsy is a frequent complication of brain injuries of any origin. Blood-brain barrier (BBB) dysfunction, a common hallmark of brain lesions, has been shown to induce epileptogenesis by the associated extravasation of serum albumin and TGF-β signaling. In pursuing of understanding of post-injury epileptogenesis and explore the role of inflammatory cascade we performed in-vitro and in-vivo experiments to study the effect of albumin and TGF-β1 on the secretion of cytokines, and their possible role in neuronal excitability. Results: In primary glial cultures, TGF-β1 induces rapid upregulation of the cytokine IL-6, followed by elevation of TNF-α and IL-1β levels. IL-6 was mainly upregulated in

astrocytes, but not in microglia, via phosphorylation and nuclear translocation of SMAD2/3. Notably, expression, phosphorylation and nuclear translocation of SMAD3 are more abundant in astrocytes then in microglia. In-vivo recordings following intraventricular application of IL-6 led to development of spontaneous seizures, from day 3 after perfusion initiation. Intracellular recordings of neocortical layer V pyramidal neurons obtained from IL-6-treated mice (72-96 hrs after icv injection) showed no alterations in intrinsic neuronal properties, but frequency-dependent prolonged afterdepolarization in response to extracellular stimulation. Finally, real time PCR and Immunohistochemistry showed significant elevation in markers of excitatory synapses both in vitro and in the brains of albumin treated mice. Conclusion: TGF-β signaling in astrocytes, via differential SMAD2/3 signaling, results in the early upregulation of IL-6, which is sufficient to induce neuronal hyperexcitability, probably through astrocytic-dependant mechanism. Early increased neuronal excitability is followed by synaptogenesis, aletered rythmogenesis and epilepsy. Transparently stressed Mishor E 1, Reuveny A 2, Levkowitz G 3* 1 Dept. of Molecular Cell Biology, Weizmann Institute of Science 2 Dept. of Molecular Genetics, Weizmann Institute of Science 3 Dept. of Molecular Cell Biology, Weizmann Institute of Science Corticosteroids are steroid based hormones secreted from the adrenal gland cortex in response to a challenge via the Hypothalamic-Pituitary-Adrenal (HPA) axis. Corticosteroids act on the brain in the stress response as a feedback link between the periphery and the CNS. The aim of this research is to examine the feedback of corticosteroids on the brain using new genetic perturbations of the HPA axis. Disruption of the HPA axis was achieved by ablation of Adrenocorticotropic hormone (ACTH) secreting cells. The cells were ablated using a new POMC:GAL4;UAS:NTR-Cherry transgenic line, which induces cell death in a genetic identity-based, temporal restricted manner. In addition, using optogenetic tools developed in our lab (POMC:Channelrhodopsin-2EYFP, POMC:GCaMP5, HUC:GCaMP5) we are able to manipulate and observe ACTH cells' activity in live freely moving larvae. In order to assess endocrine stress response, whole body cortisol levels were measured after a homeostatic challenge using an ELISA assay. For quantitative assessment of behavior during stress response in zebrafish larvae, various behavioral assays were tested on transgenic fish with disrupted HPA axis response. All the upper mentioned approaches combined would advance the ability to observe, assess and understand the processes and neural circuits underlying the stress adaptive response. Examining genetic, molecular and behavioral end points, on top of live neuronal

J Mol Neurosci

imaging will provide an integrated and unbiased understanding of the corticosteroid feedback effect. Distinct spatiotemporal odor outputs from the mouse olfactory bulb Mizrahi A. 1,2 *, Adam Y. 1,2 1 Dept. of Neurobiology, 2The Edmond and Lily Safra Center for Brain Sciences , The Hebrew Univ. of Jerusalem Sensory inputs to the mammalian olfactory bulb (OB) are organized as discrete odor maps that are transmitted downstream to distinct cortical regions. Whether and how odor maps are transformed in the OB is unknown. We used in vivo two-photon calcium imaging to map odor representations by populations of external tufted cells (eTCs) and mitral cells (MCs). We found that odor representations by eTCs faithfully reflected sensory inputs while MCs representations were spatially distributed and heterogeneous. Temporally, eTCs quickly adapted while MCs showed diverse temporal response patterns upon persistent odor exposure. Since local circuits may shape projection neuron computations, we described response profiles of glomerular interneurons (GLINs). GL-INs representations were spatially punctate but temporally rich, suggesting that they contribute to MC computations. Our data suggest that sensory odor maps are computed by eTCs and MCs in different ways forming two distinct and parallel information streams transmitted out of the OB. Effects of morphology and anchoring on new word learning in typically developing children and children with language impairment Moav-Scheff R. 1, Yifat R. 1, Banai K. 1* 1 Dept. of Communication Sciences and Disorders, Univ. of Haifa Background: Anchoring, an implicit learning process that allows individuals to benefit from repeating information has been suggested to play a role in dyslexia as well as in normal early reading acquisition. Although language development involves the implicit learning of linguistic regularities, anchoring has not been studied in the context of impaired language development. Our goal here was to determine whether typically developing (TD) preschool children and children with developmental language impairments (LI) differ in their use of morphological information as an anchor during new word learning. To this end children played a game in which they were exposed to the names and cartoon pictures of alien characters. Their implicit learning of the names and name/picture associations were then tested. Results: In general, typically developing children did better than children with LI in all word learning tests, but both groups used the morphological information to a similar extent. Nevertheless, an analysis of error patterns in a matching task

in which children were given the characters' names and were required to select their pictures from three options, revealed significant group differences. Specifically, on error trials, TD children overwhelmingly selected a character that was encountered during the exposure phase whereas children with LI also selected novel characters that did not appear during the exposure phase. Conclusions: Typically developing children and their LI counterparts appear similarly sensitive to Semitic morphological regularities. However, children with LI exhibit weaker reliance on stimuli encountered during exposure, consistent with an anchoring deficit. That anchoring mechanisms are functional during the preschool period and can be impaired in children LI prior to the onset of formal reading instruction, suggests that anchoring deficits might be an antecedent of reading deficits. This study was supported by the Israel Science Foundation. A novel inhibitor of the insulin/IGF signaling pathway protects from age-onset, neurodegeneration-linked proteotoxicity Moll L. 1, El-Ami T. 1, Carvalhal Marques F. 1, Volovik Y. 1, Reuveni H. 2, Cohen E. 1* 1 Biochemistry and Molecular Biology, The Hebrew Univ. 2 NovoTyr Background: Aging manipulation is an emerging strategy aimed to postpone the manifestation oflate-onset neurodegenerative disorders such as Alzheimer's (AD) andHuntington's diseases (HD) and to slow their progression once emerged. TheInsulin/IGF (Insulin-like growth factor) signaling cascade (IIS), a prominentaging regulating pathway, results after its activation in a negative regulationof the downstream transcription factors DAF-16/FOXO, SKN-1/NRF and theheat shock factor 1 (HSF-1). Reducing the activity IIS protects Caenorhabditis elegans from proteotoxicity of various aggregative proteins, including the AD-associated peptide, Aβ and the HD-linked peptide, polyQ40 mediated by DAF-16 and HSF-1. Similarly, IGF1 signaling reduction protects mice from AD-like disease. These discoveries suggest that IIS inhibitors can serve as new drugs for the treatment of neurodegenerative maladies including AD and HD. Results: In this study we show that NT219, a novel IIS inhibitor, mediates a long-lasting,highly efficient inhibition of the IIS pathway by a dual mechanism; it reducesthe autophosphorylation of the IGF1 receptor and directs the Insulin receptorsubstrates 1 and 2 (IRS 1/2) for degradation in mammalian cells. In C.elegans the treatment with NT219 results in an increase of target genes of the IIS. We demonstrate that the treatment of C.elegans with NT219 increases stressresistance towards heat and UV. Additionally it protects from ADandHD-associated proteotoxicity in nematodes expressing Aβ or polyQ40 in theirbody wall muscles. In these nematodes

J Mol Neurosci

NT219 causes an improvement of age-dependent paralysis and motility. In contrast to daf-2 RNAi, the treatment with NT219 does not affect lifespan of C.elegans. Conclusion: Our discoveries support the theme that IIS inhibition has a therapeutic potentialas a cure for neurodegenerative maladies and point at NT219 as a promisingcompound for the treatment of these disorders through a selective manipulationof aging. This study was generously supported by the Rosetrees Trust (EC) and by the European. Vixapatin, a C-type lectin-protein from Vipera xantina palestinae venom can be used as a pharmacological tool for development of novel CNS drugs selective for α2β1 integrin* Momic T. 1 , Katzhendler J. 1 , Reuven R. 1 , Eble J.A. 2 , Marcinkiewicz C.3 and Lazarovici P.1* 1 School of Pharmacy Institute for Drug Research, The Hebrew Univ. of Jerusalem, Jerusalem; 2Center for Molecular Medicine, Dept. of Vascular Matrix Biology, Frankfurt, Germany; 3Dept. of Bioengineering, College of Engineering, Temple Univ., Philadelphia, USA The integrin are family of heterodimers of α and β subunits receptors, which adhere to multiple ligands and mediate cellcell and cell-extracellular matrix interaction. Integrins have been identified in the brain and neuronal stem cells as signaling molecules, resulting in cytoskeleton reorganization, regulation of cell proliferation, cell survival and neuronal adhesion and migration, neurite outgrowth and myelination. The collagen I receptor - α2β1 integrin is expressed in various regions of the developing brain including the rostral migratory stream, cerebral cortex and its present on the surface on each of the major cell type in the brain. α2β1 is overexpressed in many brain tumor cells such as glioblastoma and neuroblastoma. A modern approach for brain cancer treatment is based on inhibition of the cells adhesion, migration, growth and generation of a network of blood capillaries, i.e., angiogenesis. The integrin α2β1 seems to be important in angiogenesis and brain tumor progression, therefore novel drugs targeting and blocking this integrin are required. C-type lectin protein (CLP), called Vixapatin was isolated from Israeli snake Vipera palestinae venom and purified by HPLC. In quail chorioallantoic membrane assay Vixapatin inhibited C6 cells induced a strong angiogenic effect, most probably due to release of VEGF. Treatment with 1 μM Vixapatin, a concentration found not cytotoxic to the cells, reduced the C6 induced angiogenic effect by 95%. In addition, effect of Vixapatin on migration of C6 cells in Boyden chamber assay was investigated. Vixapatin inhibited the migration of cells towards collagen I by 35%, while the migration of the cells towards collagen IV was not significantly affected. These findings suggest that α2β1 integrin is involved in C6 tumor-

induced angiogenesis and that Vixapatin has a potent antiangiogenic effect. Vixapatin potently inhibits α2β1-mediated angiogenesis and hence will provide a lead structure to design synthetic α2β1integrin inhibitor drugs. Such collagen receptor inhibitors would enable the design of a variety of drugs towards therapy of different brain tumors. * PL holds the Jacob Gitlin Chair in Physiology at Hebrew Univ. and is affiliated and acknowledges the support by the David R. Bloom Center for Pharmacy and the Dr. Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at The Hebrew Univ. of Jerusalem, Israel. Neurotoxicity, neuroinflammation and increased vulnerability to dopaminergic toxins induced by 3,4-methylenedioxymethamphetamine (MDMA) in mice Morelli M. 1*, Frau L. 1, Costa G. 1 1 Dept. of Biomedical Sciences, Univ. of Cagliari, Via Ospedale 72, Cagliari, Italy Background: Clinical reportsshow higher propensity to develop Parkinson's disease (PD) in amphetamineusers. Moreover 3,4-methylenedioxymethamphetamine (MDMA), a popular recreational drug predominantly used by teenagers, inducesdopamine neuron degeneration in mice. On thesebasis, the present study evaluatedin mice the external factors influencing MDMA-related dopamine neuron toxicity and the role of age in theseresponses. Moreover the effects of MPTP, a toxin known to induce PD in humans,was studied in mice treated during adolescence with MDMA. Results: Activation ofastroglia and microglia by GFAP and CD11b and degeneration of dopaminergicneurons by tyrosine hydroxylase (TH) immunohistochemistry was evaluated. Results revealed a significant decrease of TH(+) neurons in substantianigra pars-compacta (SNc) after MDMA in both adult and adolescent mice, whereasTH(+) fibers in CPu were decreased in adult mice only. Caffeine and a crowdedenvironment (10 mice x cage) induced a more pronounced dopamine neuron degenerationin adolescent than adult mice. In CPu ofadolescent mice, caffeine potentiated MDMA-induced astroglia (GFAP) without alteringmicroglia (CD11b), whereas in SNccaffeine did not influence MDMAinduced glial activation. Moreover in mice chronically treated with MDMA (10mg/kg, twice weekly for 9 weeks),administration of MPTP induced a higher microglial and astroglial response bothin the striatum and SNc compared with vehicle+MPTP-treated mice. Inflammatorychanges were associated with a decrease in TH(+) in the SNc of MDMAtreatedmice and with a further decrease in the striatum and SNc of MDMA+MPTP-treatedmice. Conclusions: Association ofMDMA with caffeine or its administration in a crowed environment may constitutea risk

J Mol Neurosci

factor for dopaminergic neuron degeneration. Moreover chronicadministration of MDMA during late adolescence in mice may exacerbates theneurodegeneration and neuroinflammation caused by MPTP. The neural response to social hierarchy cues conveyed in faces – a MEG study Morgenstern, L. 1*, Gilboa-Schechtman, E. 1,2, Goldstein, A. 1,2 1 Gonda Multidisciplinary Brain Research Center, Bar Ilan Univ., Ramat Gan, Israel 2Dept. of Psychology, Bar Ilan Univ., Ramat Gan, Israel Background: Social hierarchy is considered a rudimentary principle of social organization among a wide variety of animal species as well as humans. The neural representation of social hierarchy has been examined in several studies, but information regarding its temporal unfolding and the contribution of situational conditions in different individuals is still lacking. The current research was designed to shed more light on the neural processing of social dominance cues, using MEG technology. Methods: Based on previous literature, we used neutral faces tilted upwards or downwards, to transmit high and low social dominance, respectively. We scanned male and female participants during the performance of two different tasks. Results: Our results revealed a differential neural response to dominance cues at an early stage (170ms) and also at later processing stages (400ms). Moreover, our results suggest the existence of gender differences in the processing of social dominance cues, but only when they are task irrelevant. Conclusions: Our findings support current theories which indicate a rapid and implicit processing of social hierarchy cues but also point to a possible discrepancy between men and women in the neural resources dedicated to social dominance cues when they are task irrelevant.

such as i) Excessive ATP use for NAD synthesis and inhibition of mitochondrial function with subsequent energy failure (particularly important in neurons) ii) apoptosis-inducing factor (AIF) translocation from the mitochondria to the nucleus (present in neurons, endotelial and other cells) iii) excessive expression of inflammatory mediators (well demonstrated in glial cells) or iv) reduced expression of pro-survival factors. Thus PARPs seem to play key roles in post-ischemic brain damage and are now considered interesting targets for therapies aimed at reducing stroke pathology. We recently characterized several series of potent PARP inhibitors, extremely active in reducing postischemic damage in stroke models in vitro and in vivo. In particular, we will describe the pharmacological properties of hydroxyl-dimethylaminomethyl- thieno[2,3-c]isoquinolin5(4H)-one (HYDAMTIQ), a potent and brain permeable inhibitor able to drastically reduce post-ischemic brain damage and neurological impairment after middle cerebral artery occlusion in mice and rats. In male rats with tMCAO, HYDAMTIQ (0.110 mg/kg ip) administered 3 times starting 4 h after MCAO reduced infarct volumes by up to 70% , reduced the per cent loss of body weight by up to 60 % and attenuated the neurological impairment by up to 40%. Similarly, in age matched female rats, HYDAMTIQ reduced brain damage. Protection, however, was less pronounced than in their male counterparts. Treatment decreased post-ischemic accumulation of PAR (the product of PARP activity) and the presence of OX42 positive inflammatory cells in the ischemic cortex. It also reduced sensorimotor deficits for up to 90 days after MCAO. Our results show that HYDAMTIQ is a potent PARP inhibitor that confers robust neuroprotection and long-lasting improvement of post-stroke neurological deficits

Poly(ADP-ribose)polymerase 1 (PARP-1) and post-ischemic brain damage Moroni F. Dept. of Neuroscience, Univ. of Florence, Viale Pieraccini 6; 50135 Firenze (Italy)

In animals with pMCAO, HYDAMTIQ administered 30 min after MCAO reduced infarct volumes by approximately 40 %. In animals with focal cortical ischemia, HYDAMTIQ Local electrical stimulations of the ventral prelimbic cortex ameliorates depressive-like behavioral traits in a genetic rat model for major depression Moshe H 1*, Zangen A 1 1 Ben- Gurion Univ., Beer Sheva, Israel

Poly(ADP-ribose) polymerases (PARPs) are enzymes able to catalyse the transfer of ADP-ribose units from NAD to substrate proteins and are particularly abundant in cell nuclei where they play key roles in the maintenance of genomic integrity and control of cell cycle and gene expression. Brain ischemia overactivates PARPs and PARP-deficient mice or animal treated with PARP inhibitors have a drastically reduced brain damage in various stroke models. PARP “over activation” occurs not only in neurons but also in astrocytes, microglial cells, endothelia and infiltrating leukocytes. The ensuing cell death occurs through various molecular mechanisms

Background: Approximately 25% of all patients suffering from Major Depressive Disorder (MDD) fail to respond to traditional antidepressant pharmacotherapy, thus raising the need for novel therapeutic alternatives. One approach that is highly effective in treating drug-resistant MDD is electroconvulsivetherapy (ECT), however such extensive and wide-spread brain stimulation often induces severe side effects which may outweigh the therapeutic benefit. It has been suggested that repeated local stimulations of specific brain circuits may achieve a similar therapeutic effect while minimizing the associated side effects, thereby offering a novel therapeutic

J Mol Neurosci

approach for MDD. The current study investigated how local subconvulsive electrical stimulations (SCES) affect depressive-like behaviors in a genetic rat model for MDD. Methods: an extracellular stimulating electrode was unilaterally implanted in the left ventral prelimbic cortex (vPLC) of Depressive Rat Line (DRL) rats. These rats have been selectively bred in our lab to express depressive-like behavioral traits, which are resistant to Desipramine treatment but not to ECT. DRL rats received 10 sessions of SCES or sham stimulations, after which depressive-like behaviors were quantified. In addition, the effects of stimulation on Brain Derived Neurotropic Factor (BDNF) levels at specific regions of the brain reward system are being evaluated. Results: compared with sham stimulations, repeated SCES of the vPLC increased sucrose preference, and swimming duration in the Forced Swimming Test. Discussion: we show that the vPLC can be locally stimulated to ameliorate genetically-induced depressive-like behavioral traits in rats. Brain connectivity in Schizophrenia: A TMS-EEG network study Naim-Feil, J. 1*, Moses, E. 1, Peled, A. 2,3, Arzouan, Y. 4, Levit-Binnun, N. 4 1 Dept. of Physics of Complex Systems, The Weizmann Institute of Science, Rehovot, Israel 2Ruth and Bruce Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa,Israel 3 Institute for Psychiatric Studies, Sha'ar Menashe Mental Health Center, Hadera, Israel 4 Sagol Center for Applied Neuroscience, School of Psychology, Interdisciplinary Center (IDC),Herzliya Background: Schizophrenia is a complex and devastating psychiatric disorder. The difficulty in identifying the involvement of specific brain regions in schizophrenia has led to the proposition that schizophrenia may be better understood as a disorder of global brain dysconnectivity. However, until recently, a concise quantification of the extensively interconnected human brain has been difficult to obtain. Recently though, neurophysicists have suggested that topological measures based on Graph Theory can quantify complex networks of the brain; thus, providing researchers with a unique research tool to examine global network connectivity in the schizophrenia brain. Methods: Delivery of brief brain stimulation pulses allow us to safely and transiently perturb the brain network, while electroencephalography (EEG) simultaneously measures the TMS-evoked neural changes across cortical regions of the brain. In our preliminary study, the network effects of TMS perturbations, applied to the frontal regions, were characterized across participants with schizophrenia (n=14) and healthy controls (n=12). Followed by an examination into the relationship between the network response to the TMS perturbations and symptoms of schizophrenia/soft neurological signs.

Results: Following network perturbation (TMS pulse) the schizophrenia network exhibited altered connectivity (number of links) and lowered clustering co-efficient relative healthy controls. Additionally, an association between these aberrant network metrics and negative symptoms/soft neurological signs were observed. Conclusions: The schizophrenia network is characterized by connectivity abnormalities in response to external perturbation of the frontal regions. Our findings are the first to show that these network abnormalities relate to negative symptoms and soft neurological signs of schizophrenia. We greatly appreciate the generous support and funding of the Israeli Science Foundation. Automatic effects of numerical magnitude on grip aperture during grasp Namdar G. 1*, Ganel T. 1 1 Dept. of Psychology, Ben-Gurion Univ. of the Negev, BeerSheva 84105, Israel It has been shown that the hand's aperture during grasp is affected by irrelevant numerical values of numbers embedded on the objects to be grasped, with large digits leading to larger aperture compared to small digits. It has been proposed that such interactions between magnitude processing and visuomotor control support the idea that a common underlying neural system mediates the processing of magnitude as well as the computation of object size for motor control. It was also proposed that the effects of magnitude on motor preparation are automatic. The purpose of the current study was to directly test this proposal by asking subjects to explicitly attend to the color of the digits, while ignoring their task-irrelevant numerical magnitude. The results showed that numerical magnitude affected grip aperture during initial stages of the grasp, even when such information was irrelevant to the task in hand. These findings suggest that magnitude effects on grasping preparation are automatic. Phosphorylation of Connexin43 enhances injury in stroke Naus C 1 *, Freitas-Andrade M. 1 , Bechberger J. 1 , Lampe P. 2 1 Cellular & Physiological Sciences Life Sciences Institute, Faculty of Medicine Univ. of British Columbia Vancouver, Canada 2 Fred Hutchinson Cancer Research Center Seattle, Washington USA Background: Astrocytic gap junctions have been reported to be involved in neuronal survival in ischemic conditions. In astrocytes, gap junctions are composed primarily of the channel protein, Connexin43 (Cx43). These channels provide a substrate for the formation of a functional glial syncytium. While several reports have demonstrated that Cx43 is an important factor in cerebral ischemia, the molecular mechanisms involved remains elusive. The transmembrane regions

J Mol Neurosci

of Cx43 are relatively conserved with other connexins, however, the cytoplasmic region is divergent and has been shown to be critical for the regulation of Cx43. Recently, a study showed that in response to atherogenic stimuli and vascular injury, Cx43 is phosphorylated at its C-terminus mitogenactivated protein kinase (MAPK) residues and that this is a key regulator of vascular smooth muscle cell (VSMC) proliferation and vascular scar tissue formation in vivo. Results: In this study, wild-type (WT) mice and mice containing Cx43-MAPK null phosphorylation (MK4) mutation were subjected to permanent unilateral middle cerebral artery occlusion (MCAO). After 4 days of recovery, brain sections were histologically evaluated for infarct volume. Immunofluorescent analysis of astrocyte reactivity, microglial activation, Cx43 expression, vascular elements and apoptosis was also performed. A significant ~2-fold decrease in infarct volume was measured in MK4 mice, compared to WT littermates. In the penumbra, an increase in astrocyte reactivity was observed in MK4 animals, compared with WT mice. Consistent with the infarct volume data, a significant reduction in cell death in the MK4 group was measured, compared to corresponding controls. Conclusion: This study suggests that inhibiting MAPK-Cx43 interaction is associated with neuroprotection in ischemic conditions. Heart & Stroke Foundation of Canada (CN, MFA); NIH GM55632 (PL); Canada Research Chair (CN). Auditory scene analysis and auditory objects Nelken I. 1,2* 1 ELSC, Hebrew Univ. 2 Neurobiology, Hebrew Univ. Like other sensory organs, the ears are exquisitely sensitive physical measurement devices with wide dynamic range and wide frequency selectivity. However, the information they supply is given in terms that are not easily amenable for interpretation in terms of the resulting perceptual entities. Even basic perceptual qualities such as pitch and timbre are not directly represented in the early auditory system. We have previously hypothesized that a major computational task of the auditory system is to create objects - perceptual entities that serve as containers for properties such as pitch, timbre, sound level, location in space, and so on - and that this task is largely completed by the level of primary auditory cortex. One major stumbling block that this hypothesis needs to surmount is the rather fluid definition of the term auditory object. I will review the attempts to define this notion, suggest a new definition - auditory objects as instantiations of predictive models that fit well the auditory scene - and discuss the (still rather weak) evidence supporting it. Supported by grants from the ISF and the Israeli Ministry of Science (Israel-France collaboration)

Sleep and consciousness: recent results and future directions Nir Y. 1,2* 1 Sagol School of Neuroscience & 2 Dept. of Physiology and Pharmacology, Sackler School of Medicine, Tel Aviv Univ. I will describe an overview of recent research and future plans studying electrical brain activity during sleep and its relation to cognition and consciousness. In a recent set of studies, intracranial EEG and neuronal activities were examined during sleep in human epilepsy patients. We found that slow waves and sleep spindles (the two fundamental brain oscillations of NREM sleep, traditionally regarded as global synchronous phenomena) actually occur mostly locally. Next, we confirmed that in freely behaving rats, slow waves and silent periods in sleep likewise occur predominantly locally. Moreover, after a long period of being awake, while both EEG and behavior indicate wakefulness, local populations of neurons go offline, exhibiting "local sleep". Finally, such local sleep occurs in in awake people who are sleep deprived and can lead to cognitive consequences such as lapses of attention. Another line of research focuses on disconnection from the external environment - conditions in which sensory stimuli do not trigger behavior and fail to be incorporated into our stream of consciousness. To this end, we examined neuronal responses to sounds in rats across wakefulness and different sleep states. Responses of single-units in primary auditory cortex are generally comparable in wake and sleep, calling into question the proposal that the thalamus does not relay peripheral signals effectively to the cortex in sleep. Finally, I will present how cutting-edge tools such as optogenetics can be used to dissociate local neuronal activity from global states in the context of sleep and anesthesia. Supported by the I-CORE Program, (grant No. 51/11) TRPV1 dependent neurotoxicity involves the mitochondrial Na+/Ca2+ exchanger in nociceptors Nita I., Caspi Y., Sekler I., Binshtok A. Dept. of Physiology and Cell Biology, Ben-Gurion Univ. of the Negev,Beer-Sheva Dept. of Medical Neurobiology, Faculty of Medicine , The Hebrew Univ., Jerusalem Background: Previous studies have demonstrated that prolonged activation of the non-selective cationic channel TRPV1 leads to a rise in mitochondrial calcium levels, followed by a depolarization of trans-mitochondrial potential. This change in mitochondrial potential leads to a change in the Na+/Ca2+ exchanger activity, from forward to reverse mode, which further increases the levels of mitochondrial calcium. This increase in mitochondrial calcium could underlie the well described effect of chronically activated TRPV1 channels on cell vitality. However, a causal link between the change in mode of the exchanger and cell death under prolonged

J Mol Neurosci

TRPV1 activity has yet to be established. Here we sought to investigate the contribution of mitochondrial Na+/Ca2+exchanger activity to cell death. To this end, we used HEK expressing TRPV1 cells and nociceptive neurons that inherently express TRPV1 channels. We compared the levels of mitochondrial calcium, mitochondrial membrane potential and cell vitality in naïve cells and in cells transfected with small interfering RNA for modulating expression of the Na+/Ca2+ mitochondrial exchanger. Results: Capsaicin induced a steep and transient rise in intracellular and mitochondrial Ca2+. The rapid and significant accumulation of Ca2+ in the mitochondria caused a change in mitochondrial potential, and reversal of the mitochondrial Na+/Ca2+exchanger. Knockdown of the mitochondrial Na+/ Ca2+exchanger leads to a decrease in the number of dead HEK cells expressing TRPV1 compared to the control. Conclusion: These results suggest that the change in mode of the exchanger leads to calcium accumulation and hence calcium based toxicity. Therefore, under conditions of constant TRPV1 activity, downregulation of the exchange is beneficial and leads to decreased cell death. Multiple Ca2+ channel dependent components in growth-hormone secretion from male rat anterior pituitary somatotrophs Sosial E 1, Nussinovitch I 1* 1 Dept. of Medical Neurobiology, IMRIC, Hebrew Univ. Faculty of Medicine, Jerusalem, Israel Introduction: The involvement of L-type Ca2 channels in both 'basal' and 'stimulated' growth-hormone (GH) secretion is well established, yet knowledge about the involvement of non-Ltype Ca2+ channels is lacking. In a recent study we demonstrate the existence on non-L-type Ca2 channels in pituitary somatotrophs (Tzour et al 2013). In the current study we investigated whether or not non-L-type Ca2+ channels participate in regulating the secretion of GH from male rat somatotrophs. To this end GH secretion was monitored from dissociated anterior pituitary cells which were incubated for 15 minutes with 2 mM K+ ('basal' secretion), 40 or 60 mM K+ ('stimulated' secretion). Results: The role of non-L-type Ca2+ influx in regulating GH secretion was investigated using highly specific channel toxin blockers; ω-agatoxin-IVA, ω-conotoxin GVIA and SNX-482, to block P/Q-, N-and R-type Ca2+ channels, respectively. Our results demonstrate that P/Q-, N-and R-type Ca2+ channels contributed ~21%, ~20% and ~ 11%, respectively, to 'basal' GH secretion, and ~16%, ~22% and ~ 13%, respectively, to K-stimulated GH secretion. Altogether, non-L-type Ca2+ channels contributed ~52% to 'basal' GH secretion and ~51% to Kstimulated GH secretion. As expected, L-type Ca2+ channels contributed the major components in both 'basal' and Kstimulated GH secretion; ~34% and ~49%, respectively.

Summary: This study demonstrates distinct components in both 'basal' and 'stimulated' GH secretion which depend on Ca2+ influx through L-type and non-L-type Ca2+ channels. The existence of multiple pathways for Ca2+ influx in somatotrophs, capable of regulating multiple distinct components in GH secretion, provides a subcellular mechanism for selective regulation, or fine-tuning, of GH secretion under different physiological conditions. Tzour et al (2013). Multiple pathways for high voltage-activated Ca(2+) influx in anterior pituitary lactotrophs and somatotrophs. J Neuroendocrinology 25, 76–86). Supported by the Israel Science Foundation (ISF) Grant no. 1325/08 to I.N. Targeting neurogenesis modifies behavioral symptoms in mouse model of Alzheimer's disease Offen D, 1*, Shruster A, 1 1 Felsenstein Medical Research Center, Tel Aviv Univ. Background: Alzheimer's disease (AD) affects 13% of the population over the age of 65. Behavioral and neuropsychiatric symptoms are frequent and affect 80% of patients. Adult hippocampal eurogenesis,which is impaired in AD, is involved in learning and memory. It remains unclear, however, whether increasing adult neurogenesis improves behavioral symptoms in AD. Results: In 3xtgAD mouse model of AD chronic Wnt3a overexpression in the ventral hippocampus dentate gyrus (DG) restored adult neurogenesis to physiological levels. The restoration of adult neurogenesis led to full recovery of danger assessment impairment and the effect was blocked by ablation of neurogenesis with X-irradiation. Finally, we found that the expression of the 5-HT1A receptor in 3xtg-AD mice is selectively decreased and normalized by adult neurogenesis in the bed nucleus of stria terminalis (BNST). Conclusions: Our findings indicate that reestablishing a functional population of hippocampal newborn neurons in adult AD mice rescues behavioral symptoms, suggesting that adult neurogenesis may be a promising therapeutic target for alleviating behavioral deficits in AD patients. New synergistic genetic treatment extends survival of ALS mice Benkler C. 1, Ben Zur T. 1, Barhum Y. 1, Offen D.* 1 Felsenstein Medical Research Center, Sackler Faculty of Medicine, Tel-Aviv Univ., Israel Background: Amyotrophic Lateral Sclerosis (ALS) is a fatal, rapidly progressive, neurodegenerative disease caused by motor neuron degeneration. Despite extensive efforts the underlying cause of ALS and the path of neurodegeneration remain elusive. Astrocyte activation occurs in response to central nervous system (CNS)

J Mol Neurosci

insult and is considered a double edged sword in many pathological conditions. Furthermore, we have previously described a reduced astrocytic glutamatergic and trophic response to activation. Results: Here we describe a novel method that will compensate for the astrocytic dysfunctions in ALS by utilizing a synergistic gene therapy approach. In a mouse model of ALS (SOD1 G93A), intra-cisternal and intra-muscular injections of three lenti-viral constructs delayed body weight loss, preserved reflex score and motor performance, significantly delays symptom onset and prolonged survival by 120% and 136% from symptom onset in male and female ALS mice respectively. Whereas treatment with each of the genes individually had little effect. Conclusions: Our approach to increase the anti-oxidant response in combination with reducing the glutamate excitotoxic levels in the central nervous system as well as depleting the systemic glutamate bio-availability has proven to be a very effective therapeutic strategy in the ALS mouse model. We hope that our study might provide a novel strategy to slow disease progression and alleviate symptoms of patients suffering from ALS.

biocompatibility of ND substrates by culturing rat hippocampal neurons on various ND surfaces (bare, functionalized, O- and H- terminated). Our results showed that: (a) Neurons and glia do not grow to form neuronal networks on bare NDs. (b) NDs soaked in serum do not improve the adhesion and growth of neurons and glia. (c) In contrast, conventional functionalization of NDs with poly-D-lysine (PDL) improves the adhesion and survivability of neurons cultured on NDs to a level of classical culture on glass. We conclude that reliable and durable growth of primary neurons and glia on NDs requires chemical functionalization. These findings suggest that functionalized ND (but not pristine ND) substrates can serve as an advantageous neuronal interface provided that proper chemical functionalization is applied. This work was supported by EU FP7 MERIDIAN grant #280778 and Marie Curie EU FP7 grant #26872.

They say “Diamonds are a girl’s best friend” but primary neurons don’t like them as a substrate Ojovan S.M. 1, Rabieh N. 1, McDonald M. 2, Erez H. 1, Nesladek M. 2, Spira M.E. 1,3* 1 Dep. Neurobiology, A. Silberman Inst. of Life Science, Hebrew Univ. of Jerusalem, 91904,Israel 2 IMOMEC division IMEC, Hasselt Univ. Campus, Diepenbeek, B 3590, Belgium 3 [email protected]

Background: Although the whisking system is one of the most prominent model systems in the study of sensory processing, little is known about the function of this system and its afferent sensory pathways in awake, behaving animals. We have recorded the whisking behavior and neuronal activity of freely moving mice during unilateral optogenetic inhibition of the ventral posterior medial (VPM) and posterior medial (POm) thalamic nuclei. Results: We have found that optogenetic inhibition of thalamic projection neurons led to specific changes in the way mice interacted with their environment. Whereas, under control conditions in the absence of neuronal modulation, mice typically explored the objects in their environment with their whiskers, thalamic inhibition led to a more than four-fold increase in the percentage of time mice investigate walls directly with their snouts (laser off: 1.4%; laser on: 6%, p<0.05). The percentage of time mice performed other exploratory behaviors was not changed significantly by optogenetic inhibition of the whisking thalamus. In control experiments, no significant change was found in any of the categorized exploratory behaviors. Inhibition of neuronal activity was confirmed with neuronal recordings and c-Fos staining. Conclusions: Together, these results indicate that the sensory information conveyed by the whisking-related nuclei of the thalamus plays an important role in motor-sensory exploratory behavior, as mice rapidly adopt alternate motor-sensory strategies during transient inhibition. As only 'snout touch' behavior was affected by inhibition, there is evidence for strong compensatory mechanisms within the whisking system, perhaps resulting in changes in whisking kinematics.

Brain Machine Interface Technologies (BMITs) and Multielectrode Arrays (MEA) are progressing from research stage to clinical applications. BMITs are successfully applied to control prosthesis, to treat neurological disorders and to restore sensory functions. A critical part in BMIs is a biocompatible endpoint-element that physically and electrically interfaces the devices with neurons. Recent studies focused on the applications of nanodiamonds (NDs) in tribology, drug delivery, bioimaging and tissue engineering, protein mimicry and as a filler material for nanocomposites. NDs are chemically and biochemically inert, have an excellent mechano-optical properties, high surface areas, tunable electrical properties and surface chemistry. These features make ND electrodes and coating ideal for interfacing neurons with MEA. It was reported (Thalhammer et. al., 2010 and Ariano et. al., 2009, using a neuronal cell line) that NDs provide an excellent substrate for neuronal adhesion, growth and that "functional neuronal network formation takes place on ND substrate in the absence of extracellular matrix protein". Here we re-examined the

Changes in motor-sensory exploratory behavior induced by optogenetic inhibition of thalamic activity Oram T. B. 1*, Ahissar A. 1, Yizhar O. 1 1 Weizmann Institute of Science

J Mol Neurosci

Challenges to episodic memory – the neural correlates of dual-task and proactive-interference loads Oren N.1,4,5,6, Shapira-Lichter I.4,5, Lerner Y.4,5, Hendler T.1,2,3,4, Giladi N.1,5 Ash E6 1 Faculty of Medicine, 2Sagol School of Neuroscience, and 3 School of Psychological Sciences, Tel-Aviv University, Tel Aviv 69978, Israel; and 4Functional Brain Center, Wohl Institute for Advanced Imaging, 5Department of Neurology and 6 Center for Memory and Attention Disorders, Tel-Aviv Sourasky Medical Center, Tel Aviv 64239, Israel. The neuronal substrates recruited when facing an episodic memory task with dual task (DT) and proactive interference (PI) loads are elusive. Our aim was to examine the neuronal patterns associated with these challenges. Using fMRI, we tested 25 young adults. Subjects watched pairs of related short movies (encoding phase), while performing easy or hard linguistic task (DT). Pairs of movies were played in succession and presented the same characters doing similar actions (PI). After each movie, subjects recognized pictures from the last movie (retrieval phase). Outside the scanner they completed the Rey Auditory Verbal Learning Test (RAVLT). In the linguistic task, there were effects for load in accuracy and reaction time. In the recognition task, PI measure of accuracy level was positively correlated with PI measure in the RAVLT. Analysis of the DT condition revealed 2 sets of brain regions. The first, comprised of bilateral frontal areas, was more activated in the encoding during hard DT than the easy DT. Of these, the left inferior and middle frontal gyri showed the opposite pattern during retrieval. The second set, consisted of right posterior regions, including temporoparietal junction (rTPJ), was less activated in the encoding during hard DT than the easy DT. In the PI condition, second movie of a pair, compared to the first, was associated with higher activations in posterior areas bilaterally, including low- and high-order visual areas and precuneus. Increased DT load during encoding recruited bilateral frontal areas probably due to heavier reliance on executive control. Lower activations in the rTPJ, presumably part of the ventral attention system (Corbetta et al 2008), during the demanding task may present difficulty orienting attention and switching between tasks. Greater recruitment of bilateral posterior areas when encountering materials resembling previous elements might competition between new and old memories. Early postnatal exposure to chlorpyrifos (organophosphate pesticides) caused long term changes in fear learning and emotional responses in BALB/C and C57/Bl6 adult mice Oriel S. 1, Dori A. 2, Kofman O. 1* 1 Dept. of Psychology and Zlotowski Center for Neuroscience, Ben-Gurion Univ. of the Negev, 2 Talpiot Medical Leadership Program, Dept. of Neurology and Joseph Sagol Neuroscience Center, Sheba Medical Center, Tel Hashomer

Background: The widespread use of organophosphate pesticides such as chlorpyrifos (CPF) has raised concern about the potential consequences of fetal and childhood exposure. CPF is a developmental neurotoxicant able to target the immature central nervous system at doses well below the threshold of systemic toxicity and may affect brain development. Emerging evidence from human and rodent studies indicates that CPF is associated with impaired cognition and behavioral problems. Therefore, the long term consequences in adulthood of repeated subtoxic exposure of CPF during critical brain growth remained unexplored. This original study was designed to investigate the potential risk of CPF exposure during the postnatal period on memory and emotional responses in adults. To further explore this phenomenon, three large cohorts of adult BALB/C and C57 mice pretreated with 1 mg/kg CPF daily on post-natal days (PND) 4-10 were tested on the classical conditioned fear and active avoidance paradigms in order to detect emotional and learning disturbances. Results: No cholinergic signs of toxicity were observed. The effect of postnatal CPF on fear conditioning was strain-dependent. C57 mice required more training sessions to acquire conditioned fear , whereas in BALB/C mice, which show less conditioned fear than C57 mice, CPF exacerbated freezing. In addition, a significant lower rate of learning in the active avoidance task was apparent only in BALB/C mice pretreated with CPF but not in C57 mice. Expression of splice variants for acetylcholinersterase revealed increased expression of synaptic and soluble AChE in the hippocampus of BALB/C mice and decreased expression of these transcripts in the amygdala of C57 mice. Conclusion: Repeated exposures to sub-toxic doses of CPF during critical postnatal period lead to both strain prolonged impairment in fear memory at different manner in BALB/C and C57 mice. Decoding letter position in word reading Ossmy O. 1,2*, Ben-Shachar M. 3,4, Mukamel R. 1,2 1 Sagol School of Neuroscience, Tel-Aviv Univ. 2School of Psychological Sciences, Tel-Aviv Univ. 3The Gonda Multidisciplinary Brain Research Center, Bar-Ilan Univ. 4English Dept., Linguistics Division, Bar-Ilan Univ. A fundamental computation underlying visual word recognition is the ability to transform a set of letters into a visual word form. Neuropsychological models argue that letter position in a single word is encoded by a separate module that may be independently affected, resulting in dissociable subtype of peripheral dyslexia. We used functional magnetic resonance imaging (fMRI) and supervised machine learning techniques to classify letter position based on activation patterns evoked during reading. Across the entire brain, activity patterns in the left posterior intraparietal sulcus (LIPS) provided the best classification accuracy (80%) with respect to letter position. Importantly, the same set of voxels in LIPS that showed

J Mol Neurosci

highest classification performance of letter position using one target letter also showed highest classification performance using a different target letter. A functional connectivity analysis revealed that activity in the letter localization region in LIPS covaries with activity in the Visual Word Form Area (VWFA), confirming cross-talk between these regions during visual word recognition. The results converge with reports of patients with acquired letter position dyslexia, who suffer from left parietal lesions. Taken together, these findings provide direct and novel evidence for the role of left IPS within the reading network in processing relative letter positions. This study was supported by the I-CORE Program of the Planning and Budgeting Committee

(Apr 28, 2013). 5. M. Kuzma-Kozakiewicz, E. Usarek, A. C. Ludolph, A. Baranczyk-Kuzma, Neurochem Res 36, 978 (Jun, 2011). 6. Y. Jouroukhin, R. Ostritsky, I. Gozes, J Mol Neurosci 48, 597 (Nov, 2012). Support: AMN, Adams Super Center for Brain Studies, Gildor Chair.

Amyotrophic lateral sclerosis (ALS) shows brain tauopathy that can be ameliorated by microtubule-interacting peptide drug candidates Ostritsky R. 1, Jouroukhin J. 1, Giladi E. 1, Gozes I. 1,2,3,4* 1 Dept. of Human Molecular Genetics and Biochemistry, Faculty of Medicine, TAU 2The Adams Super Center for Brain Studies 3The Lily and Avraham Gildor Chair for the Investigation of Growth Factors 4 The Elton Laboratory for Neuroendocrinology

The perceptual grouping of similarly oriented, discrete elements into a continuous contour is known as 'contour integration'. During contour integration, neuronal population in V1 enhance their responses to the contour elements while simultaneously suppress their responses to the noisy background elements. However, the spatial extent of these responses, e.g. whether the contour enhancement extends over the entire contour, is unknown. To investigate this question, two monkeys were trained on a contour detection task and were required to report the presence or absence of a contour. We simultaneously imaged the population responses in V1 at high spatial and temporal resolution using voltage-sensitive dye imaging. The size of the imaged area in V1 is small, and therefore cansimultaneously image only few contour or background elements. This poses a serious limitation on our ability to understand whether contour integration is a local or global phenomenon in V1. To overcome this limitation, we used the monkeys' eye position, as a spatial scanning tool for the cortical extent of contour integration. Throughout the trial, while attempting fixation, the monkeys made few fixational saccades (FSs). As a result, following each FS, the fixed imaged area in V1, encodes different elements of the contour and background. By following the animal's gaze position after each FS, we could image large parts of the stimulus and study the population responses over many stimulus elements from the contour and background. We found that contour enhancement is present over large parts of the contour area and that background suppression increases as a function of distance from the contour reaching background elements that are relatively far away from the contour itself. Thus background areas far from the contour are more suppressed than background areas closer to the contour. These results imply that contour integration in V1 is a global process involving large areas of the visual stimulus.

Clinical studies have started to recognize amyotrophic lateral sclerosis (ALS) as a complex multi-systems disorder. For example: 1] post-mortem evaluations revealed widespread neuronal and glial hyperphosphorylated tau deposition with increased tau pathology in ALS patients suffering from cognitive impairment (1); 2] resting state functional MRI showed decreased brain activity in patients compared to controls (2), 3] MRS at the basal ganglia and thalamic levels indicated neuronal loss or dysfunction and alterations (3). Here, we investigated if tau-brain pathology is recapitulated in the Tg (SOD1-G93A)1Gur ALS mouse. Protein extraction, polyacrylamide gel electrophoresis and Western blot analysis identified a marked increase in tau hyperphosphorylation in the cerebral cortex of the ALS mice, coupled to a decrease in tau expression (4). The cerebral cortex, compared to other central nervous system regions, was previously shown to exhibit the most marked decrease tau expression which was correlated with disease progression, in this ALS model (5). Treatment with NAP (davunetide), a MT-interacting drug candidate, protected against ALS-tau hyperphosphorylation in a dose-dependent manner (4). Similarly, all D-amino acids, D-NAP, also protected against tau hyperphosphorylation in this ALS model (6). Tau pathology was correlated with deficiency in axonal transport, which was ameliorated by NAP treatment (4), translating structural to functional protection. 1. W. Yang, M. J. Strong, Amyotroph Lateral Scler 13, 178 (Feb, 2012). 2. C. Luo et al., PLoS One 7, e45470 (2012). 3. K. R. Sharma, G. Saigal, A. A. Maudsley, V. Govind, NMR Biomed 24, 1270 (Dec, 2011). 4. Y. Jouroukhin et al., Neurobiol Dis 56C, 79

Sampling the spatial extent of contour integration with fixational eye movements: evidence for global processing in V1 Gilad A. 1*, Oz R. 1, Slovin H. 1 1 The Gonda Multidisciplinary Brain Research Center, BarIlan Univ., Ramat Gan, Israel

Three-dimensional optical probing of bio-engineered neuronal ‘Optonets’ Paluch S. 1, Dana H. 1, Marom A. 2, Brosh I. 1, Shoham S. 1* 1 Biomedical engineering, Technion, IIT 2The InterDept.al Program in Biotechnology, Technion, IIT

J Mol Neurosci

Background: Planar neural networks and interfaces serve as versatile in vitro models of central nervous system (CNS) physiology, but adaptations of related methods to three dimensions (3D) have met with limited success. Opto-physiology methods are optimally suited for non-contact volumetric interfacing. Indeed, two photon laser scanning microscopy (TPLSM) neuronal imaging using calcium-sensitive dyes or genetically-encoded indicators is routinely used to image the activity of small neuron ensembles in vivo. However, scanning methods cannot generally achieve large scale dense 3D imaging at rates required for action potential detection. Methods: we develop a novel multiphoton microscope for studying of a bio-engineered brain-like neural tissue 'Optonet' growing in a transparent hydrogel. The design contains a 3D scanning-line temporal-focusing (SLITE) subsystem to provide rapid volumetric imaging performance: dense 3D sampling at tens of volumes/sec of structures with mm-scale dimensions and μm resolution. The system also contains a temporal- focusing (TF) holographic subsystem based on a Spatial Light Modulator (SLM) to enable 3D targeting of multiple individual neurons simultaneously. Results: we demonstrate volumetric functional imaging of 'Optonets' containing over 1000 developing cells with complex spontaneous activity patterns. In addition, in order to enable future studying of in-vivo brains that are highly scattering, image processing strategies including analytic evaluation of tissue scattering effects, are established. Discussion: Further studying of our bioengineered 'Optonets' by actively targeting specific neurons and subpopulations in a three dimensional ensemble can be achieved by combining our TF based holographic photo-stimulation subsystem with optogenetic probing. These developments may also prove to be a useful tool for studying deep three dimensional neuronal circuits for network dynamics studies and the control of large neuronal populations. Can brain activity at rest be of any use to cognitive neuroscientists? Papo D. 1,2* 1 Technical Univ. of Madrid 2Centre for Biomedical Technology Background: Resting state activity is often considered as complementary, in opposition as it were, to task-related brain activity. Why then should cognitive neuroscientists get interested in resting brain activity, and to what extent can studying resting brain activity help characterizing the neural correlates of cognitive processes? he different roles played by rest in functional neuroimaging and electrophysiological studies are illustrated. It is shown that, in functional neuroimaging, rest is essentially equated to an energy consumption level, and used as a baseline for gauging local amplitude modulations, while in electrophysiological studies, task-independent brain

activity is endowed with complex generic properties, with important implications on various operational properties of brain activity. Results: The relationship between spontaneous and stimulusrelated brain activity is understood in terms of the fluctuationdissipation theorem (FDT). This theorem of classical physics establishes a general relationship between the (nonequilibrium) response of a system to small external perturbations and the (equilibrium) internal autocorrelation of fluctuations of some observable of the system in the absence of the perturbations. Thus, resting and task-related activities are not complementary, but two sides of the same coin: the connection between the response to external perturbations and the time correlation of the unperturbed system allows understanding the former from the latter. Ultimately, cognitive function can be described in terms of generic properties of ongoing brain activity. Conclusions: Describing task-related with task-independent ongoing brain activity allows characterizing cognitive processes with a rich set of physically grounded descriptors e.g. in terms of convergence to the basin of attraction of given probability density functions, symmetries and symmetry breakings, universality classes, degrees of FDT violation. Measuring brain temperature without a thermometer Papo D. 1,2* 1 Technical Univ. of Madrid 2Centre for Biomedical Technology Background: The effects of temperature on various aspects of neural activity from single cell to neural circuit level have long been known. However, how temperature affects the systemlevel of activity typical of experiments using non-invasive imaging techniques, such as magnetic brain imaging orelectroencephalography, where neither its direct measurement nor its manipulation are possible, is essentially unknown. Results: Starting from its basic physical definition, we discuss possible ways in which temperature may be used both as a parameter controlling the evolution of other variables through which brain activity is observed, and as a collective variable describing brain activity. On the one hand, temperature represents a key control parameter of brain phase space navigation. On the other hand, temperature is a quantitative measure of the relationship between spontaneous and evoked brain activity, which can be used to describe how brain activity deviates from thermodynamic equilibrium. These two aspects are further illustrated in the case of learning-related brain activity, which is shown to be reducible to a purely thermally guided phenomenon. The phenomenological similarity between brain activity and amorphous materials suggests a characterization of plasticity of the former in terms of the well-studied temperature and thermal history dependence of the latter, and of

J Mol Neurosci

individual differences in learning capabilities as materialspecific properties. Finally, methods to extract a temperature from experimental data are reviewed, from which the whole brain’s thermodynamics can then be reconstructed. Conclusions The assessment of temperature and thermal history enables both a dynamical description of brain activity, and a complete characterization of its thermodynamics, affording neuroscientists a description of the object of their investigations with a sound physical basis. Amygdala-prefrontal circuitry in aversive learning and memory: from physiology to psychopathology Paz R * Neurobiology, Weizmann Institute of Science I will describe different behavioral models for aversivelearning, their potential role in anxiety-disorders, and the underlying neural circuitry that mediates them. Specifically, I will focus on adaptive flexible learning, as with extinction or reversal paradigms; safety learning; and generalization of aversive memories; and show how information transfer and sychornization between single neurons in the amygdala and prefrontal cortex mediate these types of learning and their failure. These paradigms are validated in human subjects, controls and anxiety patients, in behavior and imaging (fMRI). Together, the findings point to a combined mechanism that is necessary for daily life and survival, but can result in psychopathologies when the balance between the systems is breached. Role of Cadm (Necl/SynCAM) in myelination Peles E 1* 1 Dept. of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel Background: Peripheral nerve myelin is a specialized multilamellar membrane produced by Schwann cells that spirals around the axon. The myelin units (internodes) are separated from each other by a non-myelinated gap known as the node of Ranvier. This configuration allows fast saltatory propagation of action potentials along myelinated axons. The interaction between myelinating Schwann cells and the axons they ensheath is mediated by cell adhesion molecules of the Cadm/Necl/ SynCAM family. This family consists of four members; Cadm4/Necl4 and Cadm1/Necl2 are found in both glia and axons, while Cadm2/Necl3 and Cadm3/Necl1 are expressed by sensory and motor neurons. In the present study we set to examine the role of Cadm proteins in myelination in vivo by generating mice that lack each member of this family. Results: By generating mice lacking each of the Cadm genes, we found that Cadm4, but not Cadm1, Cadm2 or Cadm3, plays a role in the establishment of the myelin unit in the peripheral nervous system. Mice lacking Cadm4 (PGK-Cre/ Cadm4fl/fl) develop focal hypermyelination characterized by

tomacula and myelin outfoldings, which are the hallmark of several Charcot-Marie-Tooth neuropathies. The absence of Cadm4 also resulted in abnormal axoglial contact and redistribution of ion channels along the axon. These neuropathological features were also found in transgenic mice expressing a dominant negative mutant of Cadm4 lacking its cytoplasmic domain in myelinating glia Tg(mbp-Cadm4dCT), as well as in mice lacking Cadm4 specifically in Schwann cells (DHH-Cre/ Cadm4fl/fl). Consistent with these abnormalities, both PGKCre/Cadm4fl/fl and Tg(mbp-Cadm4dCT) mice exhibit impaired motor function and slower nerve conduction velocity. Conclusion: These findings indicate that Cadm4 regulates the growth of the myelin unit and the organization of the underlying axonal membrane. Odor-induced increases in delta power imply an olfactory mechanism of sleep protection Perl O.1, Arzi A.1, Sela L.1, Samnon P.1, Holtzman Y.1, Oksenberg A.2, Hairston IS.3, Sobel N.1 1 Dept. of Neurobiology, The Weizmann Institute of Science, Rehovot, Israel 2 Loewenstein Rehabilitation Hospital, Raanana, Israel 3 Dept. of Behavioral Sciences, Tel AvivYaffo Academic College, Tel Aviv, Israel Exposure to purely olfactory odorants during sleep results in no, or minimal behavioral and physiological arousal. Nevertheless, these odors are detected and processed by the sleeping brain. Moreover, it has been proposed that olfactory stimuli may serve to enhance sleep via a non-thalamic sensory gating mechanism. Here we set out to test this hypothesis by examining the effects of odors delivered during sleep on slow wave activity (SWA) and the occurrence of K-complexes (KC) during Stage 2 sleep. We asked whether purely olfactory odors delivered during sleep activate sleep "protective" mechanisms, as reflected in SWA power increase, thus promoting deep sleep. To this end we performed a spectral analysis of EEG recording obtained from 36 subjects (19 F, age 23-36) who were repeatedly presented with odor stimuli (10 sec. stim. dur. 10-15 min. ISI) over the course of a single-night polysomnography study. We found a significant bilateral increase in power of high delta activity (2-4Hz) following odor presentation during slow wave sleep F(1, 34) = 5.65, p < 0.05). These results strongly indicate that olfactory stimuli may indeed serve to enhance sleep by acting as sleep "protective" agents. Binding in memory – from theory to practice. Pertzov Y 1* 1 Dept. of Psychology, Hebrew Univ. of Jerusalem It has been suggested that objects are maintained as integrated units in working memory and when forgotten they are lost as a whole, without leaving any trace. To study the relevance of

J Mol Neurosci

this claim to real-life situations, we investigated how objectlocation information is remembered – and forgotten. We used a localization task with a continuous, analogue scale of reporting with difficult-to-verbalize stimuli and variable delays. Participants frequently mislocalized items precisely near the original position of other items in memory ('swap errors'). Moreover, when objects were forgotten they did not disappear completely from memory, but rather the links (bindings) between identity and location became vulnerable with time, so swap errors increased with longer retention intervals. Maintaining objectlocation links was found to be especially fragile in patients with focal, bilateral damage of the medial temporal lobes (MTL), specifically the hippocampus. Increased binding errors also occurred in pre-symptomatic carriers of an autosomal dominant gene (PSEN1 or APP) which gives 100% risk of developing Alzheimer's disease. Hippocampal volume in these individuals, who scored within normal range in standard neuropsychological tests, correlated inversely with the number of binding errors. These findings further strengthen the claim that the hippocampus is necessary for maintaining associative information across short retention intervals, challenging traditional accounts of MTL function as exclusively involved in long term memory. The findings also offer an insight into the early cognitive deficits associated with Alzheimer's disease and demonstrate the potential of this task for early diagnosis and management of the disease. Menstrual state may selectively alter sensitivity to body odors Pinchover L. * Endevelt , Y. Bar-Zvi D. Frumin I. Sobel N. Dept. of Neurobiology, Weizmann Institute of Science. Rehovot, Israel Reports of gender differences in olfaction are inconsistent. Several studies found that women outperform men in various olfactory tasks (discrimination, identification, detection), yet other studies failed to replicate this. Potential sources of variance underlying this discrepancy include the types of odorants used, and accounting for varying performance across the menstrual cycle in women. We set out to ask whether there is a gender difference and an effect of menstrual phase in olfactory discrimination of ordinary chemical mixtures (Mix) and body odors (BO). 31 subjects (17 F, Age = 25.6 ± 0.5, no oral contraceptives) participated in a 3-alternative forced choice discrimination task (chance = 33%) for Mix and BO (t-shirts obtained from men and women) that was repeated once a week for 4 weeks. An ANOVA with conditions of gender (M/F), and odor type (Mix/BO) revealed neither significant main effects (both F (1,29) < 1.8, p > 0.2) nor interaction (F (1,29) = 1.3, P = 0.3). A follow-up ANOVA in women only, with conditions of odor type (Mix/BO) and

menstrual phase (Before / After ovulation) revealed no significant interaction (F (1,16) = 1.0, P = 0.3). Nevertheless, given the small number of women, we proceeded to test the post-hoc planned comparisons. Whereas for Mix women performed equally well before and after ovulation (%Mix_before = 48 ± 6, %Mix_After = 47 ± 6, t(16) = 0.1, p = 0.9), for BO they performed better before versus after ovulation (%BO_before = 61 ± 3, %BO After = 52 ± 3, t (16) = 2.5, P < 0.05). These results imply a selective influence of menstrual phase on the perception of BO, but a larger sample remains to be tested in order to determine whether this interaction is significant. Body odors have evolutionary importance in mate preferences. The critical timing for mate selection is immediately before ovulation. The current results implicate a chemosensory mechanism that may contribute to such mate selection when it is most important. Event-related potential (ERP) evidence for two processes underlying automatic number comparison Pinhas M. 1*, Buchman C. 1, Lavro D. 1, Tzelgov J. 1, Berger A. 1 1 Psychology, Ben-Gurion Univ. of the Negev Two processes are known to be involved in number comparisons: an analog comparison process and an end-value identification process. Although previous studies implicate these processes in intentional comparisons of numbers, the indicators for the involvement of both processes in automatic number comparison has received limited research attention. The present study tested the brain correlates associated with automatic number processing as marked by the size congruity effect (SiCE). Event-related potentials (ERPs) were recorded as three groups of adult participants compared the physical size of number pairs. We manipulated two task-irrelevant factors: the intrapair distance (within-groups) and the smallest end value in the set (0, 1, or 2) between-groups. Behavioral results showed independent modulations of the SiCE by intrapair distance and by the presence of the smallest end value in the pair. ERP results revealed parieto-occipital distance effects reflected as increased N1 (165 - 200 ms), P2p (230 - 280 ms), and P3 (300 - 370 ms) amplitudes for far (compared to close) distances. Furthermore, a spatially extended centro-parietal P300 was enhanced and peaked earlier for congruent versus incongruent trials. Importantly, the P300 congruity effect (congruent minus incongruent) was enlarged for physical comparisons of the smallest end value than for nonend value pairs. The presence of an end value within the pair also modulated P300 latency. These results provide the first neural evidence for the involvement of two distinct automatic processes that seem to encode the primary aspects of symbolic numerical information.

J Mol Neurosci

Beclin1, autophagy and neurodegeneration Pinkas- Kramarski R. 1*, Erlich S. 1 , Mizrachy L. 1 , Alexandrovich A. 2, Lindenboim L. 1, Segev, O. 3, Hirsch J. A. 3, Stein R. 4, Shohami E. 2 1 Neurobiology, Tel Aviv Univ. 2Dept. of Pharmacology, the Hebrew Univ.. 3 Dept. of Biochemistry. Tel-Aviv Univ.. 4 Neurobiology, Tel-Aviv Univ.. Autophagy, a bulk degradation of sub-cellular constituents, represents the major pathway by which the cell maintains a balance between protein synthesis and protein degradation. Beclin1, a Bcl-2 interacting protein previously found to promote autophagy. We investigated the interaction between antiand pro-apoptotic Bcl-2 proteins with Beclin1. Our results show that Beclin1 directly interacts with Bcl-2, Bcl-xL, Bclw and to a lesser extent with Mcl-1. Beclin1 does not bind the pro-apoptotic Bcl-2 proteins. BH3-only proteins inhibited the interaction between Beclin1 and Bcl-xL. Structural modeling suggests that Beclin1 contains a putative BH3-like domain, which may interact with the hydrophobic grove of Bcl-xL. Mutation of the Beclin1 amino acids predicted to mediate this interaction inhibited Beclin1/Bcl-xL association. Our results suggest that Beclin1 may modulate the interactions between anti- and pro-apoptotic Bcl-2 proteins. Autophagy was documented in several neurodegenerative diseases. Using the closed head injury (CHI) model we investigated the possible role of autophagy in neurodegeneration. We demonstrated that the levels of Beclin1 are dramatically increased near the injury site in neurons and astrocytes. Double staining of Beclin1 and TUNEL indicate that most of the cells that exhibit double staining are neurons and not astrocytes. These findings show for the first time that Beclin1 may play a role in brain responses to head trauma. These observations led us to the hypothesis that elevated autophagy following injury may represent a mechanism to discard injured components. To examine this hypothesis we used rapamycin (mTOR inhibitor and autophagy inducer). Rapamycin injection following CHI significantly improved the recovery as judged by neurological score. Thus, we suggest that enhanced autophagy following head trauma may serve as a neuroprotective mechanism, as well as a novel target for treatment of traumatic brain injury. Possible mechanism of direction selectivity in the archer fish retina Pinsky E. 1,2, Donchin O. 1,2,3, Segev R. 4,2* 1 Dept. of Biomedical Engineering, Ben-Gurion Univ. of the Negev, Beer-Sheva 84105, Israel 2 Zlotowski Center for Neuroscience, Ben-Gurion Univ. of the Negev, Beer-Sheva 84105, Israel 3 Dept. of Neuroscience, Erasmus MC, Rotterdam, The Netherlands 4 Dept. of Life Sciences, Ben-Gurion Univ. of the Negev, Beer-Sheva 84105, Israel

Direction selectivity is a basic neuronal computation mechanism found in various brain areas. The retina sets a good example of this mechanism: the computation is done in the retina circuitry, and the retinal ganglion cells' output to the brain has direction selective features. The accepted model for this mechanism in mammalian retina is based on the asymmetry of the inhibitory input from starburst amacrine cells to the retinal ganglion cells. Recently, direction selectivity was found also in the archer fish retina that could participate in the neural mechanism enabling fast reaction of the fish to moving objects. In order to study the directionally selective mechanism in the archer fish retina, we conducted a pharmacological study of the retinal ganglion cells. We found that blocking of GABAA receptors eliminates the archer fish retina sensitivity to motion all together. This is in contrast to the mailman retina where blocking of GABAA receptors interferes with direction selectivity alone. These results might indicate a cellular mechanism that differs from the mechanism found in mammals. PPAR-alpha: a new target for the treatment of nocturnal frontal lobe epilepsy Muntoni AL 1, Melis M 2,1, Pillolla G 3, Aroni S 2, Lecca S 2, Marrosu F 3, Puligheddu M 3, Pistis M2,1* 1 CNR Institute of Neuroscience, Cagliari, Italy 2Dept. of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, Univ. o 3Sleep Disorder Center, Dept. of Public Health, Clinical and Molecular Medicine, Univ. of C Background: Neuronal nicotinic acetylcholine receptors (nAChRs) are involved in the molecular mechanisms of epilepsies, such as the nocturnal frontal lobe epilepsy (NFLE). Consistently, nicotine elicits seizures and mimics the excessive nAChR activation observed in animal models of the disease.We previously discovered that nicotine-induced effects are suppressed by ligands to the peroxisome-proliferator-activated receptor-α (PPARα) via negative modulation of nAChRs. PPARα are nuclear receptors, expressed by neurons in many brain regions.Thus, we investigated whether treatments with PPARα ligands (WY14643 and the clinically available hypolipidemic fenofibrate) reduce the severity of nicotine-induced seizures in experimental animals and are effective in pharmacoresistant NFLE patients. Results Preclinical studies. We performed behavioural and electroencephalographic (EEG) experiments in C57BL/J6 mice. Convulsive doses of nicotine evoked seizures and bursts of spike-waves discharges in all mice. Acute WY14643 (80 mg/kg i.p.) or chronic fenofibrate (0.2% w/w in the diet for 14 days) significantly protected against nicotine-induced seizures when compared with controls. Clinical study. Fenofibrate (600 mg/die per os) was administered as adjunctive therapy to pharmacoresistant NFLE subjects. Preliminary data indicate that all patients who completed the initial 6-month trial (n=9) reported significant subjective (sleep/seizure diaries) and objective (video-polysomnographic and EEG

J Mol Neurosci

recordings) improvement in both seizure frequency and sleep quality, and requested to carry on with the treatment. Conclusions: We show that PPARα agonists reduce behavioural and EEG expressions of nicotine-induced seizures in animals and, remarkably, improve NFLE symptoms in patients. The present results give support the role played by nuclear receptors PPARα in the regulation of nAChR function in the CNS and highlight PPARα as a novel target for antiepileptic drugs. The research was sponsored by grants from FIRE-AICE and MIUR Intramembrane cavitation as a predictive bio-piezoelectric mechanism for ultrasonic brain stimulation Plaksin M. 1,2*, Shoham S. 2, Kimmel E. 2 1 Russell Berrie Nanotechnology Institute, Technion, Haifa, Israel 2 Faculty of Bio-Medical Engineering, Technion, Haifa, Israel Background: Low intensity ultrasonic waves can remotely and non-destructively excite central nervous system (CNS) neurons. While diverse applications for this effect are already emerging, the biophysical transduction mechanism underlying this excitation remains unclear, lacking both qualitative and quantitative understanding of this physical effect which can guide future investigations. To address this gap, we introduce a new "Neuronal Bilayer Sonophore" (NBLS) model for understanding the biophysical effect of ultrasound waves on neurons, mediated by the development of pulsating nano-bubbles inside the membrane as predicted to emerge by our recent biomechanical membrane-acoustic model (Krasovitski et al., PNAS 2011). Results: We show how the pulsating membrane leaflets can induce the generation of action potentials as an indirect result of membrane capacitance and potential oscillations that lead to slow charge accumulation across the membrane, until it is discharged as an action potential. This new understanding explains the slow effect of ultrasonic stimulation and predicts the very recent measurements (King et al., Ultrasound Med. Biol. 2013) of muscle responses to ultrasound stimulation in the motor cortex of mice in vivo (!) Conclusions: Understanding these interactions using these new concepts could facilitate the development of the only method allowing controlled non-invasive stimulation of excitable tissue with millimeter spatial resolution essentially anywhere in the brain, with various applications in the diagnosis and treatment of brain disorders. Further studies on the Lymantria dispar feromonal gland and terminal abdominal ganglion: fine structure and neurochemistry Poddighe L. 1, Boi M. 1, Melis T. 1, Serra M.P. 1, Quartu M. 1, Del Fiacco M. 1* 1 Dept. of Biomedical Sciences, Section of Cytomorphology, Univ. of Cagliari, Italy

Background: The intersegmental membrane between the 8th and 9th abdominal segments houses the feromonal gland of the female gypsy moth Lymantria dispar (Lepidoptera Lymantridae), a fitofagous pest of shade and fruit trees. Contrary to what proposed by Solari et al. (J. Comp. Physiol., 2007), we have shown that the gland receives nerve fibres (Boi et al., J. Morphol 2009), indicating that the feromone secretion is at least in part under neural control. The terminal abdominal ganglion (TAG) appears to influence the moth calling behaviour and pheromone production. We describe here the results of our further studies on the fine structure of the glandular and abdominal epithelium and the organization and chemistry of the TAG. Results: The intersegmental membrane harbours a single layer of variously shaped cells with a rich system of basal plasmalemma labyrinthine infoldings and apical microvilli, and a variable amount of cytoplasmic osmiophilic granules. Nerve fibres approach the cell monolayer and impinge on it. A similar monolayered epithelium extends to sheathe the hemocoel surface of the apodemes. Its cells also contain osmiophilic granules and apical microvilli. However, their rich basal labirinth extends to the lateral membrane and they host ample vacuol-like spaces that contain osmiophilic granules. In the TAG, beneath a peripheral capsule, a cortical zone contains neuronal perikarya of different shape and size, largely in one row, and a central wider area hosts a neuropil. Immunoreactivity to serotonin occurs in a few perikarya and in a rich central fibre plexus. A number of perikarya are also immunoreactive to histamine, glutamic acid decarboxylase and octopamine. Conclusions: TAG neurochemistry suggests the involvement of serotonin, histamine, GABA and octopamine in its neuronal activity. Where is the pheromone stored and its emission pathway remain to be elucidated. Support/Acknowledgment: Work funded by Fondazione Banco di Sardegna, Sassari, Italy. Blood-brain barrier dysfunction underlies impaired neurovascular coupling Prager O. 1,2, Schocknecht K. 3, Chassidim Y. 1,2, Kamintsky L. 1,2, Dreier JP. 3, Friedman A 1,2* 1 Dept.s of Physiology & Cell Biology, Faculty of Health Sciences 2 Zlotowsky Center for Neuroscience, Ben-Gurion Univ. of the Negev, Beer-Sheva 3 Institute of Neurophysiology, Charite Univ. Medicine, Berlin, Germany Background: Neurovascular coupling (NVC) describes the critical modulation of regional cerebral blood flow (rCBF) during neuronal activity and increased metabolic demands. Recent studies in human and experimental animals indicate that NVC may be impaired in diverse neurological pathologies and may be spatially correlated with impaired blood-brain barrier (BBB) permeability.

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We aim to test the hypothesis that BBB dysfunction may directly induce NVC impairment and which further contribute to cellular injury. Methods: The open-window technique was used in anesthetized rats and the cortex was perfused with the potassium channel (Kv) blocker, 4-aminopyridine (4-AP), to induce recurrent seizures. Electrocorticography (ECoG) recordings, direct imaging of pial vessels, cerebral blood flow monitoring (using laser-doppler flowmeter) and measurements of tissue oxygenation and pH were performed. BBB dysfunction was introduced with either photothrombosis or with exposure of the cortex to artificial "serum like" electrolytic solution containing albumin. Vessels permeability was assessed by quantitative analysis of fluorescent angiography (Prager et al., 2010). Results: In the intact brain we show pronounced and reversible dilation of arterioles in response to neuronal activation. However, in the BBB-dysfunctional brain, NVC is clearly impaired and 02-saturation levels within the brain tissue are reduced upon neuronal activation. Conclusions: We suggest that intact functional BBB is required for the normal NVC. *This study is supported by the German-Israeli Foundation (GIF). How can a high avidity tarantula toxin promote prolonged pain? Priel A. 1* The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew Univ. The transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the heat- and capsaicinreceptor and/or the vanilloid receptor 1, is a pivotal receptor of the pain pathway. The acute pain associate with TRPV1 activation is well document. Best example for this intense but short lasting pain is the TRPV1 specific activator capsaicin (the ‘hot’ ingredient of Chili pepper). The main reason for the acute pain evoked by TRPV1 activation is the Ca2+depended desensitization that begins immediately after channel opening. Recently, we identify the pain-producing component of the Earth Tiger tarantula venom. A peptide toxin consist from two ICK toxins linked together, we named it as the double-knot toxin (DkTx). We showed that DkTx is a specific activator of TRPV1 with extremely high avidity. Many reports point out to the prolonged pain associate with the venom of this spider. Thus, our question is how DkTx activation of TRPV1 results in prolonged pain and not acute pain, as capsaicin. To answer this question we examine the differences in nociceptors activation by DkTx or capsaicin. In addition, we determine the desensitization evoked by the two different activators. Here we will present our results including our model for the unique activation of the pain pathway by the peptide toxin- DkTx. Supported by the ISF, GIF, and the National Institute of Psychobiology in Israel

Concept cells Quian Quiroga, R 1* 1 Univ. of Leicester Intracranial recordings in subjects suffering from intractable epilepsy allow studying the firing of multiple single neurons in awake and behaving human subjects. These studies have shown that neurons in the human medial temporal lobe respond in a remarkably selective, invariant and explicit manner to particular persons or objects, such as Jennifer Aniston, Luke Skywalker or the Tower of Pisa. I will show the main characteristic of these neurons and argue that such a sparse, explicit and abstractrepresentation is crucial for declarative memory functions. Targeting charged cytotoxic compounds selectively into specific cells via TRP channels Raizel HI. 1, Lev S. 1, Honigman A. 2, Binshtok AM. 1* 1 Dept. of Medical Neurobiology, Faculty of Medicine. The Hebrew Univ., Jerusalem, Israel 2 Dept. of Virology Faculty of medicine, The Hebrew Univ.,Jerusalem, Israel Selective targeted delivery of effective agents to specific cell types is significantlyimportant in pathological conditions where the selective activation or disruption of cell functions is crucial. We developed a method for targeting specific cells by applying a compound that activates and opens large-pore cationic channels such as transient receptor potential (TRP) channels and allows the entry of a positively-charged compound which modulates intracellular processes. This facilitated entry of the compound into the cell potentiates its effect and spares any other types of cells from the achieved effects. Since TRP channels are expressed with increased levels in cancer cells and their expression profile is different than other cell types, we assumed that by using this strategy, chemotherapeutic agents will gain access into cancer cellsthrough TRP channels. We present proof of concept of the ability to target chemotherapeutic agent Adriamycin into cancer cell-lines expressing TRP channels, which leads to ablation of these cells. We previously demonstrated that mouse hepatocellular carcinoma cells (BNL1ME cell line) express functional TRPV2 channels. Using calcium imaging and fluorescence imaging we demonstratedthat activation of TRP channels by TRPV2 specific activators such as CBD togetherwith Adriamycin resulted in selective entry of this charged and fluorescentchemotherapeutic agent into BNL1ME cells, which resulted in Adriamycin-inducedcell death. We showed this same result with the nonspecific activator 2Aminoethoxydiphenyl borate (2-APB). We are now exploring whether this effect in vitro is maintained also in-vivo, in mice that are injected with BNL1ME cells. These results enable implementation of this platform on neuronal populations, not only for ablating specific cells but also for modulation of

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pathways, for basic research and in neuronal based pathologies. Supported by Marie Curie Grant and Rosetrees Foundation The effect of demyelinative damage on neighboring white matter integrity: a diffusion tensor imaging study Raz N. 1*, Bick A.S. 1, Ben-Hur T. 1, Levin N. 1 1 Dept. of Neurology, Hadassah Hebrew-Univ. Medical Center Background: To study the effect of focal demyelinative lesions on neighboring white matter, assessing questions of Wallerian and trans-synaptic degeneration. Degeneration will be studied through the model of the spatially and temporally distinct episode of optic neuritis (ON), along the well defined visual pathways; in the distal part of the same fiber bundle (optic tract) and in the successive trans-synaptic bundle (optic radiation). Methods: We collected T1-weighted and diffusionweighed images for 17 chronic ON patients and 17 normally-sighted subjects. We used probabilistic tractography algorithm to identify the optic tracts and radiations. Retinal Nerve Fiber Layer (RNFL) thickness was recorded in the patients. Results: The optic tracts of ON patients exhibited reduced axial diffusivity, which correlated with RNFL thickness values. The optic radiations of ON patients demonstrated intact axial diffusivity but reduced fractional anisotropy and an elevated radial diffusivity, which could be explained by the existence of intra-bundle lesions. No correlations were found between diffusivity measurements in the patients' optic tracts and radiations; or between RNFL thickness and the diffusivity measurements in the optic radiations. Conclusions: Our results suggest that axonal loss in the optic nerves of chronic ON patients proceeded to the optic tracts, demonstrating Wallerian degeneration. This process did not proceed to the optic radiations, opposing anterograde transneuronal degeneration. Diffusivity changes in the optic tract following ON may model normal appearing white matter pathology in MS; suggesting that a demyelinative lesion in the proximal segment of the nerve fiber results in chronic degeneration of its distal normal appearing portion. Study was supported in part by the Sidney and Judy Swartz fund for research in multiple sclerosis The case of the purple banana: Semantic novelty and repetition enhancement in the default network Reggev N 1, Maril, A 1,2* 1 Cognitive Science, Hebrew Univ. 2 Psychology, Hebrew Univ. Novelty and its influences on basic processes such as attention, memory and language have been intensely investigated in the past few decades. Notably, most studies have focused either on novelty devoid of meaning (e.g., abstract, previously

un-encountered polygons, tones or pseudowords) or on episodic novelty (in which a previously familiar event is considered novel on its first appearance in a specific experimental context). However, most instances of novelty encountered in ecological circumstances are only partially related to previous familiarity and, simultaneously, are endowed with semantic meaning. For instance, a novel computer operating system could, while being refreshingly new, contain familiar components. To examine the processing of this semantic novelty, we employed a sensitive fMRI repetition suppression paradigm aimed at identifying regions associated with processing familiar and novel items. Participants were presented with nounadjective pairs which were either familiar (schema-congruous; e.g., "Yellow Banana") or novel (schema-incongruous; e.g., "Blue Banana"); pairs were repeated once after a lag of 0-36 seconds. Results reveal two strikingly disparate neural networks involved in processing familiar and novel events. Repetitions of familiar events were associated with neural suppression mainly in ventral-lateral temporal cortex, whereas repetition of novel events elicited neural enhancement in regions associated with the "default network". Additional initial results relate subsequent memory performance to processing in these networks. These results suggest that semantic knowledge is processed via two minimally-overlapping neuronal routes. Moreover, novel information seems to require qualitatively distinct processing which possibly involves the construction of novel semantic traces. Future experiments will allow the characterization of the long-term effects of the different processing of novelty and familiarity. Contributions of synaptic envelope to long-term single neuron response fluctuations Reinartz S. 1,2*, Biro I. 3, Gal A. 1,4, Giugliano M. 3,5, Marom S. 1,2 1 Network Biol. Res. Labs, Lorry Lokey Interdisciplinary Center for Life Sciences & Eng., Technion, IL 2Dept. of Physiology, Faculty of Medicine, Technion, Haifa, IL 3Theoretical Neurobiology & Neuroengineering Lab, Dep. Biomed. Sci., Antwerp Univ., Wilrijk, BE 4Faculty of Electrical Engineering, Technion, Haifa, IL 5Dept. of Computer Science, Univ. of Sheffield, UK Single neuron spike trains show significant firing rate variability over extended time scales, characterized by longmemory processes and complex statistics. Rich temporal dynamics of single neuron activity is also observed in response to ongoing, repeated presentation of the same stimulus. Two main sources for temporally complex single neuron activity are described in the literature: the network that the neuron interacts with, and the kinetics of ionic channels underlying single neuron excitability; the temporal dynamics of both are broadly distributed. In this work we ask if and how the synaptic envelope of a given neuron contributes to the temporal

J Mol Neurosci

complexity of a neuronal response over extended time scales. Being the contact layer between the network and the single cell, the synaptic envelope of any given neuron constitutes a bottleneck that might modulate the network effects on neuronal responses. We developed means to activate single neurons in vitro through their synaptic envelopes over extended time scales, enabling clear separation between two determinants of neuronal response variability: membrane excitability dynamics vs. synaptic dynamics. Our findings suggest that under physiological conditions, the long-term temporal statistics are significantly impacted by the dynamics of synaptic transmission. Supp. from FP7/2007-2013 #269459, MATERA #3-7878, NOI-BOF2009, MATERA+ #90455 is kindly acknowledged Emergent design of neuronal devices Renault R. 1,2,3* 1 Univ. Diderot (Paris, France), MSC lab 2 Institut Curie (Paris, France), MMBM lab 3Weizmann Institute of Science (Rehovot, Israel) Background: Exploiting neuronal plasticity of cultures in vitro is a seductive concept for building adaptive computers. However, given the dense and random connectivity of neuronal cultures, it is difficult to control a particular set of synapses without affecting the rest of the connections. To circumvent this limitation, we constrain the growth of primary cultures of neurons in PDMS microfluidic chips, consisting of small populations (10s to 100s of neurons) connected through organized spindles of axon channels. After transfecting the neurons with a light gated ion channels (ChR2) we use optical fibers coupled to LEDs to stimulate the different populations individually. Calcium imaging was used to measure the responses. We aim at quantifying how long term stimulations affect the transmission of activity between populations. We also raise the issue of the physical connectivity between populations and how it relates to the network's behavior. In order to disambiguate the intricate connectoms of our neuronal devices, we use a combination of confocal microscopy on fixed tissues and time lapse imaging of fluorescent neurons (Brainbow). Results: So far, we have validated that Calcium Orange indicator is spectrally compatible with ChR2 to record activity in neuronal cultures without background stimulation. The microfluidic axon channels allow both physical and functional connectivity to settle between populations, a prerequisite for the study of plasticity effects. In the meantime, we have highlighted some resilient features of neurites outgrowth which largely dictate the morphogenesis of the network into the microfluidic chips. Conclusions: Using these results to model both how physical constraints shape the connectivity in the devices and how plasticity works between small neuronal populations would allow us to simulate and eventually evolve more efficient

architectures of neuronal devices, with a range of possible applications going from robotics to prosthetics. Active sound generation modulates activity in auditory cortex regardless of tactile feedback Reznik D.1,2, Mukamel R. 1,2* 1 Sagol School of Neuroscience 2The School of Psychological Sciences, TAU Perception of sensory stimuli is modulated when they are the product of self-generated actions (i.e. action consequences) compared with passively perceived physically identical stimuli. Such modulations have been reported both at the behavioral and the physiological levels. Recently, we have reported stronger fMRI signal in auditory cortex (STG) during active sound generation relative to passive perception of identical sounds. These results suggest a role of motor cortex in modulating auditory cortex activity by a forward efference copy during active sound generation. However, since actions are typically coupled with tactile feedback (e.g. when pressing a button), the role of efference copy from motor cortex or that of somatosensory feedback in such modulations is unclear. This issue is pertinent given that neurons in STG have been reported to be sensitive to passive tactile stimulation. In the current fMRI study, we used a novel design that allowed us to decouple motor-related signals from tactile-related signals in auditory cortex. In the “tactile” condition, subjects played short musical sequences by pressing keys on a piano keyboard while online auditory feedback was provided. In the “non-tactile” condition we used a motion detecting glove and provided movement-related auditory feedback without a tactile component. The fMRI signal from six healthy subjects in both conditions was compared with that evoked by identical auditory stimuli passively perceived. Our results suggest that enhancement in auditory cortex during active sound generation does not depend on tactile feedback. These results support the notion that an efference copy originating from motor cortex modulates activity in auditory cortex during active sound generation and that the role of somatosensory feedback in such modulation is less likely. Witnesses cannot lie plump: behavioral study of different types of deception Riegel M. 1, Falkiewicz M. 2, Marchewka A. 1, Szatkowska I. 2* 1 Nencki Institute of Experimental Biology, Laboratory of Brain Imaging, Warsaw, Poland 2Nencki Institute of Experimental Biology, Laboratory of Psychophysiology, Warsaw, Poland Background: Most of experimental studies concerning deception show that lying is a more demanding cognitive process and takes more time than telling the truth. However, some findings indicate that deceptive responding generates reaction times similar to truthful responding. The aim of our study was

J Mol Neurosci

to re-consider the question of response latency in the context of lying and to investigate whether giving the untruthful answer took longer than telling the truth in two specific situations: when the subjects lie as participants of the events and when they lie as witnesses of the events. To reach this aim we developed a new ecological urban-gaming paradigm. Deception was the integral part of the last stage of the game and, likewise in the real life, the participants were not under any constraints to deceive the interviewer. Results: Thirty-two healthy volunteers (18 males) at the age of between 20 and 30 took part in the study. We compared the reaction times in this group when they were lying and when they were telling the truth answering two kinds of questions: addressed to participants and to the witnesses of the events during the urban gaming. We conducted the hierarchical linear modeling, which showed that the stable effect of lying and telling the truth was statistically significant. The effects of interaction showed specifically that the reaction times for lying and for telling the truth differed significantly only in the case of the questions addressed to the witnesses and not participants of the events. Conclusion: The findings suggest that the elongation of reaction times for lying as compared to telling the truth is related to the type of lying. As far as witnesses are concerned, lying takes them much longer than telling the truth - witnesses cannot lie plump. This study was supported with a grant (2011/01/B/ HS6/04611) from the Polish National Science Center. Modeling of complex PTSD-like behaviors in rats Ritov G. 1,2, Boltyansky B. 2, Richter-Levin G. 1,3,2* 1 Neurobiology and Etiology Dept., Univ. of Haifa, Israel 2The Institute for the Study of Affective Neuroscience (ISAN) 3 Psychology Dept., Univ. of Haifa, Israel Often, in animal models of Posttraumatic stress disorder (PTSD), freezing behavior in the context of a previously experienced stress is taken as an indication of PTSD-like symptoms. However, in order to take into consideration individual differences, a single behavioral measure is not sufficient. To that end we have implemented a behavioral profiling approach which is based on two novel behavioral tests, the Water Associated Zero Maze (WAZM) and the continuous saccharine preference test. The WAZM enables the formation of an association of the maze with an underwater trauma, and by that, the assessment of complex behaviors following an exposure to the context which immediately precedes a traumatic experience. The continuous saccharine preference test enables a fine measurement of consumption behavior over a long period of time without the need for water deprivation, single housing or interruption of transferring to a test cage. Rats were exposed to the WAZM and immediately after to an underwater trauma. One month later rats were re-exposed to the context of the WAZM. During that month, rat's saccharin preference was measured every third day. Behavioral findings

indicate that even after one month, re-exposure to a contextual reminder cue, which immediately precedes the traumatic experience, does initiate PTSD-like symptoms in the WAZM. When combining this complex behavior with the continuance saccharin preference results we were able to profile the animals into sub categories of affected style. The distribution of these affected profiles resembled human psychiatric literature. This work was supported by A DOD award number W81XWH-11-2-0111 to GRL.

The adaptive arm of the ER stresses – A possible therapeutic target for traumatic brain injury Rubovitch V 1*, Baratz-Goldstein R. 1, Pick CG 1 1 Dept. of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv Univ.. Israel We have previously reported that mild traumatic brain injury (mTBI) induced various short and long term cognitive deficits as well as apoptosis in the mice brains. Apoptosis may be caused by prolonged and severe accumulation of misfolded proteins and protein aggregation in the endoplasmic reticulum (ER). ER stress enables the cell to adapt and survive by upregulating translation of stress response proteins and attenuating global protein synthesis. Insulin like growth factor (IGF-1) is known to be neuroprotective. Hence, the present study was aimed at establishing a novel mechanism for IGF-1 neuroprotection, which involves the adaptive arm of the ER stress. As expected, IGF-1 administration significantly improved memory deficits following mTBI (as assessed by the Y-maze and the Novel Object recognition tests). In addition, mTBI induced a timedependent elevation of the ER stress sensor protein ATF6 (Activating transcription factor 6). IGF-1 administration had a significant effect on CHOP (C/EBP homologous protein) and phospho-eIF2-alpha (elongation initiation factor alpha) expression following mTBI as was seen by western blot analysis. In addition, immunofluorescent examinations revealed that under IGF-1 administration CHOP was significantly co-localized with phospho-eIF2-alpha in the cortices and hippocampi of mTBI mice. These results confirmed our working hypothesis that IGF1 exerts at least part of its neuroprotection via the adaptive pathway of the ER stress. A direct activation of eIF2-alpha by the selective phosphatase inhibitor Salubrinal completely abolished the mTBI-induced damage to the cognitive deficits. Altogether, these results reveal a novel neuroprotective mechanism for IGF-1 and suggest the adaptive eIF2-Alpha pathway as a possible target for pharmacological therapy. Caudo-rostral coupling between alpha-1 adrenoceptor activated cluster of sacral interneurons and rostral lumbar motoneurons Roisman R 1, Cherniak M 1, Lev-Tov A 1* 1 Medical Neurobiology, IMRIC, Hebrew Univ. Medical School

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Noradrenergic activation of the sacral segments in isolated spinal cords of neonatal rats, produces alternating left-right rhythmic bursts in lumbar flexor and sacral motoneurons. Pharmacological and surgical manipulations of the spinal cord in the absence and presence of the alpha-1 adrenoceptor agonist methoxamine, revealed that the rhythm originates from ventral subpopulations of sacral interneurons the axons of which ascend to the rostral lumbar segments, exclusively through the ventral white matter funiculi (VF). Fluorescent calcium imaging of sacral interneurons back-filled with calcium sensors through cut-VF axons at the lumbosacral junction, revealed rhythmic activity of the labeled VF neurons in the presence of methoxamine. The activity of the majority of these VF-neurons was in phase with the concurrently recorded ipsilateral motor output. Injection of GFP encoding PRV Bartha virus to hindlimb flexors of newborn rats, revealed direct labeling of motoneurons and trans-synaptic labeling of sacral VF- and other sacral- interneurons. Although additional experiments are needed to determine more accurately the extent of the trans-synaptic spread of the virus, we suggest that there is a potent oligo-synaptic connectivity between sacral VF neurons and rostral lumbar motoneurons. This connectivity can play a significant role in the caudo-rostral coupling between the methoxamine-activated sacral VF neurons and lumbar flexor motoneurons. The functional significance of this caudo-rostral coupling and its mechanism of action will be discussed. Characterizing the "ups" and "downs" of functional connectivity patterns using face perception as a model domain Rosenthal G 1,2*, Freud E 3,2, Ganel T 3,2, Avidan G 3,2 1 Dept. of Cognition and Brain, Ben-Gurion Univ. of the Negev, Israel 2Zlotowski Center for Neuroscience, Ben-Gurion Univ. of the Negev 3Dept. of Psychology, Ben-Gurion Univ. of the Negev, Israel Background: A common practice in fMRI research is to examine changes in functional connectivity patterns under different behavioral tasks within and between populations. Observed patterns range from under to hyper connectivity between specified regions, but no obvious account is available for such heterogeneity. The current study sets to examine functional connectivity and its relation to univariate analysis and to behavior within the face-responsive network, using it as a model domain. The face network provides an ideal test-bed for such investigation as it is relatively well characterized at both the behavioral and neural levels in humans. The face inversion effect, in which performance is typically better for upright compared to inverted face, is utilized to manipulate behavior and concomitant network properties. Results: Subjects performed the face inversion task while connectivity patterns between regions of the face

network and the objects network were examined. In addition to connectivity analysis, dedicated sessions were conducted as a basis for univariate GLM analysis. Functional connectivity of the face network increased for upright, compared to inverted faces, mirroring the effect obtained in univariate analysis and behavior. However, connectivity of the object network showed the reversed pattern along with increased connectivity between the face and object networks. Conclusions: These patterns reveal a mechanism in which the processing of a stimulus category irrelevant to one network is routed to the other. Such mechanism may account for the 'object-like' processing attributed to inverted faces. Immune-based activation, rather than suppression, for curing Alzheimer’s disease Rosenzweig N.1,*, Baruch K. 1,*, and Schwartz M.1 1 Dept. of Neurobiology, Weizmann Institute of Science, Rehovot 76100, Israel * Equal contribution. Alzheimer's disease (AD) is a neurodegenerative disease characterized by age-associated dementia, and accumulation of amyloid-beta (Aβ plaques in the central nervous system (CNS) parenchyma. Although the pathophysiological mechanisms involved in the disease are still unclear, chronic neuroinflammation has been repeatedly linked to disease progression, and its attenuation was shown to be dependent on systemic immune cells. Here we show, in a mouse model of AD, which harbors five mutations associated with familial AD (5XFAD), that peripheral immune suppression develops along disease course. Utilization a T-cell based vaccination protocol with Glatiramer acetate (GA), which results in a reduction, rather than enhancement of suppressive T cells populations in the periphery, has led to the recruitment of inflammationresolving leukocytes to sites of plaque formation in the hippocampus and cortex; their accumulation was correlated with clearance of Aβ plaques, local resolution of neuroinflammation, and prevention of cognitive decline. Collectively, our results demonstrate that the attenuation of peripheral immune suppression in AD is required in order to mount an antiinflammatory immune response within the CNS, and emphasizes an inverse relationship between peripheral and local levels of suppressive immune cell populations, which determines disease progression. An altered olfactory profile in children diagnosed with autism spectrum disorder Rozenkrantz L. 1*, Heller I. 1, Plotkin A. 1, Weissbrod A. 1, Zachor D. 2, Sobel N. 1 1 Weizmann Institute of Science, Dept. of Neurobiology, Rehovot, Israel 2 Asaf Harofeh Medical Center, Autism Center, Zerifin, Israel

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The brain substrates implicated in autism spectrum disorder (ASD) are highly overlapping with the neural substrates of olfaction. Indeed, many anecdotal observations report altered responses to smells in children and adults with ASD. Here, we set out to test the hypothesis that olfactory responses are altered in children with ASD, and that these altered responses may serve early diagnosis. The sniff-response is a phenomenon whereby nasal airflow parameters are rapidly modulated in accordance with odorant content. For example, pleasant odors are automatically sampled with strong sniffs, yet unpleasant odors are sampled with weak sniffs. Thus, by measuring nasal airflow (sniffs) alone we obtain a non-verbal measure of olfactory perception and processing. We developed a pediatric olfactometer that delivers pleasant and unpleasant odors and measures the concurrent sniff-response. A complete experiment consisted of 26 trials, half consisting of the unpleasant odor butyric acid, and half consisting of the pleasant odor phenyl-ethyl alcohol. Inter-trial Interval was 30 seconds, and total study duration was no longer than 15 minutes. The task involved mere exposure to the odorants, and measurement of the ensuing sniff. There were no task instructions to follow, and no active task to complete. Out of 26 children referred for ASD diagnostics who started the experiment (24 boys, mean age 6.3±2.7 years), only 10 completed it, and only 6 children completed a sufficient number of trials to allow analysis (all boys, mean age 6.6±1.9 years). Nevertheless, in these 6 children there was a striking correlation of R2=0.99 (p< 0.05) between their composite sniffresponse score (difference in sniff to pleasant vs. unpleasant odors) and their independently obtained autism severity scores (ADOS). We are working to increase compliance rate in order to develop what may be a powerful olfaction-based early diagnostic tool for ASD. Increasing creativity using the placebo effect Rozenkrantz L. 1,2*, Noy L. 2,3, Hart Y. 2,3, Mayo A. 2,3, Alon U. 2,3 1 Weizmann Institute of Science, Dept. of Neurobiology, Rehovot, Israel1 2The Theatre Lab, Weizmann Institute of Science, Rehovot, Isreal 3Weizmann Institute of Science, Dept. of Molecular Cell Biology, Rehovot, Israel Background: A common, yet understudied, notion is that creativity is often suppressed by our own internal judgments. Several studies showed that inhibiting participants' consciousness positively influences creativity, using hypnosis, alcohol or simply distracting the mind while processing answers. In this study, we aim to increase creativity using the placebo effect, making participants believe they are being exposed to a substance (in the form of an odorant) which would enhance their creativity. This is hypothesized to cause participants to feel less responsible for their products, thus display higher self-confidence and less hesitation, and therefore improve

their creativity results. The control group is exposed to the same odorant without being told it influences creativity. Results: Preliminary results (N=5 in each group) showed statistically significant differences in the performance of the placebo group versus the control group, the former being faster and more fluent at generating products throughout the task (p<0.01 and p=0.01, respectively). In regards to creativity results (originality of the products), a trend towards higher originality score of the placebo group was observed. Conclusions: These results, although preliminary, support what was earlier hypothesized: given the opportunity to hold an external influence responsible, the placebo group seems to act more freely and exhibit higher self-assurance and confidence. Originality parameters showed no significant results, which may be accounted by the small sample size and the elusive nature of creativity. Expanding study population is planned. An old factor for a new “era” : alpha7-nAChR Russo P. 1*, Del Bufalo A. 1, Cesario A. 1 1 Systems Medicine area: Laboratory of Systems Approaches. IRCCS "San Raffaele Pisana" Rome, Italy. Background: α7-nAChR participates in different functions in different cells. Results: Nicotine & Donepezil (DP) induce α7 proteins upregulation in human neuronal stem as well as in bronchial epithelial cells (HBEC) & in lung cancer cells. Chronic nicotine treatment promotes HBEC malignant transformation. Transfection with α7-siRNA significantly attenuates the nicotine-mediated promotion Conclusions: Cholinergic system is an universal system of cellular communication. a7 down or up-regulation may be related to different diseases according to its cellular localization. a7 modulation may represent a new promising target to develop therapeutic strategies versus different human diseases. Prof. Carla Falugi, Univ. of Genoa-Italy Reversing Neurodevelopmental disorders in adults: from mechanisms to treatments Silva A.J Dept. of Neurobiology, Dept. of Psychology, Dept. of Psychiatry, Integrative Center for Learning and Memory, Semel Institute, Brain Research Institute, Univ. of California, Los Angeles, California, USA Abnormalities in brain development, thought to be irreversible in adults, have long been assumed to underlie the neurocognitive symptoms associated with neurodevelopmental disorders. Surprisingly, a number of recent animal model studies of neurodevelopmental disorders demonstrate that reversing the underlying molecular and cellular

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deficits can result in dramatic improvements in cognitive function even if treatments are started in adulthood. These unexpected results may reflect the considerable molecular, cellular, structural and behavioral plasticity of the adult brain. Indeed, our laboratory has uncovered mechanisms and adult treatments for animal models of Neurofibromatosis type I, Tuberous Sclerosis, and Noonan Syndrome. Altogether these findings mark a paradigmatic change in the way we understand and envision treating neurodevelopmental disorders. They raise the possibility that adult treatments could one day help the many millions of people affected with these disorders. VEGF as a novel therapeutic target to counteract the neuronal and vascular effects of apoE4 Salomon-Zimri S. 1, Antes R. 1, Michaelson D.M. 1* 1 Dept. of neurobiology, George s. Wise faculty of life sciences, Tel Aviv Univ., Israel. Background: Alzheimer's disease (AD) is associated with neural and vascular dysfunction. ApoE4, the main genetic risk factor for AD is associated with increased neurodegeneration and vascular impairments. The extent to which these pathologies are mediated by a common factor is unknown. The vascular endothelial growth factor (VEGF) has been shown to play an important role in both the neuronal and vascular systems. The objective of the present study is to test whether the apoE4 pathological effects on these systems are mediated by VEGF and to identify novel therapeutic targets utilizing the brain and the eye as complementary model systems. Results: Our previous results revealed neuronal and synaptic impairments in hippocampi of young naïve apoE4targeted replacement mice, which correlated with cognitive deficiencies. Similar results were obtained under stress conditions after activation of the amyloid cascade. In contrast, no gross effect was observed on the vasculature. This study shows that these apoE4-induced pathological effects are associated with lower VEGF levels. The eye, with its unique structure in which the neuronal and vascular systems are spatially separated, provides an excellent model to approach our research question. Examination of young naïve apoE4 neuro-retina revealed synaptic impairments and functional deficiencies. This was also found to be associated with lower VEGF levels, with no gross effect observed in the choroid vasculature. Stress conditions generated by laser-induced choroidal neurovascularization, resulted in apoE4 hyper-angiogenesis, associated with an elevation of VEGF levels in both the retina and the choroid. Conclusions: These findings show differential effects of apoE4 on the neuronal and vascular systems. VEGF levels are associated with neurodegeneration in the

neuronal system and angiogenesis in the vascular system. This sets the stage for a novel therapeutic antiVEGF treatment to counteract apoE4 pathologies. Neuro-cognitive aspects of oral and silent reading among adult dyslexic and typical readers: An fNIR experiment Saracusti, P. 1*, Breznitz, Z 1 Edmond J. Safra Brain Research Center for the Study of Learning Disabilities, Univ. of Haifa There are two different modes of reading: oral and silent. It is commonly agreed that oral reading is a reliable diagnostic tool for verifying word decoding and reading fluency abilities, whereas silent reading is a reliable measure of reading comprehension and fluency. However, there have been few studies into the similarities and differences of the neuro-cognitive aspects of the two modes, in both normal and deviant courses of reading. A relatively new device that uses functional Near-Infrared Spectroscopy (fNIR) might help to overcome measurement limitations due to vocal articulation during oral reading. This brain imaging technology measures oxygen changes in the blood within the brain. Dyslexia is a reading disability mainly characterized by deficits in oral word decoding and spelling and non-fluent reading in both oral and silent modes. The current study aims to examine the neurocognitive aspects of oral and silent reading among adult dyslexic and typical readers using fNIR technology. Currently data from 10 typical and 10 dyslexic readers showed significantly greater degrees of brain oxygenation for the former group during oral reading in the left frontal and left-posterior temporal regions as compared to the dyslexic group. During silent reading, typical readers, as compared to dyslexic readers, showed greater oxygenation in a left-posterior temporal brain region. These findings suggest that typical readers use different strategies for each reading mode, reflected in greater brain activation in Broca's area for oral reading and in Wernicke's area for silent reading. However, dyslexic readers seem to use mixed strategies for both modes of reading that are reflected in broader and non-specific brain activation. This study was supported by the Edmond J. Safra Philanthropic Foundation. Stress, extinction and plasticity of mPFC: developmental differences. Schayek R. 1, Maroun M. 1* 1 Sagol Dept. of Neurobiology, Faculty of Natural Sciences, Univ. of Haifa Background: We have previously reported that extinction of fear conditioning is associated with plasticity in the

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medial prefrontal cortex (mPFC; Vouimba and Maroun, 2011). We and others previously reported that exposure to stress impairs extinction of fear and long-term potentiation (LTP), the hypothesized model of memory formation. The mPFC undergoes major changes during development and stress differentially affects brain and behavior at different stages of life, especially during the post-weaning period (Spear, 2000; Koss et al., 2011). In this study we sought to examine whether stress has similar effects on extinction and mPFC-plasticity in the post-weanling (PW) pup as compared to the adult animal. Results: Our results show that, whereas stress impairs extinction of fear in the adult animal, it resulted in enhanced extinction in the PW rat. Similarly exposure to stress was associated with impaired LTP in the mPFC of the adult rat and with enhanced LTP induction in the PW rat. Furthermore- the enhanced extinction following exposure to the elevated platform stress occludes the induction of LTP in the PW, confirming that LTP was already induced in the learning process. In contrast, in the adult animal the impaired extinction following exposure to the stress was associated with induction of LTP. We further show differential involvement of NMDA receptors in the mediation of these effects. Conclusions: These results show differential mechanisms in the way stress modulates extinction and plasticity in the PW as compared to the adults and further confirm the relevance of changes in plasticity in the mPFC to extinction. Molecular mechanisms responsible for hypoxia-induced mitochondrial dynamics in neurons Scorziello A. 1,2*, Savoia C 1,3, Sisalli MJ 4,2, Annunziato L. 5,2 1 Federico II Univ. of Naples 2Dept. of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine 3Dept. of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine 4 Federico II Uiversity of Naples 5 Univ. of Naples Federico II Mitochondria are highly dynamic organelles that continuously move, divide and fuse in a highly regulated fashion under the control of the so-called "mitochondria-shaping" protein family, thus regulating various aspects of their function, including ATP production, Ca2+ buffering, free radical homeostasis, mitochondrial DNA inheritance and organelle quality control. Neurons are particularly sensitive and vulnerable to abnormalities in mitochondrial dynamics, due to their large energy demand and their long extended processes where mitochondria need to be transported. Indeed, fragmentation of neuronal mitochondria is necessary for their transport and proper development and function of synapses. Moreover, mitochondrial fission is an early step in the mitochondrial apoptosis

pathway, and inhibiting fission can block or delay apoptosis in different cell types, including neurons. The balance between fusion and fission requires a tight control of proteins whose activity can be modulated by covalent modifications, such as phosphorylation, sumoylation and ubiquitylation. In this respect, it has been shown that Drp1, a protein which play a key role in mitochondrial fragmentation, is a direct substrate of PKA. Interestingly, we demonstrated that in cells exposed to hypoxia the mitochondrial PKA anchoring protein, AKAP121, is rapidly degraded by a mechanism mediated by the activation of the E3 ubiquitin ligase SIAH2, and mitochondrial activity, assessed as mitochondrial membrane potential and oxidative capacity, is strongly impaired. Moreover, we recently reported that AKAP12 interacts with the isoform 3 of the Sodium calcium exchanger, NCX3, on the outer mitochondrial membrane and that this interaction is crucial for mitochondrial calcium extrusion both in physiological and in hypoxic conditions. Therefore, the present study was addressed to investigate whether AKAP121 and NCX3 may participate in molecular events underlying the process of mitochondrial fission during ischemia. Individual olfactory fingerprints: from mapping odors in people-space to mapping people in odor-space Secundo L. 1*, Snitz k. 1, Pinchover L. 1, Bar-Zvi D. 1, Sobel N. 1 1 Dept. of Neurobiology, Weizmann Institute of Science. Rehovot, Israel A key step of linking neuronal olfactory coding to odorants physicochemical properties is to account for individual variability in odor perception. Therefore, one would like to parameterize individuals in a space of odor preferences to account for this variability, i.e. instead of representing odors, representing people and quantify their individual olfactory percept. We collected perceptual ratings (using VASs) from 61 participants who rated 32 odorants along 57 descriptors. Twenty seven of the descriptors were taken from Dravnieks' odor atlas and additional thirty two were selected through a semantic analysis process. Using only 15 odorants and 30 descriptors we were able to characterize an 'Olfactory fingerprint' for an individual. This fingerprint allowed us to identify a given individual out of the pool of 61 individuals with 90% accuracy. The 'Olfactory fingerprint' was generated by normalizing answers per subject per odor and then averaging across odors, i.e. generating a specific descriptor usage profile which is independent of the odors used (averaged across odors). To test if this profile is not merely a reflection of semantic usage of descriptors, we created an odor similarity matrix for each subject that is independent of the

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descriptors used. The subject's similarity matrix was generated by correlating all odor ratings within a subject. Using a same method on the similarity matrix we showed again that we are able to identify individual participants with 90% accuracy, thus showing that the profile created was not specific to the descriptor usage. Subchronic administration of delta-9-tetrahydrocannabinol (THC) to dominant negative DISC1 mice: gene X environment mouse model of schizophrenia Segal H 1*, Taler M 2, Gil-Ad I 2, Mechoulam R 3, Weizmann A 2, Offen D 1, Barzilay R 1 1 Neurosciences lab, FMRC, Sackler Faculty of Medicine, Tel Aviv Univ. 2 Biological Psychiatry Lab, FMRC, Sackler Faculty of Medicine, Tel Aviv Univ. 3 Institute for Drug Research, Medical Faculty, Hebrew Univ., Jerusalem, Israel Background: Cannabis abuse in adolescence is associated with increased risk of psychosis and conversion to schizophrenia. Δ-9-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. Disrupted in schizophrenia 1 (DISC1) gene is an important candidate risk gene for schizophrenia. Transgenic mice with expression of a dominant-negative form of DISC1 (DNDISC1) in forebrain areas display schizophreniaassociated behavioral deficits. The aim of the present study is to determine whether DN-DISC1 mice treated with THC demonstrate increased schizophrenia-like behaviors. Results: Male C57BL and DN-DISC1 mice were treated for 10 days with THC (10 mg/kg) or vehicle during adolescence-equivalent period (postnatal 42–52d). The behavioral effects of THC administration were then evaluated utilizing behavioral tests relevant to schizophreniaassociated endophenotypes: exploratory activity (open field, light/dark box), anxiety (elevated plus maze) and recognition memory (novel object recognition test). We found that DN-DISC1 mice treated with THC displayed aberrant exploratory behavior, as observed in the light/ dark box (P<0.005) and open field (P<0.05), as well as impaired recognition memory in the novel object recognition test (P<0.05), compared to vehicle treated C57BL mice. DN-DISC1 mice demonstrated increased anxietyrelated behavior in the elevated plus maze which was not statistically affected by the THC exposure. Conclusions: DN-DISC1 mice display subtle schizophreniaassociated behavioral deficits as compared to C57BL mice. Sub-chronic THC administration resulted in aggravated behavioral deficits of the DN-DISC1 mice in terms of exploratory activity and recognition memory. We hereby suggest DN-DISC1 X THC interaction as a gene X environment model for schizophrenia.

Intracerebroventricular transplantation of human mesenchymal stem cells promotes hippocampal neurogenesis and improves three core autistic-like behavioural phenotypes of BTBR mice Segal H 1*, Karvat G 2, Barzilay R 1,3, Ganz J 1, Barak N 2, Edry L 2, Offen D 1, Kimchi T 2 1 Neurosciences lab, FMRC, Sackler Faculty of Medicine, Tel Aviv Univ. 2Dept. of Neurobiology, Weizman Institute of Science 3Research Unit at Geha Mental Health Hospital, Sackler Faculty of Medicine, Tel Aviv Univ., Israel Background: Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by social interaction impairments, communication deficits and repetitive stereotypic behaviors. BTBR mice are a commonly used model of ASD as they demonstrate behavioral deficits consistent with the three diagnostic criteria for ASD. Moreover, BTBR mice exhibit decreased BDNF signaling and reduced hippocampal neurogenesis. Current available treatments offer no cure for ASD patients. In this study, we aimed to investigate the potential of mesenchymal stem cells (MSC) transplantation, which possess great potential for regenerative therapy, to improve the autistic-like behavioral phenotypes of BTBR mice. Results: Transplantation of human MSC into the lateral ventricles of 6-8 weeks old BTBR mice resulted in a reduction of stereotypical behaviors, an improvement in social behavior and a decrease in cognitive rigidity. Importantly, analysis of the overall standardized autism behavioral score revealed a significant improvement in the MSC treated mice compared to sham treated mice. Tissue analysis revealed elevated BDNF protein levels in the hippocampus accompanied by increased hippocampal neurogenesis in the MSC treated mice compared to sham treated mice. Remarkably, significant correlations were found between the autism behavioral severity score and both hippocampal neurogenesis and BDNF levels. Conclusions: Delivery of MSC to the lateral ventricles is beneficial in attenuating behavioral deficits in the BTBR mouse model of ASD. The increased hippocampal BDNF levels and neurogenesis which correlate to the amelioration in autistic-like behavior might indicate the possible mechanism underlying this improvement. Our study suggests a novel therapeutic approach for treating ASD animal models which may be translatable to ASD patients. Emotion regulatory flexibility moderates the link between repeated exposure to trauma and posttraumatic stress symptoms in active duty firefighters Segev R. 1, Keri S. 2, Sheppes G. 3, Richter-Levin G. 1, LevyGigi E. 1* 1 The institute for the Study of Affective Neuroscience, Univ. of Haifa, Israel 2National Psychiatry Center, Budapest, Hungary 3 School of Psychology, Tel-Aviv Univ.

J Mol Neurosci

Background: Conventional wisdom suggests that there should be a strong relationship between repeated exposure to traumatic events and increased rates of posttraumatic stress symptoms. However, empirical investigations, with first responders that are routinely exposed to traumatic events, fail to reveal consistent links between these variables. To explain this inconsistency, the present study offers a crucial moderating role for regulatory flexibility – differential selection between emotion regulatory strategies according to the situational demands. . We predicted that the link between repeated exposure to trauma in active duty firefighters and PTSD symptomatology would evince in low but not high regulatory flexibility individuals Methods: We used years of service as a measure of exposure to trauma and a structured clinical interview (SCID–NP–PTSD) to measure PTSD symptoms of 69 active duty firefighters, a unique population that is repeatedly exposed to traumatic events. Participants were also tested on an innovative performance based emotion regulation choice task that measures regulatory flexibility. In this task participants choose between two major regulation strategies when facing photos that vary on negative emotional intensity. Results: We found that firefighters who demonstrate poor regulatory flexibility when facing negative stimuli, display more PTSD symptoms over repeated exposure to potential traumatic events across time. Conclusions: These findings emphasize the importance of regulatory flexibility in conditions of continuous trauma exposure and suggest that the emotion regulation choice task may serve as a sensitive tool, which may help to identify in advance individuals with a higher risk to develop PTSD across time. Coding of natural sounds in the mouse auditory cortex Shalev A. 1,2, Nelken I. 1,2, Mizrahi A. 1,2* 1 Dept. of Neurobiology, Inst. for Life Sciences, The Hebrew Univ. of Jerusalem 2The Edmond and Lily Safra Center for Brain Sciences, Hebrew Univ. of Jerusalem The auditory system is used to code sounds from the environment. Early in the auditory hierarchy, circuits are organized and highly specialized for detecting basic sound features. The primary auditory cortex (A1) has been proposed to code complex features of the soundscape but its underlying coding principles and their mechanisms are not well understood. Coding in A1 has been investigated mostly using highly simplified sound stimuli like pure tones. But pure tones are quite different than the sounds animals encounter in their natural environments. Our work focuses on understanding coding principles of cortical neurons to natural sounds with special emphasis on vocalizations. Vocalizations contain several complex auditory features. For example, vocalizations are several seconds long and contain numerous syllables with varying inter-stimulus

intervals. In addition, syllables have complex features like harmonics, amplitude modulations (AM), and frequency modulations (FM). To study how A1 neurons code vocalizations, we first recorded a library of pup vocalization. Then, recorded vocalizations (as well pure tones) were used as stimuli while we recorded the spiking activity of single neurons in A1. We found that neurons in A1 responded with highly heterogeneous patterns of activation to pup vocalizations. Interestingly, neurons in A1 showed preference for specific and sometimes unique syllables in the sentence. Neuronal response parameters like basic frequency and amplitude tuning could not explain the syllable preference leading us to hypothesize that other mechanisms are responsible for neuronal response profiles. We are currently testing other response properties such as time and context to explain the complex responses of cortical neurons to natural sounds. Visual aversive learning increases generalization Shalev L. 1*, Paz R. 2, Avidan G. 1 1 Dept. of Psychology, Ben Gurion Univ. of the Negev, Israel 2 Dept. of neurobiology, Weizmann Institute of Science, Rehovot, Israel In our world, stimuli are often varied and their physical properties are rarely replicated in the exact same way. The ability to generalize across similar stimuli and respond appropriately can be very important for survival. Human studies have shown that aversive conditioned learning results in wider generalization of the conditioned stimuli. This effect was demonstrated under a number of aversive conditions, including pain, negative odors or sounds and loss-related stimuli. In the present work we investigated whether such generalization can also occur under visual aversive conditions. The visual stimuli included aversive or neutral images from the International Affective Picture System (IAPS) database. Subjects learned to associate auditory neutral stimuli, with the appearance of an image (CST+) or with no image (CST-). CST+ images were aversive in one group and neutral in a control group. Generalization for the auditory conditioned stimuli was tested and compared immediately prior to and following learning. We found wider generalization for the aversive CST+ compared to CST− within the experimental group, and in comparison with the control group. This finding further fortifies the notion that generalization during aversive learning is not modality dependent, and suggests a global mechanism, beneficial when facing dangerous situations. Extracting cortical current dipoles from MEG recordings Shapira Lots I. 1, Robinson S. E. 2, Abeles M. 1,3* 1 Gonda Multidisciplinary Brain Research Center, Bar-Ilan Univ., Ramat-Gan, Israel 2MEG Core Group, National Institute of Mental Health, NIH, Bethesda, MD, USA 3The Hebrew Univ. of Jerusalem, Jerusalem, Israel

J Mol Neurosci

Background: Recording the magnetic fields generated by electrical currents in the brain has the advantage that the fields are dependent on the primary currents, does not require a reference electrode, and can follow rapid changes. Yet, single source localization accuracy for superficial sources by MEG and EEG are comparable. This is, partially, due to the large distance between the brain and the MEG sensors.Source localization by EEG or MEG are further complicated by the strong correlations that may exist among cortical areas or between cortical areas and deep nuclei. In recent years the contribution of such correlations were minimized by the LCMV beamformer, from which Synthetic Aperture Magnetometry (SAM) is derived. The SAM method provides an evaluation of the current-dipole amplitude at a point of interest, given the recordings in all MEG channels and the covariance matrix of this activity. With this method one obtains an estimation of the continuous trace of the current dipole amplitude at the point of interest.Lately, a method to simultaneously compute the current dipoles in a group of points in a way that minimizes the correlations among them was suggested. We assume that by placing a point of interest at the center of an octagon and evaluating the current dipoles for the octagon's center and all its vertices we can get a good estimate of the local currents at the center. We call such currents Cortical Current Dipoles (CCDs). Results:We found that the correlation between CCDs is low and falls off rapidly with distance. Comparing MEG to CCD we found that the evoked auditory responses are more reproducible, have a larger signal to noise ratio and better localized. Conclusions:CCDs indeed represent local cortical activities. This research was supported in part by I-CORE of the ISF (grant No. 51/11). Enhancing memory via knockdown of eIF2α kinase PERK Sharma V. 1, Ounallah Saad H. 1, Rosenblum K. 1* 1 Sagol Dept. of Neurobiology, Center for Gene manipulation in the Brain, Univ. of Haifa, Haifa 3 Memory consolidation is critical for the proper formation of long term memory (LTM). Translation initiation and newly synthesized proteins are crucial for memory consolidation, and protein synthesis inhibitors prevent the formation of LTM. The process of translation initiation is highly complex and involves several different factors. A major factor involved in the initiation step is the eukaryotic initation factor 2 alpha (eIF2α). eIF2α activity depends on its phosphorylation levels on specific serine residue (Ser51). Phosphorylation of Ser51 on α subunit of the eIF2 is a key regulatory mechanism in controlling translation, and it is controlled in the brain by 3 kinases (PKR, PERK, GCN-2) and phosphatases. The dephosphorylation of eIF2α is mediated via PP1c and the adaptor protein GADD34. When eIF2α is phosphorylated, translation rate is

decreased and LTM is impaired and vice versa. Our research aims to decrease the phosphorylation on eIF2α in specific brain regions using viral vectors targeting the expression of the kinases, and to examine the effect of decreased phosphorylation on memory. We injected lentivirus and AAVexpressing ShRNA for PERK to the insular cortex and tested the effect on taste learning, and conditioned taste aversion (CTA). Semantic processing in literary and spoken Arabic: An event-related potential study Khateb A 1,2,3*, Shehadi-Haj M 1,2 1 The Unit for the study of Arabic language, Faculty of Education, Univ. of Haifa 2 Dept of Learning Disabilities, Faculty of Education, Univ. of Haifa 3 Edmond J. Safra Brain Research Center, Univ. of Haifa The diglossia in Arabic refers to the existence of two varieties of the same language: The spoken Arabic (SA) which is used for everyday conversation and the literary Arabic (LA) which is used for reading and writing and formal purposes. Behavioral studies claimed that the two varieties of Arabic are represented respectively as first (L1) and second language (L2) in the cognitive system. Here, we used event-related potential (ERP) analysis during a semantic categorization task with SA and LA word pairs to determine the time course of word processing in these two varieties. Behavioral and ERP analysis indicated that LA words were processed faster than SA ones as for L1 and L2 words. In particular, the ERP effects were observed during the N1-P2 components and the N400 response which occurred earlier during LA than SA. These results are discussed in the bilingual context and of word frequency effects during reading This research was supported by the by the Israeli National Science Foundation (Grant no’ 623/11) Dissecting local circuits: parvalbumin interneurons underlie broad control of olfactory bulb output Shlomai-Fuchs Y 1,2, Miyamichi K 3, Luo L 3, Mizrahi A 1,2* 1 Dept. of Neurobiology, Institute of Life Sciences, HUJI 2 The Edmond and Lily Safra Center for Brain Sciences, HUJI 3 Dept. of Biology, Howard Hughes Medical Institute, Stanford Univ. In the olfactory bulb (OB), odor information from sensory neurons is extensively processed by multiple local networks of interneurons. Local networks thus shape the activity of Mitral and Tufted (M/T) cells which convey odor information to higher brain areas. The precise function of these local networks remains elusive because of the vast heterogeneity of interneurons, their diverse physiological properties, and their complex synaptic connectivity. Here we identified the parvalbumin inhibitory interneurons (PVNs) as a prominent component of the M/T presynaptic landscape by using an

J Mol Neurosci

improved rabies-based trans-synaptic tracing method for local circuits. In vivo two-photon targeted patch recording revealed that PVNs have exceptionally broad olfactory receptive fields, and exhibit strong and persistent odor responses. Additional Trans-synaptic tracing indicated that not only do PVNs heavily innervate M/T cells but they also receive direct input from widely distributed M/T cells, suggesting a mechanistic explanation for PVNs' wide receptive fields. Both the anatomical and functional extent of this broad M/T→PVN→M/T feedback circuit contrasts with the narrowly confined local circuits thus far examined in the OB. This demonstrates that olfactory information is processed by multiple local circuits operating at distinct spatial scales. We show that integrating in vivo physiology with cell type specific synaptic tracing allows to study local circuits individually, while retaining the context of their larger networks. Social experience modulates reward perception in Drosophila Shohat-Ophir G. The Mina and Everard Goodman Faculty of Life Sciences Bar-Ilan Univ., Israel. Natural rewards and abused drugs affect the function of the brain’s reward systems, and abnormal function of these brain regions is associated with addictive behavior. Some aspects of drug reward can be modeled in the genetically tractable fruit fly Drosophila melanogaster. Flies exhibit complex addictionlike behaviors, including a lasting attraction for a cue that predicts ethanol intoxication and a preference for consuming ethanol-containing food, even if made unpalatable. In addition to genetic factors, social experience can affect drug addiction. We therefore investigated the relationship between sexual experience and alcohol preference in Drosophila. We found that in males, mating increased Neuropeptide F (NPF) levels, whereas sexual deprivation reduced NPF levels. Moreover, activation or inhibition of the NPF system reduced or enhanced ethanol preference, respectively. These results thus link sexual experience, NPF system activity, and ethanol consumption. In addition, artificial activation of NPF neurons was in itself rewarding and precluded the ability of ethanol to act as a reward. We propose that activity of the NPF/NPF receptor axis represents the state of the fly reward system and modifies behavior accordingly. Modulation of the NPF system by socially rewarding and non-rewarding experiences may thus reflects a broader mechanism by which experience is represented in the brain and converted into changes of circuit function and, eventually, modulation of behavior. To extend our understanding of this process, we are analyzing the transcriptional profile of social experience within specific subsets of neuromodulatory circuits and relating it to changes in the fly’s social group dynamics.

Holographic interfaces with neuronal populations in retinas and optonets Shoham S. Dept. of Biomedical Engineering, Technion – I.I.T. The talk will review recent work on distributed ‘patterned’ optogenetic interfacing with large populations of optically accessible neurons in two-dimensions (retinas) and three dimensions (bioengineered brain-like ‘optonets’). Our results demonstrate that patterned computer-generated holographic stimulation can achieve millisecond temporal precision and cellular resolution as a path towards simultaneously controlling populations of retinal ganglion cells and that rapid scanning line temporal-focusing (SLITE) microscopy provides a powerful tool for population-wide imaging. I will also discuss the translation of these tools towards in vivo settings, and recent findings on alternative neuro-physical excitation strategies: ultrasonic stimulation and a neurophotonic strategy based on photo-absorber induced neural-thermal stimulation (PAINTS).

Spatial vs. intermodal attention: is there a fixed hierarchy? Shrem T. 1*, Deouell L.Y. 1,2 1 Dept. of Psychology, The Hebrew Univ. of Jerusalem, Jerusalem, Israel 2The Edmond & Lily Safra Center for Brain Sciences, The Hebrew Univ. of Jerusalem, Jerusalem, I Background: When subjects are required to direct attention to stimuli in one modality at a given location, stimulus processing in task-irrelevant modalities – as manifested in EEG responses - is affected too. Such findings are often interpreted as evidence for a supramodal spatial attention mechanism, where spatial attention supersedes intermodal attention. However, these findings were obtained using paradigms in which spatial attention was manipulated transiently and frequently (on a trial by trial basis) whereas intermodal attention was sustained (between subjects or runs). In this EEG study with 20 subjects we aimed at dissociating effects of transient vs. sustained attention from effects of spatial vs. intermodal attention by reversing the paradigm used before. If spatial attention is sustained and intermodal attention is transiently cued, will intermodal attention spread to the irrelevant location? Or will it be restricted to the relevant location? We ran two experimental conditions on separate sessions, using a within-subject design. In the Sustained Modality condition the to-be-attended location was cued on a trial by trial basis while the relevant modality was sustained. In the Sustained Location condition we used a novel paradigm where the cued and sustained attention manipulations were reversed. Results: In the Sustained Modality condition we found transient spatial cueing effects on processing in the relevant as

J Mol Neurosci

well as the irrelevant modality, replicating previous findings. However, in the Sustained Location condition we found transient intermodal cueing effects on stimulus processing, which were restricted to the relevant location. Conclusions: Our results show that the superiority of spatial attention over intermodal attention is not confined to the paradigm used previously. While spatial cueing effects spread across modalities, intermodal cueing effects are only evident in the relevant location, supporting a supramodal mechanism of spatial attention. The study was supported by grant 823/88 by the Israel Science Foundation to LYD. Neuronal avalanches in human MEG and EEG Shriki O. 1* 1 Brain and Cognitive Sciences, Ben-Gurion Univ. Background: What constitutes normal cortical dynamics in healthy human subjects is a major question in systems neuroscience. Numerous in vitro and in vivo animal studies have shown that ongoing cortical dynamics are characterized by cascades of activity across many spatial scales, termed neuronal avalanches. Avalanche dynamics are identified by (1) a power law in the size distribution of activity cascades, with an exponent of –3/2 and (2) a branching parameter of the critical value of 1, reflecting balanced propagation of activity at the border of premature termination and potential blow up. Results: We analyzed resting-state human brain activity recorded using MEG and EEG. We identified large signal deflections at single sensors and combined them into spatiotemporal cascades on the sensor array, using multiple timescales. Cascade-size distributions obeyed power laws. For the timescale at which the branching parameter was close to 1, the power law exponent was –3/2. This relationship was robust to scaling of the sensor array and was absent in phase-shuffled or empty-scanner data. Using EEG data from sleep deprived subjects we found that the branching parameter and avalanche exponent increase with time awake, reflecting increased dominance of excitation in the underlying network dynamics. We also found strong correlation between avalanche metrics and behavior as measured through reaction times in a psychomotor vigilance task. Conclusions: Our results demonstrate that cortical activity in healthy human subjects at rest organizes as neuronal avalanches and is well described by a critical branching process. Such critical, scale-free dynamics have been shown to optimize information processing, implying that the human brain attains an optimal dynamical regime for information processing. Deviations from the critical balanced state, such as during sleep deprivation, can be captured by the avalanche metrics and are correlated with behavioral changes.

Mutations in synapsin IIa reveal ATP-dependent regulation of synaptic vesicle clustering and recruitment Shulman Y.P , Gitler D * Physiology and Cell Biology, Faculty of Health Sciences and Zlotowski Center for Neuroscience BGU The capability of synapses to maintain neurotransmission during intense activity depends on the replenishment of the active zone with ready vesicles. The availability of primed vesicles is dynamically determined by their usage and subsequent reconstitution, the latter occurring either by endocytosis or by the recruitment of stored pre-existing vesicles. Consequently, a reasonable assumption is that enlargement of the total vesicle store should enhance transmission, especially during periods of heavy use. Supporting this expectation is the past observation that knocking out the synapsin genes both perturbs the cluster of vesicles near the active zone and accelerates synaptic depression. Likewise, over-expressing synapsins IIa enlarges the vesicle cluster and retards synaptic depression. Here we describe mutations in synapsin IIa which do not concur with this hypothesis. Semi-quantitative synaptobrevin 2 immunostaining of cultured hippocampal neurons revealed that a mutation that annuls ATP-binding to the "C" domain of synapsin IIa (K270Q) substantially enhances its capability to cluster vesicles, without affecting vesicle mobility, as evidenced by FRAP measurements. Although more vesicles are present, electrophysiological recordings of synaptic currents in autaptic neurons revealed faster synaptic depression during high-frequency stimulation, without evidence for a change in the initial release probability. This suggests a deficit in vesicle resupply. A contrasting result was obtained with a phosphomimetic mutation (S10E) of the wellconserved PKA phosphorylation site in synapsin IIa, which enhanced vesicle clustering without affecting synaptic depression, whereas a mutation annulling phosphorylation (S10A) accelerated depression without enhancing clustering. Therefore, the mere presence of vesicles is insufficient to predict vesicle availability; our results implicate the dynamics of ATP within individual terminals in locally regulating vesicle recruitment. Neural coding of perceived odor intensity Shusterman R. 1,2, Sirotin Y.B. 3, Rinberg D. 4,5,2* 1 Neurobiology, Univ. of Haifa 2 Janelia Farm Research Campus, Howard Hughes Medical Institute 3The Rockefeller Univ. 4 Dept. of Physiology & Neuroscience, New York Univ. 5 Neuroscience Institute, New York Univ. In olfaction, as in other sensory systems, intensity is a fundamental perceptual feature. To examine how neural activity at early stages of the olfactory system contributes to intensity perception, we measured odor evoked neural activity across a population of mitral/tufted (M/T) cells in the olfactory bulb

J Mol Neurosci

(OB) of awake mice. Temporal profiles of sniff-trigged neural responses to odors changed in a complex manner both as a function of concentration and with adaptation over several repeated sniffs of our stable odor source. Across cells, changes in the latency and peak firing rate, but not the total spike count of responses on later sniffs were correlated to changes observed with a decrease in odor concentration. Principal components (PC) analysis revealed that the full temporal pattern of neural responses changes along a common trajectory in PC space for concentration and adaptation. Comparing responses after adaptation to concentration responses on the first sniff, we estimated the magnitude of intensity decrease expected following adaptation. These changes in odor intensity coded by M/T cells in mice were similar to changes in perceived odor intensity measured in human subjects. Our data suggests that temporal patterns of M/T responses in the OB encode odor intensity. Decoding of hand kinematics from a non-invasive brain computer interface Sicard G. 1,2, Katz R. 1,2, Zacksenhouse M. 1,3* 1 Brain-Computer Interfaces for Rehabilitation Lab. 2Dept. of Mechanical Engineering, Technion, Haifa, Israe 3Dept. of Mechanical Engineering, Technion, Haifa, Israel Background: Brain-computer interfaces (BCIs) aim at restoring motor orcognitive functions by acting as communication pathway from the brain to anexternal device such as a computer, a wheelchair or a prosthetic. It has beenassumed for a long time that inherent limitations of non-invasive interfaceswould prevent them from being used to decode limb movements. However recentstudies have demonstrated the ability to decode hand kinematics from EEG insingle sessions using linear decoders. Here, we aim at investigating whether linear decoders can capture time-invariant features, and compare their performance with that of convolutional neural networks (CNN). Method: Subjects were instructed to perform random reaching movements whilegazing at a fixation cross displayed on the monitor in front of them. EEGsignals were recorded from 64 channels and synchronized off-line with thekinematic data acquired through a Phantom haptic device. The experimentcomprised 20 sessions of 1 minute each, separated by a resting period. Results: Hand kinematics were decoded using a linear decoder and CNN. Lineardecoders trained on part of a single session achieved reasonably higher performanceon other parts of the same session (using cross-validation). However,performance deteriorated when the decoder was trained and tested on multiple concatenated sessions. This performance suggests that the linear decoding model is time-dependent. CNN is currently under testing, and initial results on multiple session show great improvement in performance.

Conclusion: We have showed in this study that noninvasivebrain-computer interface can be used to decode hand kinematics with reasonablehigh accuracy. However, a linear decoder model fails to capture time-invariantfeatures from the signal, and hence need to be re-trained on each session. CNN provides great improvement and may capture time-invariant features of the signal. This work was supported by the Technion Autonomous Systems Program, under grant number 2017041. The effect of chronic methylphenidate (Ritalin) treatment on behavioral parameters and BDNF levels in a rat brain Simchon Y. 1*, Weizman A. 2, Rehavi M. 3,4 1 1Dept. of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv Univ. 2Research Unit, Geha Mental Health Center, Petah-Tikva 3Dept. of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv Univ. 4Dr. Miriam and Sheldon G. Adelson Chair and Center for the Biology of Addictive Diseases A growing population of children, adolescence and adults are using the stimulant drug methylphenidate. The majority of them are diagnosed with Attention Deficit/Hyperactivity Disorder, however an increase in usage is observed among nondiagnosed or poorly diagnosed population. We investigated the long-term effects of chronic treatment with cocaine and methylphenidate on brain neurogeneration in young rats. The effects were studied behaviorally and biochemically in the prefrontal cortex. Fourteen days old rats were injected with cocaine (15mg/Kg) or methylphenidate (3mg/Kg) for 21 days, and tested behaviorally and biochemically at several ages (35, 56, 70 and 90 post natal days) following the treatments. In the open field test we found a significant differences in the activity, zone crossing, tracklenght and velocity in 35 PND compared to 56 and 70 PND (p<0.001), but there was no effect of the drugs treatment. In the object recognition test, we observed more visits in both novel and familiar objects (0.45 and 0.001, respectively) as the rats ages but a tendency toward less visits as a result of the cocaine and MPH treatments. We found higher activity in the youngest age (35 PND) (p<0.001) when looking at the novel object but no differences in activity could be observed in the familiar object. There were no differences in the ratio of duration near the novel object compared with the total duration at both objects (Discrimination ratio). An increase in the levels of BDNF protein were detected in the prefrontal cortex in MPH treated 90 PND rats (66% compared to saline treated 90 PND rats, p<0.03) although no differences were observed in its mRNA levels. Looking into the abuse potential and long term effects during and following usage of ADHD treating agents, as methylphenidate, leads us to a better understanding of the processes underlying synaptic plasticity in the developing brain.

J Mol Neurosci

Behavioral and neural correlates of emotion processing in adults with ADHD: an event-related potentials study Sivan R 2*, Orrie D 1 Dept. of Psychology, Center for Psychobiological Research, The Max Stern Yezreel Valley College 2Dept. of Psychology, Tel Hai College Background: The present study was aimed at identifying potential behavioral and neural correlates of emotional processing in adults with ADHD using scalp-recorded EventRelated Potentials (ERPs). Methods: Behavioral and ERP correlates of emotional processing were examined using a 4-stimulus visual oddball task, combining emotional and non-emotional stimuli. Responses to target and non-target stimuli were compared across groups of 21 young adults with ADHD and 19 healthy comparison subjects. Results: Participants with ADHD had poorer performance than controls on all indices of the oddball task, which was reflected in higher rates of omission and commission errors, slower RTs and lower response consistencies. The higher rates of omission errors and the slower RTs of ADHD participants compared with controls had been found only in response to the emotional targets but not in response to the non-emotional targets. The ERP results indicated that ADHD significantly interacted with the type of target stimuli. Participants with ADHD, compared with controls, showed a pronounced reduction in P3 and N3 (slow-wave) amplitudes in response to emotional targets but not in response to the non-emotional targets. Conclusions: The current results provide some indication of modulation of emotion processing in adults with ADHD. ERP alterations, reflected in abnormally reduced P3 and N3 to emotional targets may suggest ADHD-related abnormal recruitment of neural resources to process emotional content and disturbances in attention allocation and evaluation of emotional stimuli. Behavioral and brain function measures of emotional function may provide valuable additional tools for use in clinical assessment of ADHD in adulthood. Regulation of synaptic plasticity by ongoing spiking patterns in hippocampal networks Slomowitz E 1, Maor R3, Vertkin I1, Chechik G 3 Slutsky I1,2 1 Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University; 2Sagol School of Neuroscience, Tel Aviv University; 3The Gonda brain research center, Bar Ilan University. One of the basic properties of neural networks is their ability to undergo experience-dependent changes. This ability spans all different levels, from the network as a whole to single synapses and includes a wide range of mechanisms, from synapse-specific Hebbian-like plasticity to more global,

homeostatic changes. A fundamental challenge is to understand how the interplay between these diverse mechanisms tune the properties of neuronal networks. Extensive experimental evidence suggests that activity blockade triggers a wide spectrum of homeostatic mechanisms to stabilize mean firing rates in neural circuits. Multiplicative synaptic scaling of excitatory quantal amplitude has been proposed as a mechanism which maintains firing rates, while preserving plasticity rules of individual synapses. However, synaptic scaling often acts in concert with other compensatory changes, raising the question of how firing patterns, synaptic dynamics and Hebbian-like plasticity are regulated in the face of environmental changes. To address these questions, we combined long-term recordings of spikes using micro-electrode arrays (MEAs), intracellular patch-clamp recordings and FM-based imaging of synaptic vesicle recycling. We show that network firing rates are transiently suppressed and highly synchronized following a chronic increase in synaptic inhibition via GABABRs, but return to baseline rates, while desynchronizing, during the second day of perturbation. The restoration of firing rates is associated with recovery of inhibition-excitation balance and increase in mEPSC frequency and amplitude. Notably, long-term potentiation was not maintained after stabilization of firing rates, but correlated to the period of network synchrony. Thus, independent regulation of ongoing firing rates and patterns enables synaptic metaplasticity under a constantly changing environment. We hope that our work will contribute to understanding the relationship between the structure of spontaneous network activity and the capacity of synapses to encode and store new information. Cross modal measure of intricacy Snitz k 1*, Yablonka A, Weissler K, Jacobson M, Sobel N, Pinchover L., Bar-Zvi D 1 Dept of Neurobiology, Weizmann institute of Science Intuitively we can distinguish an intricate image or sound from simple ones. However, characterizing intricacy of stimuli in a consistent manner remains a challenge. We propose that perceptual variance can be taken as a measure of stimulus intricacy. The more variance - the more intricate the stimulus. For this property to be a property of the stimulus it needs to be consistent regardless of the question asked. Last year we were able to show that this property exists consistently for three sets of olfactory data. This was done by showing that random choices of about 30 descriptors produce highly correlated variance rankings (r = 0.86). This year we have conducted a vision experiment and repeated the result in vision. This latest result extends the scope of the intricacy property to vision and enables the investigation of cross modal properties. Moreover, many measures of intricacy of visual stimuli are used in designing visual experiments, our measure of intricacy can

J Mol Neurosci

now be compared to intuition and other measures. We will discuss possible logical implications of our measure and suggest other logical hypotheses that can be tested with it. Cavefish as a model for the evolution of sensory systems Soares D. 1* 1 Dept. of Biology, Univ. of Maryland Caves and other subterranean habitats represent one of the most challenging environments on the planet. Other than salamanders, teleost fishes are the only vertebrates that have successfully colonized and have lives completely restricted to caves. Despite being known to science for over 150 years, only recently have cavefishes become model systems for evolutionary studies. Several cavefishes have provided valuable insights into how fishes have evolved to cope with life in perpetual darkness and often limited food resources. However, much less is known about the biology of other cavefishes and their sensory modalities. Here, I examine the sensory tradeoffs for living in caves. Hypertrophy of mechanosensation seems to be most common adaptive strategy but we know little of other possible sensory modalities in these animals. Only comparative studies, nested within well-resolved phylogenies, can elucidate generalities for sensory adaptation of fishes to subterranean habitats.

Selective increase in the association of the β2 adrenergic receptor, β Arrestin-1 and p53 with Mdm2 in the ventral hippocampus one month after underwater trauma Sood R. 1,2,3,4, Harrington LB.* 1,2,3,5*, Ritov G. 6,2,3,7, Levin GR 8,9,10,11 1 Dept. of Human biology 2Faculty of Natural Sciences 3Univ. of Haifa,Mt.carmel,Haifa,Israel [email protected] 5 [email protected] 6The sagol Dept. of Neurobiology 7 [email protected] 8The sagol Dept. of Neurobiology, Faculty of Natural Sciences 9Dept. of psychology, Faculty of social sciences 10The institute for the study of affective neuroscience(ISAN),Univ. of Haifa 11Mt. Carmel,Haifa, ,Israel Although activation of the sympathetic nervous system is a critical stress response aimed at maintaining homeostasis, its prolonged activity is harmful in the long run. A seminal study showed that chronic infusion of mice with a beta 2 adrenergic receptor (b2AR) analogue causes long-term DNA damage in a pathway which involves beta Arresin-1-mediated activation of Mdm2 and subsequent degradation of the tumor suppressor protein p53. The objective of the present study was to test whether a single acute stress, which manifests long lasting changes in behavior, affects the interaction of Mdm2 with p53, beta 2AR, and beta Arrestin-1 in the dorsal and ventral hippocampal CA1. Adult rats were subject to underwater trauma, a brief forceful submersion under water. Twenty six

days later behavioral tests were conducted and immediately followed by biochemical analysis. Elevated plus maze tests showed that almost a month after trauma the animals present heightened levels of anxiety. An examination of the CA1 hippocampal areas of the same rats showed that underwater trauma caused a significant increase in the association of Mdm2 with beta2AR, beta Arrestin-1, and p53 in the ventral but not dorsal CA1. Whether these changes represent a protective mechanism against the long term effects of cells death following acute trauma remains to be determined. The Israel Science foundation grant MR assisted Vascular and Volumetric Imaging (MAVVI) for objective findings in schizophrenia Spanier A.B. 1*, Joskowicz L. 2,3,4,5, Israeli D. 6,7 1 The Selim and Rachel Benin School of Engineering, the Hebrew Univ. 2 Head, Computer-Assisted Surgery and Medical Image Processing Laboratory 3 School of Engineering and Computer Science 4 The Edmond and Lily Safra Center for Brain Sciences - ELSC 5 The Hebrew Univ. of Jerusalem 6 Head of the Dept. of Day Hospitalization Jerusalem mental health center 7 Affiliated with the Hebrew Univ.-Hadassah School of Medicine, Jerusalem. Background: Schizophrenia is a long-term mental disorder involving altered relations between thought, emotion, behavior and cognition. There is increasing demand for objective diagnoses of schizophrenia. The diagnosis of schizophrenia has been the subject of many research debates. MRI studies postulate that schizophrenia is a brain disorder with altered brain structure, whereas fMRI studies suggest that schizophrenia is a reduced BOLD signal in various brain regions. We hypothesize that the brain vessels and vascularity may serve as important factors promoting differences in volume and functionality between schizophrenia patients and controls. We tested this hypothesis by comparing precontrast and postcontrast DCE-T1- MRI. Methods: 42 first episode schizophrenia patients and 28 matched controls participated in this study. MR imaging was performed using a DCE-MRI with GD-DTPA. All subjects underwent the same imaging protocol. FreeSurfer software was used to obtain brain volumes of the subcortical and cortex for all patients. The neuroanatomical volumes were inspected for accuracy in all subjects. No obvious errors were observed for any subject, and so all analyses were 100% automated. The vascular dynamics was obtained by a standard subtraction - early post- minus pre- contrast scan. Results: Based on the volume analysis we show the ability to classify a novel subject (as either schizophrenia or control) with up to 73% sensitivity and 65% specificity in various brain regions including the basal ganglia hippocampus and

J Mol Neurosci

amygdala. Taken together, volumetric analyses with the dynamic vascularity improve the classification accuracy to 93% sensitivity and 65% specificity. Conclusion: Our method shows promising results in the direction of objective findings in schizophrenia. The combination of vascular and volumetric findings may suggest a possible common pathway in the schizophrenic process as altered vascularity may lead to volume abnormalities. Pathology of Down Syndrome manifested in network and single neuron properties of hippocampal neuronal cultures Stern S 1*, Segal M 2, Moses E 1 1 Physics of Complex Systems, Weizmann Institute of Science 2 Neurobiology, Weizmann Institute of Science Background: Down Syndrome (DS) is the most common chromosomal abnormality in humans, with many phenotypic characteristics-mental retardation is probably the most prominent one. Embryonic hippocampal neuronal cultures from two mouse models (TC1 and Ts65Dn) for DS were compared to control littermate cultures to detect possible cellular phenotypes of DS. Network behaviour was assessed using calcium imaging, and whole cell patch clamp technique was used to measure differences in single cell properties. Results: Calcium imaging, measured with fluo4, revealed smaller amplitude, shorter duration network bursts, with no change in basal calcium level, which was measured using Fura-2. Baclofen, a GABA-B agonist, suppressed network bursts with lower concentration in DS networks than in control networks. In patch clamped neurons, the threshold for excitation, after-hyperpolarization (AHP) amplitude and input resistance were reduced, while spike height was increased in DS cells compared to controls. Following blockage of sodium currents we found that potassium currents (slow and fast) are reduced in DS cells. Network activity was different with electrophysiological tools as well: bursts were shorter, the total amount of time the network spent bursting was shorter, and network bursts were less synchronized. Most of the differences appeared in both mouse models. Conclusions: DS cells were different both in the basic cell properties and in the assembly into a network. The changes in spike properties, along with reduced potassium currents all point to changes in potassium channels. We speculate that this may be due to possible overexpression of two potassium channel regulators, KCNE1 and KCNE2, whose genes reside on chromosome 21. The altered network activity along with baclofen experiments may be caused by increased inhibition. Two types of inwardly rectifying potassium channels genes reside on chromosome 21: KCNJ6, KCNJ15, and may be the cause of this increased network inhibition.

Th1 polarization of Tcells injected into the cerebrospinal fluid induces brain immunosurveillance Strominger I 1, Fisher Y 1, Biton S 1, Nemirovsky A 1, Baron R 1, Monsonego A 1* 1 The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences, an Although CD4 T cells reside within the cerebrospinal fluid (CSF), it is yet unclear whether and how they enter the brain parenchyma and migrate to target specific antigens. We examined the ability of Th1, Th2 and Th17 CD4 T cells injected intracerebroventricularly to migrate from the lateral ventricles into the brain parenchyma in mice. We show that primarily Th1 cells cross the ependymal layer of the ventricle and migrate within the brain parenchyma by stimulating an IFN-g-dependent dialogue with neural cells, which maintains the effector function of the T cells. When injected into a mouse model of Alzheimer's disease, Ab-specific Th1 cells target Ab plaques, increase Ab uptake and promote neurogenesis with no evidence of pathogenic autoimmunity or neuronal loss. Overall, we provide a mechanistic insight to the migration of CSF CD4 T cells into the brain parenchyma and highlight implications on brain immunity and repair. Understanding learning to read through fMRI of rapid letter detection in skilled adult readers and dyslexic 10-year old children Boros M. 1, Eger E. 2, Dufau S. 3, Chanceaux M. 4, Anton J-L. 5, Pech C. 5, Różycka J. 1, Grainger J. 3,6, Ziegler J.C. 3,6, Cohen L. 7,8, Dehaene S. 2,9, Szwed M. 1,3,6* 1 Dept. of Psychology, Jagiellonian Univ., Kraków 2INSERMCEA Cognitive Neuroimaging Unit, Gif sur Yvette, France 3 Laboratoire de Psychologie Cognitive, CNRS, Marseille, France 4) Laboratoire de Psychologie Cognitive, CNRS, Marseille, France 56Aix-Marseille Univ., Marseille, France 7 CENIR, ICM Research Center, UMRS 975, Paris, France 8 AP-HP, Hôpital de la Salpêtrière, Dept. of Neurology, Paris, France 9College de France, Paris, France Background: The study of neural bases of reading offers an opportunity to ask general questions on the nature of learning and expertise. Learning to read results in the development of the Visual Word Form Area (VWFA), a reading area in highlevel visual regions of the ventral stream. Most of fMRI work on reading used word stimuli, which engage top-down linguistic influences. Here, we examine children and adults in a rapid detection task with letters, digit, symbol and false-font strings that do not engage such feedback. We ask the following: 1) will we replicate the underactivation of the VWFA that is commonly found in children with dyslexia in reading tasks? If not, will we find deficits in other brain regions? 2) which brain regions are more active when skilled adult readers succeed in making a correct letter detection as opposed to an incorrect detection? Can we substantiate reports of expertise-

J Mol Neurosci

dependent engagement of retinotopic visual areas in reading (Szwed et al., 2011, in press)? Results: Relative to control subjects, 18 10-year old dyslexic children showed the largest underactivation not in the VWFA but in the in the dorsal visual stream. These dorsal visual stream regions were not activated in skilled adult readers. In contrast, in the rapid letter detection task with skilled adult readers, we found that retinotopic visual areas were activated more for correct vs. incorrect trials for (over-practiced) letters, but not for (novel) false fonts. Correct vs. incorrect trial differences for both letters and false-fonts were found in the VWFA. Conclusions: Our data suggest that learning to read 1) involves changes in dorsal stream brain regions that seem different from regions involved in skilled reading in adults, 2) leads to expertise-dependent recruitment of early retinotopic areas. This suggests that neural effects of learning on the visual system go beyond changes in the VWFA region. They might also explain several dorsal stream deficit accounts of dyslexia Supported by an ERC grant to JG and an NCN grant to MS Development of a novel animal model of clozapine-resistant schizophrenia: behavioral and neurobiological characterization Taler M 1*, Gil-Ad I 1, Tarasenko I 1, Weizman A 1,2, Krivoy A 3,4 1 Lab of Biological Psychiatry, FMRC and Sackler Faculty of Medicine, Tel Aviv Univ., Israel. 2 Research Unit, Geha Mental Health Center, Israel 3 Lab of Biological Psychiatry, FMRC and Sackler Faculty of Medicine, Tel Aviv Univ., Israel 4 Geha Mental Health Center, Israel Background: Schizophrenia is a chronic debilitating disorder affecting 1% of the population. There are two evidence-based features strongly connected to schizophrenia: A genetic component, and a variability of clinical severity. The most severe form of the disorder (which consists of 15-20% of all schizophrenia patients) is termed after specific treatment failure: Clozapine Resistant Schizophrenia (CRS). Animal models of schizophrenia are used to evaluate novel therapies for the disorder. However, there is no validated model of CRS. In the current study we intended to develop a novel CRS model. Results: C57/bl mice were used. Two behavioral tests performed -1. Novel object recognition (NOR) for cognition 2.Social preference (SP) for sociability. To induce schizophrenia like symptoms, animals were treated with sub-chronic phencyclidine (PCP) (10mg/kg/d x8). Behavior was assessed in response to clozapine (po). Clozapine at a dose of 4mg/kg was found to yield the best response. We also noticed large variability in the response to clozapine. We computed a composite score (average of SP and NOR indices for each animal) and then selected the most extreme non-responders and responders, males and females mice (1st generation). We mated them for the trans-generational experiments. We evaluated two generations of responsive colony and resistant colony,

and found that in the second generation of the resistant colony, males were non-responsive to clozapine in the SP task (preference index) while females of the same colony and males and females of the responsive colony responded to clozapine treatment in the same behavioral task as the original colony. Conclusions : This finding may suggest the heratability of the unique trait of clozapine resistance. These results are consistent with human data, showing a more severe and early form of the disorder in males. More studies are needed to evaluate biochemical differences in brains of animals from the two coloneis. Phasic alertness enhances holistic face perception in congenital prosopagnosia Tanzer M 1,2,3, Weinbach N 1,2,3, Mardo E 1,4, Henik A 1,2,3, Avidan G 1,2,3* 1 Dept. of Psychology 2 Zlotowski Center for Neuroscience 3 Ben-Gurion Univ. of the Negev 4 Univ. of Haifa Background: Congenital prosopagnosia (CP) is a severe deficit in face processing which occurs in the absence of any obvious brain damage. Accumulating evidence ascribe the difficulties typical to this disorder to a more general impairment in deriving holistic relations between facial features. Herein we further examine the nature and extent of the holistic deficit in CP, but more critically we investigate a potential way to ameliorate holistic face perception in individuals with CP. Results: We employed the face inversion effect in which performance is typically better for upright compared to inverted face, as an index for holistic processing. Critically, in half of the trials, an auditory warning cue, known to elicit phasic alertness and enhance holistic processing, preceded the face stimuli ('warning' trials), while in the other half, only a face (upright or inverted in separate blocks) was presented ('no-warning' condition). As expected, in the no-warning condition controls showed the typical face inversion effect. In contrast, and consistently with our previous studies, the CP group differed from controls and showed an equal, or even superior performance for the inverted compared to upright faces, evincing a holistic processing deficit. However, in the warning condition, both CP and controls benefited from the warning cue such that their reaction time was faster but only for the upright faces. Moreover, in the CP group, the warning cue abolished the abnormal inversion superiority effect. Conclusions: These findings imply a possible mechanism for enhancing holistic face processing in CP and may shed light on potential amelioration of this disorder. Moreover, the results confirm previous findings and stress the critical role of holistic perception as an underlying mechanism of the deficiency in face processing in these individuals. This research was supported by a grant from the Israeli Science Foundation (ISF, 384/10) to GA.

J Mol Neurosci

The role of vocal learning in the acoustic communication of the Egyptian fruit bat Taub M. 1*, Prat Y. 1, Yovel Y. 1 1 Zoology, Tel Aviv Univ., Tel-Aviv 69978, Israel Introduction: Vocal learning is a process of altering vocalizations, according to auditory inputs. The absence of this ability may limit the complexity of vocal communication. While human vocal ontogeny clearly includes learning, research of other vocal species (including primate) failed to confirm its existence. Notable exceptions are songbirds, and a few mammals, including bats. This study focuses on the vocal ontogeny of an extremely social and vocal mammal-the Egyptian fruit bat (Rousettus aegyptiacus). We assess the importance of exposure to adult vocalizations during vocal development, and present strong evidence for vocal learning. Results: The vocal development of acoustically isolated pups was compared to that of normal pups that grew up hearing adult vocalizations as well as to adult repertoires. Before the age of 80 days there was no significant difference between the two groups, but there was a significant difference between both groups and the adult baseline, as expected. However, at the age of 100-200 days, when vocal ontogeny stabilized, there was a significant difference between the isolated group and the adult baseline and between the isolated and control groups, while there was already no significant difference between the control and adult baseline. Conclusions: These results reveal that vocal communication of pups, which were exposed to adult vocalizations at a young age, resembled adults while they matured. In contrast, the communication of pups that never heard adults developed vocal communication significantly differed from that of normal adult Egyptian fruit bats. In addition, our rich database enabled the definition of different phases in vocal ontogeny, which further reveal differences between the two groups. These findings suggest that vocal learning has an important role in this species. Instead of focusing on courtship or territorial songs, we directly assess an entire vocal communication system, related to all daily social interactions Rhythmic brain neuronal activity is modulated by the degree of novelty of a social stimulus Tendler A. 1, Wagner S. 1,2* 1 Dept. of Neurobiology, Univ. of Haifa, Haifa, Israel 2 Center for Gene Manipulation in the Brain, Univ. of Haifa, Israel Rhythmic local field potential (LFP) neuronal activity in the theta band range (4-10 Hz) is thought to communicate between neuronal ensembles in distinct brain regions. This neuronal communication is crucial for high level cognitive functions such as social and linguistic skills, and its disruption may underlie cognitive disorders such as autism. We used chronic telemetric recordings from socially behaving rats to monitor

rhythmic activity in a limbic network linked to social behavior. Social encounters were associated with enhancement of theta power proportional to the degree of novelty of the social stimulus. This modulation of theta rhythmicity, which was specific for social stimuli, was not due to changes in investigation behavior but appears to reflect an internal brain state associated with social arousal. MEC temporal correlations suggest organized functional projections from deep to superficial layers Tocker.G 1,2, Barak.O 2, Dredikman.D 2* 1 The Gonda Multidisciplinary Brain Res.Center, Bar-Ilan Univ. 2 1Rappaport Faculty of medicine, Technion – Israel Institute of Technology Grid cells in the medial entorhinal cortex (MEC) are known to fire with a spatially reproducible hexagonal pattern, when the animal is foraging in the open field. The pattern of each cell can be characterized by a typical spatial frequency, orientation and spatial phase. It has been shown that the population of grid cells can be classified into discrete modules. Previous studies have shown that the relative spatial phase between two grid cells belonging to the same module is invariant between environments. This could be explained by attractor models of grid cells, which share the tenet that cells closer in phase are also more strongly interconnected. In order to check this hypothesis, we compared the temporal correlations between pairs of grid cells and their spatial phase difference. We found that in layer II of the MEC, grid cells belonging to the same module were temporally correlated with a ~0-1 millisecond shift. The temporal correlation increased in strength inversely with the spatial phase difference between the cells. This implies that layer II grid cells with similar spatial phase receive substantial common input. A similar phenomenon was not found in deeper layer grid cells. To explain these phenomena, we suggest an attractor model where layer III-V project strongly to layer II, such that path integration mechanisms moving activity bumps in the deeper layers drive the movement of activity bumps in layer II. Modulation of neuro-inflammation by angiotensinrelated drugs: possible implications for Alzheimer's disease Torika N. 1, Asraf K. 1, Mali E. 1, Fleisher-Berkovich S.* 1* 1 Dept. of Clinical Biochemistry and Pharmacology, BenGurion Univ. of the Negev, Faculty of Background: Neuro-inflammation is associated with the pathology of Alzheimer's disease (AD) and its components include brain cells such as microglia and astrocytes. These cells are responsible for the release of neurotoxic factors such as cytokines and reactive oxygen species including nitric oxide (NO) that eventually leads to neuronal damage.

J Mol Neurosci

Renin- Angiotensin System (RAS) is a hormonal system which mediates cardiovascular regulation and its major effector is angiotensin II (AngII). Lately this system has been discovered also in the brain. AngII is formed from angiotensin I by angiotensin converting enzyme (ACE). There is increasing evidence that RAS may contribute to neuro-inflammation associated with AD. Thereby, specific inhibition of brain RAS has been suggested as a potential therapeutic strategy for AD. In this study we examined the role of Ang II AT1 Receptor Blockers (ARBS) and angiotensin converting enzyme inhibitors (ACEI) in regulation of neuro-inflammation. The in vivo study was conducted on transgenic mice that express five Familial Alzheimer's Disease mutations (5FAD) APP (3 mutations) and PS1(2 mutations). These mice overproduce Aβ42 and exhibit amyloid plaque pathology similar to that found in AD. Results: Intranasal administration of 1mg/kg/day of Telmisartan (ARB) to two month old 5FAD mice for 3-8 weeks resulted in a significant decrease of amyloid beta plaques, an important feature of AD, and in microglial activation, as detected by CD11b immunofluorescence, in the hippocampuses and the cortex. Similar changes were observed in the cortex but not in the hippocampus of mice treated with the same dose of Perindopril (ACEI). Conclusions: Our results indicate that intervention in the brain renin angiotensin system with ARBs or ACEI may serve as a new approach for the treatment of brain disorders, such as AD, where inflammation plays a significant role. This research was supported by the Israel Science Foundation (grant 101/11).

Diet and DNA methylation in Alzheimer’s disease Troen A.M. 1* 1

Institute of Biochemistry Food and Nutrition Science, The Hebrew Univ. of Jerusalem Recognition of the importance of DNA methylation in aging and in brain plasticity has raised interest in the role that epigenetics may play in neurodegenerative disease, and the extent to which these processes may be modified by diet, drugs and environment. This is particularly true with respect to Alzheimer's disease (AD), for which dietary determinants of impaired methylation are important risk factors (such as low folate, vitamin B12, and possibly choline status), and potential therapeutic agents. In humans, manipulation of dietary folate and choline has been shown to alter DNA methylation in peripheral lymphocytes. In animal models of AD, dietary manipulation of folate and other B-vitamins has also been shown to reversibly disrupt the promoter methylation and expression of some genes in brain, correlating with neuropathology and behavioral

deficits. While these observations are consistent with the neuroepigenetic hypothesis of AD, the evidence that DNA methylation is specifically altered in the disease is inconsistent, and there is scant evidence to date that diet correlates with DNA methylation in patients. Alternatively, the relation of these metabolic risk factors to AD may be driven by the global impairment of other neurologically important methylations involving phospholipids, signaling proteins or neurotransmitters, or by alternative nutrient-specific processes such as the folatedependent impairment of DNA synthesis and repair that compete with methylation reactions for their dietary substrates. In light of this complexity, the safety and efficacy of therapeutic methyl-donors such as S-Adenosylmethionine (SAMe or AdoMet) for use in individual AD patients, may depend on identifying and specifically treating the primary metabolic deficit and its attendant consequences. Alpha synuclein deficiency exacerbate disease progression in multiple sclerosis mouse model Trudler D. 1,2, Levy-Barazany H. 3, Frenkel D. 3,2* 1 Dept. of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv Univ., Tel Aviv 2 Sagol School of Neuroscience, Tel Aviv Univ., Tel Aviv, ISRAEL 3 Dept. of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv Univ., Tel Aviv Background: The normal function of alpha synuclein (αSyn) is poorly understood, but it is implicated in the regulation of vesicle dynamics, and is important in neuronal plasticity. αSyn is the major component of Lewy bodies, the pathologic hallmark of Parkinson's disease (PD). In addition, extracellular αSyn has been proposed to have a role in neuroinflammation in PD. Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS) characterized by the formation of focal demyelinating plaques in the brain and spinal cord. It has been demonstrated that αSyn is upregulated in neurons and glia in spinal cord (SC) lesions of experimental autoimmune encephalomyelitis (EAE), MS mouse model. In addition, MS patients showed increased levels of αSyn in the CSF as compared with healthy controls. Therefore, we postulated that αSyn knockout mice will display a reduction in EAE progression as compared to WT mice. Results and Conclusions: Surprisingly, we discovered that the absence of αSyn exacerbates EAE disease progression. Moreover, we discovered that both αSyn knockout CD4+ T cells and antigen presenting cells, that are important for T-cell activation, show increase in secretion of pro-inflammatory cytokines as compared to WT mice. These results suggest that αSyn has an important role in immune cell activation. Further research on the expression of αSyn in immune cells may increase our understanding of its physiological function and its role in mediating neuroinflammation in neurological diseases, such as MS and PD, towards future therapeutic application. ISF

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Sensorymotor transformations in the rat whisker somatosensory system In Vivo Tsur O 1, Azouz R 1* 1 Physiology and Cell Biology, Ben-Gurion Univ. of the Negev Rodents move their whiskers actively to distinguish between surfaces and objects having subtly different textures and shapes. Coding of this multifaceted tactile information requires the integration of sensory and motor signals. This integration is mediated through multiple nested sensorimotor feedback loops that span from the brainstem to the cortex. In the current study, we examine the functional role of one of the major loops which involves projections from brainstem trigeminal nuclei to the facial motorneurons. We record from trigeminal ganglion neurons and EMG signals from the muscles of the mystacial pad during vibrissae and muscle stimulation. We find the tactile stimulation results in muscle contraction which in turn impact sensory responses of first-order sensory neurons. These results indicate that the brainstem loop has a dual role in sensorymotor transformations in which the motor system may control the tactile input to the somatosensory system and in turn sensory stimulation modifies the way animals move their whiskers. LTP induction in the learning and memory area in the brains of octopus and cuttlefish is mediated by nitric oxide (NO) Turchetti-Maia A.L. 1,2*, Hochner B. 1,3, Shomrat T. 1,4 1 Dept. Neurobiology, Silberman Institute of Life Sciences, The Hebrew Univ., Jerusalem, Israel 2 ELSC , The Hebrew Univ., Jerusalem, Israel 3 ICNC , The Hebrew Univ., Jerusalem, Israel 4 The Ruppin Academic Center, School of Marine Sciences, Michmoret, Israel The behavioral complexity of the cephalopod molluscs Octopus vulgaris and Sepia officinalis is comparable to that of vertebrates, but their brains show a simpler organization. The vertical lobe (VL) system, involved in learning and memory in all modern cephalopods, comprises three neuron types. Superior frontal lobe neurons (SFLn) send their axons to the VL where they innervate millions of small amacrine interneurons (AM) en passant. These AMs then converge onto large efferent neurons (LN). The synaptic inputs to the AM are glutamatergic, while the synaptic connections from AM to the LN are cholinergic. While the neuronal connectivity is similar in both octopus and cuttlefish, the short- and long-term synaptic plasticities are different. The activity-dependent LTP of the glutamatergic SFLn-AM synapses in the octopus is absent in the cuttlefish. In contrast, the cuttlefish shows LTP of the cholinergic AM-LN synapses. Thus, in these animals, LTP is not restricted to glutamatergic synapses. In the current study we tested the involvement of NO in VL plasticity because NO may mediate LTP irrespectively of the nature of

the neurotransmitter and because it was shown that NO synthase inhibitors impair memory formation in cephalopods and other molluscs. To test this we examined the effect of LNAME and D-NAME (2-10mM), a NO synthase inhibitor and its inactive analogue, on LTP induction in VLs of octopus and cuttlefish. While both drugs had an inhibitory effect on neural activity in VL slices, only L-NAME, the active inhibitor, blocked the induction of LTP. Short-term facilitation was unaffected. These results suggest that NO does indeed mediate LTP in cephalopods. These findings, together with results from other molluscs, suggest that NO plays a general role in complex forms of learning and memory in molluscs. Smith Lab HUJI, BSF, Golda Meir and Lady Davis Postdoctoral Fellowships for T-MAL. The proinflammatory agent lipopolysaccharide augments calcium signaling from astrocytes to neurons Tzour A. 1, Yaari Y. 1, Binshtok A. 1* 1 Dept. of Medical Neurobiology; Institute for Medical Research Israel-Canada, The Hebrew Univers Brain inflammation is known to cause major changes in glial cells, particularly in astrocytes and in microglia. However, the impact those changes have on signalling between glial cells and neurons has not been explored in depth. Here we have investigated the effects of the bacterial lipopolysaccharide (LPS), a proinflammatory agent, on glia-neuron signaling in adult rat hippocampal slices. Application of LPS caused an increase in Ca2+ levels in both astrocytes and PCs. This effect was present when slices were preincubated with the microglia toxin minocycline, but was abolished by preincubation of slices with the astrocytic toxin L-amino-adipic acid (L-AA). However, L-AA application did not prevent Ca2+ elevations in PCs induced by caffeine or by mGluR activation. The LPSinduced increase in astrocytic Ca2+ levels was due to Ca2+ release from the endoplasmic reticulum (ER), as it was abolished by ER Ca2+ depletion. Blockade of metabotropic purinergic (P2Y) receptors by suramin prevented the LPSmediated Ca2+ increases, whereas application of the selective P2Y1 receptor agonist ADPβS mimicked its effect. Interestingly, preincubation with L-AA prevented the ADPβSinduced Ca2+ elevations in PCs. The ADPβS-induced Ca2+ elevations in PCs, but not in astrocytes, were blocked by the mGluR antagonist MCPG, suggesting that activated astrocytes communicate with neurons using glutamate as a gliotransmitter. LPS also increased the amplitude of EPSPs recorded in PCs and induced spontaneous firing of action potentials. Moreover, application of LPS lead to reduction of rheobase and to increase in steepness of f-I curve in the PCs. Our findings suggest that LPS, by acting primarily on astrocytes, causes an increase in extracellular ATP, which, in turn, activates P2Y1 receptors in astrocytes, causing glutamate secretion. The glutamate activates mGlu receptors in PCs,

J Mol Neurosci

causing the increase in intracellular Ca2+, as well as enhancement of their intrinsic excitability. Supported by ERC (AB), ISF (YY), and the Henri J. and Erna D. Leir Chair for Research in Neurodegene Visualizing short-term neuroplasticy in behaving rats using MRI-DTI Tzur-Moryosef S 1*, Assaf Y 2,1 1 Sagol School For Neuroscience, Tel Aviv Univ. 2 Neurobilogy Dept., Tel Aviv Univ. Neuroplasticity, the ability of the brain tissue to reshape functionallyand structurally following the acquisition of a new skill or experience, is oneof the big enigmas in neuroscience. Exploring structuralneuroplasticity by diffusion MRI (DTI) has the advantage of providingquantified detection of multi-regional and temporal processes in the behavinganimal or human. Until now, studies have been concentrated mainly on structuralchanges that occur after long-term training. However, few studies demonstratedsome DTI changes following short-term training. One of our studies showed thattraining in a car racing game for 2 hours induces changes in the hippocampusand parahippocampal gyri. Herein, we aim to characterize the dynamic process ofneuroplasticity using comparable short and long-term learning paradigms inadult rats. Moreover, we performedhistology in rodent brains in order to reveal the molecular underpinnings ofDTI results. The main paradigm wasscanning rats before and after training on a short version of the Morris watermaze (one-day; learning group, n=24; two control groups, n=10 each). ANOVA statistics between-groupswithin-time indicated a significant decrease of mean diffusivity in hippocampusand visual corex of the learning group. In which regions histology indicatedsubstantial effects for 3 markers: BDNF, SYP and GFAP. Overall, the learninggroup displayed higher intensity of staining, in-line with the decrease indiffusivity (higher density/viscosity of tissue). Results indicated widespreadchanges, while the most prominent focus in hippocampus and visual cortex, aswas expected in this kind of spatial-visual task. The extent of changes in DTIindices, together with the molecular changes in astrocytes (GFAP), synapses(SYP) and neurons (BDNF) suggests that all components of the neural network arecapable of rapid remodeling in response to cognitive experiences. Neural codes for 2-D and 3-D space in the hippocampal formation of bats Ulanovsky N Dept. of Neurobiology, Weizmann Institute of Science, Israel The work in our lab focuses on understanding the neural basis of spatial memory and spatial cognition in freely-moving, freely

behaving mammals – employing the echolocating bat as a novel animal model. I will describe our recent studies, including: (i) recordings of 3-D head-direction cells in the presubiculum of crawling bats, as well as recordings from hippocampal 3-D place cells in freely-flying bats, using a custom neural telemetry system – which revealed an elaborate 3-D spatial representation in the mammalian brain; and (ii) recordings of 'grid cells' in the bat's medial entorhinal cortex, in the absence of theta oscillations – which strongly argues against the prevailing computational model of grid formation. I will also describe our recent studies of spatial memory and navigation of fruit bats in the wild, using micro-GPS devices, which revealed outstanding navigational abilities and provided the first evidence for a large-scale 'cognitive map' in a mammal. Neuroprotection and neurogenesis following AT2 activation after traumatic brain injury Umschweif G. 1 *, Shabashov D. 1 , Alexander A. 1 , Trembovler V. 1, Horowitz M. 2, Shohami E. 1 Institute of Drug Research,Faculty of Medicine, The Hebrew Univ. of Jerusalem, Jerusalem, Israe 2 Dept. of Physiology, Faculty of Medicine, The Hebrew Univ. of Jerusalem, Jerusalem, Israel Background: Angiotensin II receptor type 2 (AT2) agonists have been shown to limit brain ischemic insult and to improve its outcome. The activation of AT2 was also linked to induced neuronal proliferation and differentiation in vitro. Aims: In this study we examined the therapeutic potential of AT2 activation following traumatic brain injury (TBI) which has been shown to exert brain pathology similar to that of cerebral ischemia. AT2 agonist, CGP42112Awas administrated for the first three sequential days post closed head injury (CHI) in a mouse model of TBI. We have followed the functional recovery of the injured mice for 35 days post CHI, and evaluated cognitive function, lesion volume, molecular signaling and neurogenesis at different time points after the impact. Results: We found dose dependent improvement in functional recovery and cognitive performance after CGP42112A treatment that was accompanied by reduced lesion volume and induced neurogenesis in the neurogenic niches of the brain and in the injury region. In the molecular level, CGP42112A induced early activation of the neuroprotective kinases Akt and ERK1/2 as well as of the neurotrophins NGF and BDNF; all were blocked by treatment with the AT2 antagonist PD123319. Conclusions: Our results suggest that AT2 activation after TBI promotes neuroprotection and neurogenesis and may be a novel approach for the development of new drugs to treat TBI victims. This study was supported in part by grant from Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (AMRF).

J Mol Neurosci

Effect of static magnetic field (SMF) on anxiety and learning behavior in young and old SD rats Uzan-Gueta R*., Loboda Y*.,Klopstock N*., Schachter, L#., and Finberg J.P.M* 1,2* 1 * Dept. of Molecular Pharmacology, Rappaport Faculty of Medicine 2 #Faculty of Electrical Engineering, Technion, Haifa, Israel. Background: There is much interest andscientific work on the interaction between magnetic fields and biologicalfunction. A variety of beneficial effects in various disease situations havebeen claimed especially for treatment of painful conditions. Little is known about magnetic field'seffect on learning, memory and anxiety behavior and adult neurogenesis. Methods: Malerats weighing 250-300g (young) and weighing 500-700g (old) were used. We performed a time course experiment exposingthe rats to 1, 3, or 5 weeks of SMF. Asmall disc-shaped magnet was fixed to the rat's skull. In control experiments adummy metal disc was used instead of the magnet. The magnet was positionedabove bregma causing field strength of 40 Gauss in the area of the hippocampaldentate gyrus. After 1,3,or 5 weeks of SMF exposure, behavioral tests werecarried out (open field, novel object recognition, elevated plus maze and socialinteraction). At the end of the experiment hippocampi were taken for geneexpression analysis using RT- PCR. Results: Young rats exposed to 1 week of SMF spentmore time near the new object in the novel object recognition test, which indicatesimproved learning/memory ability. Moreover, magnet-implanted old ratswere found to spend longer time in the elevated plus maze (EPM) open arms,which indicate decreased anxiety-like behavior. No significant behavioraleffects were seen after 3 or 5 weeks of SMF exposure. Gene expression analysisshowed a significant increase of NTF4 gene in young rats after 1 week of SMF. Conclusion: Exposure to a weak staticmagnetic field for 7 days exerts a beneficial effect on learning in young rats,and an anxiolytic effect in old rats, but adaptation occurs resulting indisappearance of these effects after 3 weeks exposure. The NTF-4 gene is knownto be involved in neurogenesis and brainplasticity, and its role in the effects observed is under investigation. NAP alpha-amino- isobutyric acid (isoNAP): toward mechanism of action Kapitansky O 1*, Vaisburd s 1, Gozes I 1 1 Human genetics and biochemistry, Tel Aviv Uni. We have recently set out to identify NAP (davunetide) analogues, providing neuroprotection and reducing tau pathology, specifically addressing protection against protein misfolding. NAP (NAPVSIPQ) is a drug candidate that: 1] had a statistically significant impact on verbal recall and visual

working memory in a patient population of mild cognitive impairment [preceding Alzheimer's disease (AD)] and 2] protected functional activities of daily living in schizophrenia patients. Recent studies have identified a new NAP analogue, including replacement of the two proline (P) residues by alpha amino- isobutyric acid to enhance beta sheet breaker characteristics, thereby reducing protein misfolding. Three lines of investigations were taken: 1] protection against the ADassociated amyloid β (Aβ)1-42 peptide toxicity in cell cultures; 2] inhibition of AD-associated tau aggregation in vitro; 3] cognitive protection in a mouse model of deficiencies of the NAP parent protein, activity-dependent neuroprotective protein (ADNP), exhibiting tau pathology and neurodegeneration. Results have shown that NAP alpha-amino- isobutyric acid (isoNAP) protected neurons against Aβ1-42-toxicity, inhibited the aggregation of the tau derived peptide VQIVYK (important for the aggregation of tau into paired helical filaments, which form the tangles found in AD) and protected the brain in a model of ADNP deficiency (1). As NAP was shown to act through interaction with microtubules, current studies are aimed at deciphering the potential interaction of isoNAP with the microtubule cytoskeleton, toward better understanding of nerve cell protection. Support: The AMN Foundation, CFTAU Montreal Circle of Friends and the Adams family. 1. I. Gozes, Y. Schirer, A. Idan-Feldman, M. David, S. Furman-Assaf, J Mol Neurosci. 2014 Jan;52(1):1-9. doi: 10.1007/s12031-013-0103-8. The Adams Super Center for Brain Studies and Sagol School of Neuroscience Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand reduces the expression of the neuroprotective Na+/Ca2+ exchanger isoform 3 in human neuronal cells Valerio O.*1,2, Di Benedetto G.1, Amoroso S.2, Bernardini R.1, Cantarella G1. 1 Dept. of Clinical and Molecular Biomedicine, Section of Pharmacology and Biochemistry, School of Medicine, Univ. of Catania, 95125 Catania, Italy; 2Dept. of Biomedical Sciences and Public Health, School of Medicine, Univ. Politecnica of Marche, 60126 Ancona, Italy. Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), a cytokine belonging to the TNF superfamily, is considered as a mediator of neurotoxicity. The constitutively expressed protein ion exchanger isoform 3 (NCX3) efficiently protects neurons from damage and death following ischemic injury. NCX3 expression is induced by NGF, a neurotrophin which binds the tyrosine kinase receptor TrkA and activates downstream kinases, such as Erk1/2 and survival related kinase Akt. Here, we verified the hypothesis that TRAIL can influence the expression of NCX3 via modulation of the NGF/ TrkA system. Differentiated human neuroblastoma SH-SY5Y cells were incubated with TRAIL and NCX3 protein expression was

J Mol Neurosci

studied by means of western blot analysis after 6, 16, 24 and 48 h. NCX3 protein expression decreased in a time-dependent fashion in SH-SY5Y cells treated whit TRAIL. Then, the expression of the phosphorylated form of TrkA has been analysed at the same time intervals, along with both phosphorylated Erk1/2 and Akt. Western blot analysis revealed that p-TrkA expression has increased in cells treated with TRAIL after 6 and 16h, whilst it declines thereafter, until it almost disappeared after 48h. A similar pattern has been observed for both p-Erk1/2 and p-Akt. Results indicate that the reported increase of TRAIL expression occurring during neural damage determines substantial loss of NCX3 expression and, consequently, abrogates its neuroprotective effects. Finally, the TRAIL system could thus represent a potential target for treatment of neural damage involving NCX3. The synapsins: from organization of synaptic terminals to epilepsy, autism and intellectual disability Valtorta F 1,2*, Benfenati F 3,4 1 San Raffaele Vita-Salute Univ., Milan, Italy 2 Divison of Neuroscience, San Raffaele Scientific Institute, Milan, Italy 3 Italian Institute of Technology, Genoa, Italy 4 School of Medicine, Univ. of Genoa, Italy The synapsins (Syns) are a family of neuronal phosphoproteins associated with the cytosolic surface of synaptic vesicles (SVs) and interacting with the actin cytoskeleton in the nerve terminal. Experimental evidences suggest a role for Syns in SV clustering and recycling at the presynaptic terminal, in neuronal development and in synaptogenesis. Nonsense and missense mutations in the SYN1 gene have been identified in individuals affected by epilepsy and/or autism and/or intellectual disability. In addition, Syn knock-out mice display epileptic and autism-like phenotypes as well as learning deficits. We have studied the development of Syn knock-out mice and found that they exhibit synaptic deficits that precede the onset of epilepsy, suggesting that in these mice alterations in neurotransmitter release are cause, rather than consequence, of seizures. We are also interested in elucidating the molecular and cellular mechanisms by which mutated Syns generate the pathological phenotype in humans and in understanding the differences between mutations that generate the sole epileptic phenotype, those associated with autism or mixed autism/ epileptic phenotype and those associated solely with intellectual disability. We have studied the impact of these mutations on the biochemical and functional properties of the Syns, on neuronal development, viability and morphology and on synaptic transmission in mature neurons. All together, our findings raise the possibility that distinct mutations in the Syn I molecule give rise to distinct phenotypes, and may therefore shed light on the pathological routes involving Syn I that lead to epilepsy, autism spectrum disorders, intellectual disability or a combination thereof.

Perception of hierarchical figures in ADHD: A unique difficulty in seeing the trees? Vaskevich A. 1*, Mohaban D. 1, Shalev, N. 1,2, Baisa, A. 2, Shalev, L. 2,3 1 The School of Psychology Sciences, Tel-Aviv Univ. 2 Constantiner School of Education, Tel Aviv Univ. 3 Sagol School of Neuroscience, Tel-Aviv Univ. In the present study we examined the ability of individuals with or without Attention Deficit Hyperactivity Disorder (ADHD) to inhibit responses to irrelevant stimulus aspects. We administered a modified version of the Navon's letters task to young adults with ADHD and to control participants, in which the relative saliency of the global/local aspect was systematically manipulated. Participants identified the global and local levels of hierarchical figures which were presented in three different display sizes. Results showed that participants with ADHD had a specific difficulty in processing the local level even though relative saliency was controlled. This result may be explained by the requirement to attend to details while ignoring the global configuration when processing the local level. Although such a deficit is reported here for the first time, somewhat surprisingly it is in line with one of the DSM symptoms upon which ADHD is clinically diagnosed. Blood-brain barrier permeability enhancement induced by low-frequency transcranial magnetic stimulation: proof of concept and underlying mechanisms in a combined animal and human study Vazana U. 1,2,3, Veksler R. 4,2,3, Pell G.S. 5, Prager O. 4,2,3, Chassidim Y. 4,2,3, Roth Y. 5, Shahar H. 5, Ruggero R. 6, Niarucelli W. 6, Inghilleri M. 6, Zangen A.. 7,2,3, Friedman A. 4,1,2,3* 1 Dept. of Biomedical Engineering 2 Zlotowski center for Neuroscience 3 Ben-Gurion Univ. of the Negev,Beer-Sheva, Israel 4 Dept. of Physiology and Cell biology 5Brainsway Ltd, Jerusalem, Israel 6 Dept. of Neurological Sciences, Sapienza Univ. of Rome, Rome, Italy 7 Dept. of Life Sciences Background: The blood-brain barrier (BBB) is designed to maintain a stable extracellular environment by limiting the penetration of intravascular molecules into the brain. While an intact BBB is essential for proper brain function, it also limits the delivery of chemotherapeutics and the effective treatment of primary and metastatic brain tumors. Thus, a strategy to increase the efficacy of drug delivery to the brain should preferably induce a local and reversible increase in vessels' permeability.Transcranial magnetic stimulation (TMS) is a non-invasive method that uses electromagnetic field generation to induce low–level currents in the cerebral cortex. We evaluated the ability of repetitive TMS (rTMS) to enhance BBB permeability. Results: Using novel dynamic fluorescent-angiography based imaging approaches and quantitative image analysis, we show

J Mol Neurosci

that low frequency, high intensity (1Hz, 10min, 130% of motor threshold) stimulation results in a moderate, but significant increase in vessels' permeability. rTMS under conditions in which neuronal activity is blocked did not result in a permeability change. We thus implemented a similar protocol in human subjects, following removal of primary (Grade IV) malignant glial tumors. Deep TMS (dTMS) in the hemisphere ipsilateral to the tumor was followed by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).Image analysis confirmed a mild, but significant increase in BBB permeability following dTMS in 10 out 15 patients, most prominent in the tumor bed. Conclusions: In a healthy rat neocortex, a significant increase in vessels' permeability was found in response to repetitive neuronal activation. In humans, we show the ability of dTMS to significantly increase vessels' permeability to Gd-based contrast agent, more prominently in brain areas in close vicinity to the resected tumor. Our results suggest that rTMS may be used as a non-invasive approach to produce controlled BBB opening for drug delivery. Eye tracking - a window into neurological function and processes Vezekenyi NL , Tobii Technology AB Eye tracking is unobtrusive and both time and cost effective compared with other neurological analysis methods. A growing number of researchers therefore use eye tracking to investigate for instance developmental aspects of visual and neurological functions, neurological diseases and brain damage. We at Tobii Technology, the global leader in eye tracking solutions, develop products that allow unrestricted, natural testing scenarios, while allowing researchers to study and quantify gaze patterns and eye movements in an objective and automated way that increases reliability and reduces variability. In our presentation we will introduce our product offering specific for neuroscience studies, such as eye movement studies, visual processing, search mechanisms or clinical areas like neurological diseases or brain damage, and more. We will introduce case studies for example on how eye tracking can be combined with other physiological data such as EEG, its usage in medical diagnostics or in studies with physically debilitating neurodevelopmental disorder patients. Herbal treatment for anxiety like behavior in ICR mice Versano . Z 1, Doron. R 2,3, Rehavi.M 1* 1 Dept of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel-Aviv Univ. 2Dep. Of Behavioral Science, the Academic Col. Tel-Aviv Yaffo 3 Dept. of Education and Psychology, The Open Univ. Anxiety disorders havebeen major public health concerns in the last decade. The rising numbers of reports of anxiety is

leading to an increase needs to find an appropriate treatment for these disorders. The conventional treatments for anxiety disordersarethe selective serotonin reuptake inhibitors (SSRIs) and the serotonin–norepinephrine reuptake inhibitors (SNRIs), although they can cause side effects. Therefore, it is essential promote the search for alternative treatment such as the herbal medicines. The aim of the present study was to evaluate the anxiolytic effect of a new herbal treatment developed in our lab, on mice that were exposed to several stress manipulations (maternal separation, UCMS- unpredictable chronic mild stress), compared to conventional treatment with the SSRI ecitalopram. Mice were randomly assigned to one of 4 treatment groups: (a) A control group receiving only the vehicle (saline) (b) Escitalopram 15 mg/Kg (c) The novel herbal treatment 15 mg/Kg (d) The novel herbal treatment 30mg/Kg Following a 3- week treatment,we have evaluated anxiety-like behaviors in the elevated plus maze (EPM), and the novel open field (NOF) tests, and biological changes, using Enzyme-linked immunosorbent assay(Elisa) for evaluation of brain derived neurotrophic factor (BDNF) levels in brain as well as radioimmunoassay for blood corticosterone levels evaluation. We have found that both escitalopram and the herbal treatment reduced the anxiety-like behaviors in the EPM and NOF tests compared to the control group. Surprisingly, we observed a significantincrease in the level of BDNF in the brains of mice treated with the herbal treatment compared to the ones treated with escitalopram and the control mice. Our results indicate that the new herbal treatment has potential for treating anxiety symptoms. Israel Science Foundation ,Israel Science Foundation,the Open Univ. of Israel Figure-Background processing in a seemingly low-level olfactory station Vinograd A. 1,2, Livneh Y. 3,2, Adam Y. 3,2, Mizrahi A. 3,2* 1 Dept. of Neurobiology 2 The Edmond and Lily Safra Center for Brain Sciences 3Dept. of Neurobiology,The Hebrew Univ. of Jerusalem, Jerusalem, Israel. One of the most basic computations of the olfactory system is odor discrimination. Discrimination is fundamental for a wide range of behaviors like locating food, identify predators and prey, and spatial orientation. Under natural conditions, odor detection and discrimination can be challenging because odors appear against other odorous backgrounds. Thus, odors must be separated from their background – a process called Figure Background Separation (FBS). Little is known about where in the olfactory system and how FBS is computed. We tested whether computations associated with FBS occur already at the level of the olfactory bulb (OB), which is the first station of olfactory processing in the brain. Specifically we studied whether odor habituation and separation of

J Mol Neurosci

figure from background are computed in the OB. To do so, we imaged calcium activity of mitral cells (MCs) in response to a FBS protocol (combinations of 'figure', 'background' and 'figure over background'). Imaging was carried out using in vivo two photon microscopy which allowed us to screen hundreds of MCs. We imaged ~600 neurons from 6 mice and our first analysis show that ~80% of responsive MCs show habituation, and at least 10% clearly show responses akin to FBS computation (e.g. different response to figure over background as compared to a binary mixture). Thus, we argue that FBS is computed already at the level of the OB. Furthermore, these results suggest that the OB can perform a higherlevel computation and not only low-level computations as previously suggested. Synaptopodin and the spine apparatus regulate denervation-induced homeostatic synaptic plasticity Vlachos A. 1*, Ikenberg B. 1, Lenz M. 1, Becker D. 1, Reifenberg K. 2, Bas-Orth C. 1, Deller T. 1 1 Institute of Clinical Neuroanatomy, Neuroscience Center, Goethe-Univ. Frankfurt, Germany 2 Central Laboratory Animal Facility, Johannes Gutenberg Univ., Germany Background: The actin-binding molecule synaptopodin (SP) is required for the formation of the spine apparatus (SA), an enigmatic cellular organelle composed of stacked smooth endoplasmic reticulum, which has been linked to synaptic plasticity. However, SP/SA-dependent synaptic plasticity remains not well understood. Here, we studied the role of SP/SA in denervation-induced homeostatic synaptic plasticity using the entorhinal denervation in vitro model. Results: In entorhino-hippocampal slice cultures prepared from SP-KO mice, which lack the SA, a compensatory increase in excitatory synaptic strength cells was not observed after partial deafferentation. By crossing SP-KO mice with a transgenic mouse line, which expresses GFP-tagged SP under the control of the Thy1.2 promoter, the ability of dentate granule cells to form the SA and to homeostatically strengthen excitatory synapses was rescued. Interestingly, homeostatic synaptic strengthening was accompanied by a compensatory increase in SP-cluster sizes/stability and SA-stack number. Conclusions: Our results disclose that SP/SA is an important component of the molecular machinery which adjusts the strength of excitatory synapses to persisting changes in network activity. Since denervation of brain regions connected with lesion sites occurs in a large number of neurological diseases, it appears plausible that a broad range of neurological diseases will be accompanied by SP/SA-dependent compensatory, i.e., homeostatic synaptic responses of denervated neurons. Supported by Deutsche Forschungsgemeinschaft (CRC1080)

Role of eye dominance in target tracking using Eye Gaze input interface: The Laterality uniqueness of Ocular dominance Wagner M Elbaum T Ariel Univ., Ariel, Israel Technion - Israel Institute of Technology Lateralization represents preference of one limb or one of sensory mechanism pairs. Eye lateralization is usually referred to as ocular dominance, or eyedness. Whether eyedness is analogous to handedness remains unclear. "Cyclopean eye theory" claims that ocular dominance plays no role in perceiving or gaze direction. We performed two experiments aimed to examine the role of ocular dominance in gaze motor control, exploring whether eyedness analogies to handedness. We studied the effects of ocular dominance on gaze location and tracking accuracy in eye-gaze interface dynamic tracking tasks. Target tracking tasks were performed either in open loop (experiment-1), or in closed loop (experiment-2) paradigms, measuring gaze location and tracking accuracy. Participants performed 2D tracking tasks composed of 2 targetmotion-profiles (straight/ curved lines), with 4 velocity levels. Participants were tested for sighting dominance (Dolman's test). Ocular Dominance theory proposes the sightingdominant eye as reference point for visual direction. Accordingly, we expect higher dominant eye to target accuracy. In contrast, "Cyclopean eye theory" proposes mid-binocular location, referred to as "Cyclopean eye" or Egocenter, as reference point for visual direction. Accordingly, higher cyclopean eye to target accuracy is expected. In experiment 2 feedback cursor was coupled either to the dominant eye, or to the mid-binocular location. Here, according to the Ocular Dominance theory, optimal performance is expected with dominant eye coupling. Conversely, according to the "Cyclopean eye theory" optimal performance is expected with mid-binocular coupling. Results show higher accuracy of the "Cyclopean eye" in experiment 1, and higher performance efficiency with binocular cursor coupling in experiment 2, indicating an advantage of the "Cyclopean eye theory". In turn, results contradict the proposed analogy of eyedness and handedness. Implication for eye input interface is presented. Representation of self-motion in the early stages of the vibrissal somatosensory system Wallach A. 1*, Bagdasarian K. 1, Ahissar E. 1 1 Dept.of Neurobiology, Weizmann Institute of Science Sensation is an active process, in which the activity of the sensory organ affects and selects the nature of the sensed data that are derived from the external environment. The vibrissal somatosensory system of rodents is currently the most popular animal model in the study of mammalian active perception. Rats, mice and several other rodent species use the long hairs

J Mol Neurosci

(vibrissae or whiskers) on either side of their snout to interrogate their proximal surroundings. Exploratory rhythmic movements of the whisker array, known as 'whisks', are used to actively acquire tactile information on both the position and nature of nearby objects. This information is conveyed from the whisker follicles via the trigeminal nerve towards the brainstem, and from there to higher level processing stations. The sensory information streamed into the vibrissal system during active sensation and the processing it undergoes in the different pathways are still largely unknown. One of the main factors hindering a systematic characterization of these signals and processes is that the natural self-generated movements are shut-down under anesthesia. We generated awake-like whisking in anesthetized animals using a closed-loop stimulation paradigm, which artificially controls the whisker-pad movements in real-time. This closed-loop system consists of (i) an on-line whisker tracker, (ii) an artificial neural network implementing the inverse model of the whisker-pad's neuromuscular system, (iii) a PID controller adapting to slow drifts in the system's response and (iv) configurable stimulation of the facial nerve. Using this novel set-up, we were able to characterize the representation of self-motion in the early processing stages of the system, in the context of natural, awake-like behavior. Preliminary analysis revealed representation of whisking motion in the Interpolar Trigeminal nucleus of the brainstem, with protraction phases over-represented in comparison to retraction phases. The role of alerting in modulating perceptual saliency Weinbach N. 1*, Henik A. 1 1 Ben-Gurion Univ. of the Negev Background: The aim of the present study was to examine the effects of transient high arousal (phasic alerting) on perceptual processing and attention to salient events. Participants were presented with a large arrow (global level) comprised of smaller arrows (local level) and were required to indicate the direction of the large or small arrows in different blocks. The saliency of the global and local levels was manipulated to create a global-salient and a local-salient condition. Brief alerting signals were presented in half of the trials prior to the target. Results: The results showed that alerting enhanced attention towards the more salient dimension, irrespective of the required mode of perceptual processing (i.e., global or local). Alerting caused greater interference from an irrelevant salient dimension and reduced interference from the less salient irrelevant stimuli, compared with a no-cue condition. Conclusion: These results provide the first direct evidence of how phasic alerting can increase and reduce conflict in the same task based on saliency perception. These findings can help understand disorders such as hemispatial neglect in which both arousal and attention to salient events are

impaired. The present results challenge previous theories suggesting that alerting acts to increase conflict interference. We argue that alerting is an adaptive mechanism that diverts attention to salient events, but comes at a cost when diverting attention to less salient details is required. Visual expertise in the absence of holistic processing in congenital prosopagnosia Weiss N. 1, Mardo E. 2, Avidan G. 1* 1 Dept. of Psychology, Ben-Gurion Univ. of the Negev, Beer Sheva 2 Dept. of psychology, Univ. of Haifa Background: A major question in face perception is whether faces comprise a distinct visual category that is processed by specialized cognitive and neural mechanisms, or whether face processing merely represent an extreme case of visual expertise. Method: Here, we address this issue, by studying O.H, 22 years old woman with congenital prosopagnosia (CP), a lifelong impairment in face perception in the absence of an obvious brain damage. Interestingly, despite her deficit, O.H reported having superior recognition skills for horses, due to her work with horses since she was 7 years old. To examine her holistic perception with faces and horses, we used the inversion effect, i.e. better performance for upright compared to inverted faces, which is a well-established indication of holistic face processing. We conducted an identical task for horses, and used response time, accuracy and eye movement data as dependent measures. O.H performance was compared to data obtained from two age and gender-matched control groups each including 10 participants that were either horse experts, having 7-23 years of experience with horses or non-experts. Results: As expected, both control groups exhibited the face inversion effect, while O.H did not show the effect. As for horses, O.H. exhibited superior performance for upright horses compared to upright faces, but this was not qualified by an inversion effect for horses. Similarly, neither of the control groups exhibited an inversion effect for horses. Interestingly, gaze behaviour toward upright and inverted horses was indicative of horse expertise. Particularly, non-experts tended to focus their gaze towards the upper part of image of the horse, while in contrast, experts and O.H focused their gaze towards the head, regardless of image orientation. Conclusions: these results suggest that visual expertise can be acquired independently from the mechanisms mediating face recognition and is not necessarily dependent on holistic processing. The study was supported by an ISF grant 384/10 to GA Linking firing patterns of entorhinal cells to behavior in a reorientation task Weiss S 1,2, Eilam D 2, Derdikman D 1* 1 Rappaport Faculty Of Medicine, Technion 2 George Wise Faculty of Life Sciences, Tel-Aviv Univ.

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In a rectangular arena, disoriented rats (and other animals too) confuse between opposite, but geometrically identical corners when searching for a reward (Cheng, 1986). This rotational error effect implies that rats possess a perception of environmental geometry. However, the underlying mechanisms of this effect are yet unknown. The medial entorhinal cortex (MEC), containing grid cells, head direction cells and border cells, is a potential candidate for encoding such geometric attributes of the environment. We predict that rotational errors in this paradigm will induce a change in grid cell and headdirection cell firing patterns. In our study we have reproduced the behavioural effect of the original Cheng experiments, and are currently continuing to the next stage of linking electrophysiological recordings of grid and head direction cells in the rat medial entorhinal cortex (MEC) with "rotational error" choices. All in all, our study aims at gaining a broader understanding of the links between spatial perception and the underlying neuronal activity. Morphological segmentation and orthographic transparency in typical and dyslexic Hebrew readers: evidence from brain and behavior Weiss Y. 1*, Katzir T. 1, Bitan T. 2 1 Dept. of Learning Disabilities, The E.J. Safra Brain Research center, Univ. of Haifa, Israel 2 Dept. of Communication Sciences & Disorders, Univ. of Haifa, Israel Current evidence suggests that phonological and morphological processing play a role in typical and atypical development of reading. The dual version of Hebrew script and the rich morphology of Hebrew provide an opportunity to learn about the interaction of orthographic depth and morphological richness on reading processes among typical and dyslexic readers in a within-language design. 21 typical and 20 poor adult Hebrew readers participated in the behavioral study.18 typical adult readers participated in the fMRI study. Participants read aloud 248 frequent Hebrew nouns manipulating the following variables: morphological complexity (mono/bi-morphemic); phonological transparency (un/pointed; with/out a vowel letter); and word length (3/4 consonants). Behavioral results show greater reliance on morphological decomposition in dyslexic compared to typical readers. Only dyslexics read pointed words slower than unpointed words. Both groups benefitted from an additional consonant or vowel letter in unpointed words, whereas the opposite was found in pointed words. The findings from the fMRI study in typical readers showed enhanced activation for pointed words in right fusiform gyrus, consistent with the low familiarity of the orthography, as well as in left inferior frontal gyrus (pars-opercularis) and left inferior parietal lobule, indicating enhanced orthography-to-phonology mapping and phonological segmentation. For pointed words greater activation was found in bi-morphemic compared to mono-morphemic words in

bilateral middle & superior temporal gyri indicating enhanced semantic and phonological processing. Our results suggest that typical and dyslexic adult Hebrew readers, reading unambiguous words, do not benefit from increasing the orthographic transparency at the cost of reducing orthographic familiarity. In contrast, they do rely (to different degrees) on morphological decomposition, but not necessarily to compensate for missing phonological information. ISF grant 1142/11 and NetWords grant 09-RNP-089 Simulation of morphologically structured neural stimulation by light Weissler Y.1, Farah N., Shoham S.* 1 Faculty of Biomedical Engineering, the Technion - I.I.T., Haifa, Israel This study offers a MATLAB-NEURON based computer simulation environment for a three-dimensional morphologically structured neural stimulation. The simulation is generic and suited for different kinds of stimuli and neural models. This type of simulation can be of great importance for the understanding and investigation of optical neural stimulation which is a fast developing field. Employing advanced light projection systems, such as computer generated holography, the optical stimuli can achieve structured patterns and sub-cellular spatial resolution that fully utilizes the potential of optical neural stimulation. The introduction of these complex, high resolution spatio-temporal stimuli drives the need for a computer simulation framework which supports realistic three-dimensional modeling of both the neurons and the stimuli, providing a large variety of analysis and visualization capabilities. Advanced genetic and imaging approaches for studying Otp role in the oxytocinergic system Wircer E 1, Levkowitz G 2* 1 Dept. of Molecular Cell biology, Weizmann Institute of Science 2 Dept. of Molecular Cell Biology, Weizmann Institute of Science Disruptions of the oxytocinergic system in humans have been implicated in many pathologies, including Prader-Willi syndrome and autism. Yet, very little is known of how hypothalamic oxytocinergic neurons exert their function. Moreover, oxytocin-expressing neurons are highly heterogeneous in morphology and function and are defined and identified mainly by the existence of their major neuropeptide. Most of the research on oxytocinergic neurons has been performed in mammalian models in which these cells are not readily accessible for visualization and genetic manipulations. Recently, our lab established an Oxt:EGFP transgenic line which expresses EGFP in oxytocinergic neurons. This has opened exciting opportunities to examine the diversity in structure and function of oxytocinergic neurons by using advance

J Mol Neurosci

genetic and imaging tools in a whole organism. In my current research I'm investigating the function of the transcription factor orthopedia (Otp) in the development of oxytocinproducing cells. According to our results Otp is essential for the development of these cells and it differentially regulates different types of oxytocinergic neurons within the hypothalamus. In addition, in order to better characterize the oxytocinergic system in the zebrafish, I'm using the UASGAL4 system to fluorescently label a single oxytocinexpressing neuron and trace its axonal projections. Once we characterize the different cell types we intend to utilize optogenetic tools and identify behavioral responses associated with the activation of specific neurons. To this end we have also established an Oxt:gal4 transgenic line. This presents us with the exceptional possibility to analyze the connectivity, molecular composition and function of each neuron of the oxytocinergic system at a single-cell resolution. Role of the translational machinery in antioxidant-induced reversal of cocaine psychomotor sensitization Lisniansky E, Kohen R, Yaka R* Institute for Drug Research (IDR), School of Pharmacy, Hebrew Univ. Jerusalem It is well known that the use of cocaine cause various physiological changes in different organs, including the CNS. These changes caused severe damage and a variety of behavioral effects, and many studies are dedicated for investigating this phenomenon. In more recent studies, it has become evident that oxidative stress plays an important role in cocaine toxicity and cocaine induced addictive behaviors. Previously we have shown that cocaine induces massive oxidative stress in the pre frontal cortex and the nucleus accumbens . We found that the antioxidant Tempol abolished cocaine-induced elevation of oxidative stress in these areas both in-vitro and following cocaine injection. Importantly, Tempol at a dose that does not affect the basal levels of locomotor activity attenuated cocaine-induced psychomotor sensitization and prevented the increase in oxidative stress following withdrawal. In addition, Tempol increases the phosphorylation of eukaryote elongation factor 2 (eEF2) in cocaine sensitized rats. However, the molecular mechanism by which Tempol acts remain poorly understood. We therefore hypothesized that antioxidants exerts their neuroprotective effects via activation of the translational machinery. Using eEF2K KI mice, in which the protein kinase is present but defective, we found difference in cocaine psychomotor sensitization; KI mice showed decreased in both the development and expression of cocaine psychomotor sensitization compare to their littermates controls. Furthermore, treatment of KI mice with Tempol during sensitization had no effect on locomotor activity of untreated KI mice. However, Tempol injected to WT mice decreased the development and

expression of cocaine psychomotor sensitization. These results suggest that eEF2 play an important role in the neuroadaptations that leads to cocaine sensitized response, and currently we are exploring the underlying molecular mechanism by which antioxidants acts to reverse cocaine behavioral effects. Axonal elimination in the peripheral nervous system in health and disease Maor Nof M. 1, Sar Shalom H 1, Amit S 1,2, Yaron A 1* 1 Dept. of Biological Chemistry, The Weizmann Institute of Science, Rehovot, 76100, Israel 2 The Tel-Aviv Sourasky Medical Center, Weizmann 6 St., Tel-Aviv 64239, Israel In the developing peripheral nervous system, many neurons die shortly after their axons have reached their target fields. This neuronal elimination serves as a mean to achieve a precise match between the number of neurons and the target innervation requirements. In addition, this process ensures that misguided axons, which do not reach their appropriate targets, will be eliminated. The regulation of this process is based on the limited production of various neurotrophic factors, insufficient to sustain the entire neuronal population. Since this loss usually occurs after the axons have already fully extended, some kind of axonal disintegration must escort the death of the cell body. The talk will describe our efforts to uncover the mechanisms of axonal elimination during this process, and their relevance to axonal degeneration in pathological condition. Multi target anti Parkinson’s disease drugs targeting mitochondrial biogenesis and neurorestoration via activation of and HIF, SIRT1, PGC-1α and Tfam Youdim M.B.H * Abital Pharmapipeline Ltd.& Eve Topf Center TechnionFaculty of Medicine, Haifa Mitochondrial dysfunction is a hallmark of age-related diseases, including Parkinson's disease (PD) and Alzheimer's disease. Numerous pathways maintain and/or restore proper mitochondrial function, including mitochondrial biogenesis, mitochondrial dynamics, mitophagy and the mitochondrial unfolded protein response. The peroxisome proliferator activated receptor γ co-activator 1α ( PGC-1α) is a transcriptional co-activator that is a central inducer of mitochondrial biogenesis in cells. Recent work highlighted that PGC1α can also modulate the composition and functions of individual mitochondria. PGC1α controls global oxidative metabolism by performing two types of remodeling: (1) cellular remodeling through mitochondrial biogenesis, and (2) organelle remodeling through alteration in the intrinsic properties of mitochondria. Previously we have reported that in PD the defect in mitochondria function is associated with our recent observation of decreased expression (PCG-1alpha) in Parkinsonian

J Mol Neurosci

SNPC. The dual control of mitochondrial biogenesis and energy metabolism by silent information regulator-1 and -3 (SIRT1 and SIRT3), activate PGC-1α-mediated transcription of nuclear and mitochondrial genes encoding for proteins, promoting mitochondria proliferation, oxidative phosphorylation and energy production. The multi target drugs M30 and its derivative,HLA-20, possess potent neurorescueneurorestorative activity in cellular and animal models of PD and activate SIRT1 and PGC-1a. Neurorestorative-neurogenic activity of these drugs has been attributed to their ability to activate HIF-1a and increase brain levels of neurotrophins BDNF,GDNF, VEGF and erythropoietin in striatum and hippocampus. SIRT1 is necessary for HIF-1α protein accumulation and activation of HIF-1a target genes under hypoxic conditions. We shed light on activation of PGC-1α, Sirtuins and HIF-1a as novel therapeutic approach targeting mitochondrial biogenesis for neurodegenerative disorders. Full night, on-board audio and GPS monitoring of bat behavior in the wild Cvikel, N 1, Yovel Y 1,2* 1 Dept'. Zoology, Tel-Aviv Univ. 2 Sagol School of Neuroscience, Tel-Aviv Univ. Background: How animals move and forage in the presence of conspecifics is one of the most fundamental questions in social behavior. It cannot be studied in the lab, and is extremely difficult to study in the field because of the need to simultaneously monitor: (1) the movement of an individual. (2) Its foraging and (3) the presence of conspecifics. Even though bats account for more than a fifth of mammalian species, they are considered very hard to monitor in the wild because of their small size and their nocturnal behavior. Here, we present a new system which allows full night monitoring of an echolocating bat's movement and foraging. We mount bats with miniature devices which include GPS and an ultrasonic microphone. This system takes advantage of the bat's reliance on active sensing (echolocation) which requires emitting sound to perceive the environment. The setup thus allows studying how bats forage with conspecific competition. Results: Data shows that on the one hand bats group and swarm and are attracted to conspecifics in order to ease food finding. On the other hand, results reveal clear evidence for conspecific competition, meaning that bats' foraging success drops in the presence of conspecifics. We show that this does not result from sensory jamming by the echolocation of other bats, but probably from the need to localize other bats in order to avoid collision. Conclusions: For the first time, we tracked bats flying along hundreds of kilometers in the wild while following their foraging behavior. We found strong evidence for the existence of a classical group foraging dilemma between the need to

forage together to improve success and the need to keep a distance apart to avoid interference. The use of bat's active sensory system proved to be a powerful advantage for studying animal behavior in the wild. We are currently developing a new device which includes more sensors and an ability to record neural activity. Eran Levin, Arjan Boonman, Eran Amichai Being PRO ACTive- what can a clinical trials database reveal about ALS? Zach N. 1*, Kueffner R. 2, Stolovitzky G. 3, Leitner M. 1 1 Prize4Life, Tel Aviv, Israel and Cambridge, MA,USA 2 Ludwig-Maximilians-Univ., Munich, Germany 3 IBM T.J. Watson Research Center, Yorktown Heights, New York, USA Identifying statistically significant and biologically relevant observations for rare disease like ALSrequires large databases of patient information. The Pooled Resource Open-access ALS Clinical Trials (PRO-ACT) platform provides an unprecedented opportunity to increase our understanding of the ALS patient population. The PRO-ACT database consists of over 8500 ALS patients who participated in 17 clinical trials funded by either the industry, non profit, or government sectors. Data included demographics, family history, vital signs, clinical assessment, lab data , and survival information. The database was launched open access to researchers worldwide December 2012, and has since then attracted the attention of over 160 researchers from 20 different countries. Several assessments were made to start understanding the value of the PRO ACT database and we will describe some of them here. One such initiative included a crowdsourcing attempt -the ALS Prediction Prize challenge- to develop improved methods to accurately predict ALS disease progression at the individual patient level. The attempt brought in over 1000 solvers and solutions that can help predict the progression of ALS to aid both clinicians and clinical trial planning. The challenge also helped identify new features predictive of ALSFRS progression that will be presented as well, along with preliminary results regarding different patient sub-populations and progression profiles. These results demonstrate the value of large datasets in developing a better understanding of ALS natural history, prognostic factors, and disease variables. More sophisticated and targeted analysis will reveal even more. Understanding of the questions that are of the greatest need and how can they be answered in light of the new data availability, is of interest. Phosphorylation of tau protein in the developing brain of human apoE3- and apoE4-targeted replacement mice Zafran G. 1, Michaelson D.M.* 1 Dept. of neurobiology, George S. Wise faculty of life sciences, Tel Aviv Univ., Israel

J Mol Neurosci

Background: The apolipoprotein E4 (apoE4) is a risk factor for Alzheimer's disease. ApoE is found in neurofibrillary tangles (NFT), which are one of the major pathological hallmarks of the disease. NFT contain filaments formed from hyperphosphorylated microtubule associated protein tau. Tau phosphorylationis developmentally regulated, as fetal tau is phosphorylated at more sites thanadult tau. Results: In this study we examined the extent to which the age dependent phosphorylation of tau is effected isoformspecifically by apoE4 utilizing apoE3 and apoE4 targeted replacement mice at different ages. Biochemical analysis utilizingdistinct monoclonal antibodies (mAbs) directed against total tau and specificphosphorylated tau epitopes was performed. Immunoblot and immunohistochemicalmeasurements revealed an age-dependent decrease in the levels of total tau inboth apoE3 and apoE4 mice, which reach a plateau at the age of 1 month. Asimilar trend was observed u t i l i z i n g t h e AT 8 m A b ( p S e r 2 0 2 / p T h r 2 0 5 ) . Experimentsutilizing AT270 mAb (pThr181) revealed a transient increase in the levels ofthe phosphorylated epitope at the age of 2 weeks, which was more pronounced inapoE4 mice than in the corresponding apoE3 mice. This was followed by anisoform-independent decrease with age. A similar transient increase in thelevels of phosphorylated tau was observed in the apoE4 mice utilizing AT180 mAb(pThr231), though to a lesser extent. Taken together, these findings show thatwhile no apoE4 dependent effect on total tau levels is observed, apoE4 doeseffect tau phosphorylation in an epitope-dependent and age-dependent manner. Conclusion: These findings suggest that the apoE genotype can affect the regulation of phosphorylated tau, and by that might affect normal brain development. Klotho protects hippocampal neurons from oxidative stress via regulation of the redox system Zeldich E, Chen CD, Mills T, Liang J and Abraham CR* Dept. of Biochemistry, Boston Univ. School of Medicine, Boston, MA, USA Background: Generation of reactive oxygen species (ROS), leading to oxidative damage and neuronal cell death plays an important role in the pathogenesis of neurodegenerative disorders including Alzheimer’s disease. The present study aimed to examine the mechanism by which the anti-aging protein Klotho exerts neuroprotective effects against oxidative stress in neurons. Results: Pretreatment of rat primary hippocampal neurons and mouse hippocampal neuronal cell line HT-22 with recombinant Klotho protected from glutamate-induced cytotoxicity, which was reflected by decreases cell death, reduced accumulation of ROS and reduced release of LDH to the medium. In addition, primary hippocampal

neurons obtained from Klotho overexpressing mouse embryos were more resistent to glutamate-induced oxidative stress, as compared to neurons from WT littermates. An anti-oxidative stress array revealed that Klotho significantly enhances expression of the members of thioredoxin/peroxiredoxin (Trx/Prx) system with more prominent effect on the induction of Prx-2, which was confirmed at the mRNA and protein levels. Klothoinduced phophorylation of PI3K/Akt pathway was associated with sustained inhibitory phosphorylation of forkhead box O3a (FoxO3a) and was found as essential for the protective effect of Klotho and the induction of Prx-2. Downregulation of Prx-2 expression using a lentivirus harboring shRNA almost completely abolished Klotho’s ability to rescue the neurons, suggesting that the induction of Prx-2 is a key modulator of neuroprotection. The induction of Prx-2 was associated with an activation of NRF-2, shown by using a NRF2 reporter virus and Luciferase Assay. Conclusion: Our results demonstrate, for the first time, the neuroprotective role of Klotho and reveal a novel mechanism underlying this effect. Drug addiction is exacerbated in depressive-like states: possible role of BDNF Zilkha N. 1,2, Zangen A. 2* 1 Dept. of Neurobiology, Weizmann Institute of Science, Rehovot 2 Dept. of Life Sciences, Ben-Gurion Univ. of the Negev, Beer-Sheva Brain-Derived Neurotrophic Factor (BDNF) has been studied extensively for it's involvement in depression, and it is now widely accepted that alterations in BDNF levels in different reward-related brain regions play a major role in the pathophysiology of the disorder. In recent years, this neurotrophin has also been implicated with addiction related behaviors as well as neural adaptations, making it a perfect candidate for the scientific research of the co-morbidity between depression and addiction. In this study, we examined the effects of two distinct depression-inducing manipulations on different addictive behaviors in laboratory animals. Following behavioral procedures, we analyzed BDNF protein levels in several reward-related brain regions in order to investigate the molecular basis underlying the behavioral effects. Our results revealed that in both environmentally and genetically induced depressive-like states, addictive behaviors of cocaine self administration as well as heroin conditioned place preference were enhanced. Interestingly, these behavioral effects were accompanied with BDNF alterations associated with both depression and with drug use and relapse. However, the most prominent hallmark of BDNF reduction in the dorsal hippocampus, observed in numerous studies as a key feature of depression, was not found. This dichotomy of findings in

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BDNF levels could serve as support for the self-medication hypothesis, suggesting that the co-morbidity of depression and addiction is caused mainly from attempts of depressed patients to alleviate their condition by using psychoactive drugs.

Exchange and turnover of synaptic proteins: dynamics fast and slow Ziv, N.E. 1,2* 1 Faculty of Medicine, Technion 2 Network Biology Labs, Technion Synapses contain multitudes of proteins, which have finite lifetimes and therefore need to be continuously replaced. Given the huge numbers of synapses typical neurons have, the demand to maintain synaptic protein contents might be considerable, differing, perhaps, according to distance from global protein synthesis sites and availability of distributed protein synthesis facilities. Until recently, the turnover kinetics of synaptic proteins have not been analyzed systematically, and thus the aforementioned demands remain largely unknown. Furthermore, imaging studies indicate that synaptic proteins continuously move in, out and between synapses suggesting that synaptic proteostasis is determined by both exchange of preexisting protein copies and metabolic turnover of protein pools. Relationships between these two processes remain largely unknown. We have used dynamic SILAC, mass spectrometry (MS), FUNCAT, immunohistochemistry and bioinformatics to systematically measure the metabolic half-lives of hundreds of synaptic proteins, examine how these depend on their pre/postsynaptic affiliation or their association with particular molecular complexes, and assess the metabolic load of synaptic proteostasis. We found that nearly all identified synaptic proteins exhibited half-lifetimes of 2-5 days. Unexpectedly, metabolic turnover rates were not significantly different for pre- and postsynaptic proteins, or for proteins for which mRNAs are consistently found in dendrites. Some functionally or structurally related proteins were found to exhibit similar turnover rates, indicating that their biogenesis / degradation might be coupled. The low turnover rates measured here are in good agreement with imaging-based studies of synaptic protein trafficking, and collectively indicate that the synaptic proteostasis is dominated by local protein exchange and redistribution, whereas protein synthesis and degradation serve to maintain and regulate local, shared pools of these proteins. Neurophysiological manifestations of auditory hypersensitivity among individuals with Sensory Processing Disorder Zlotnik S*, Engel-Yeger ,B., Attias, J., Pratt, H. 1,1,2,3* 1 Occupational therapy Dept., Haifa Univ., Israel 2 Dept. of Communication Disorders, Haifa Univ., Israel 3 Evoked Potentials Laboratory, Technion - Israel Institute Of Technology

Aim: To establish a framework for studying the pathogenesis of Sensory Processing Disorder (SPD) expressed by auditory hypersensitivity, by referring to objective neurophysiological assessments and provides detailed examination of SPD from the peripheral receptor throughout the sensory pathway. Background: SPD is considered to result in extreme behavioral responses to sensory stimuli. Previous studies have validated that individuals with SPD have distinct physiological differences, as compared to those without SPD. To date, these studies did not focus on auditory responses to sensory stimuli from the peripheral up to the cortex. Participants: 34 right- handed adults with bilateral normal hearing, across 0.25 to 8000 Hz, were equally divided to either the control or to the study (SPD) group according to their scores in the sensory sensitivity/avoiding parts of the Adults Sensory Profile. Sensory hypersensitivity was presented in different sites along the auditory pathway measuring cochlear functioning by Transient-evoked otoacoustic emissions, stapedial acoustic reflexes, brain stem processing, by Auditory Steady-State Responses (ASSR) and cortical Evoked Related Potentials (ERP). Results: The study group was characterized by a consistent trend of hyper-excitability by auditory stimuli compared to the controls from the cochlea up to the cortex. Higher levels of TEOAEs and no efferent suppression effect. Lower contralateral threshold of most stapedial acoustic reflexes, consistently larger ASSR responses and consistently (although not statistically significant) larger ERP responses. Conclusions: this study indicates that SPD is not solely a subjective trait but rather, involves objective physiological responses along the auditory tract. Further research should examine the correlation between physiological responses and behavioral manifestation of SPD, to improve assessment and intervention programs to raise performance and quality of life for people with SPD. We would like to thank Dr. Shlomo Gilat who provided hours of technical support and helpful advice f Transformation-tolerant perception of visual objects in rats revealed by visual priming Tafazoli S. 1, Di Filippo A. 1, Zoccolan D. 2* 1 International School for Advanced Studies (SISSA), Trieste, Italy 2 International School for Advanced Studies (SISSA), Trieste, Italy Background: Successful use of rodents as models for studying object vision crucially depends on the ability of their visual system to construct representations of visual objects that tolerate (i.e., remain relatively unchanged with respect to) the tremendous changes in object appearance produced, for instance, by size and viewpoint variation. Whether this is the case is still controversial, despite some recent demonstration of transformation-tolerant object recognition in rats. In fact, it

J Mol Neurosci

remains unknown to what extent such a tolerant recognition has a spontaneous, perceptual basis, or, alternatively, mainly reflects learning of arbitrary associative relations among trained object appearances. Results: In this study, we addressed this question by training rats to categorize a continuum of morph objects resulting from blending two object prototypes. The resulting psychometric curve (reporting the proportion of responses to one prototype along the morph line) served as a reference when, in a second phase of the experiment, either prototype was briefly presented as a prime, immediately before a test morph object. The resulting shift of the psychometric curve showed that recognition became biased toward the identity of the prime. Critically, this bias was observed also when the primes were transformed along a variety of dimensions (i.e., size, position, viewpoint, and their combination) that the animals had never experienced before. Conclusions: These results indicate that rats spontaneously perceive different views/appearances of an object as similar (i.e., as instances of the same object) and argue for the existence of neuronal substrates underlying formation of transformation-tolerant object representations in rats. Multifeatural shape processing underlying rat visual object recognition Alemi-Neissi A. 1, Rosselli F.B. 1, Zoccolan D. 2* 1 International School for Advanced Studies (SISSA), Trieste, Italy 2 International School for Advanced Studies (SISSA), Trieste, Italy ([email protected]) Background: The ability to recognize objects despite substantial variation in their appearance (e.g., because of position or size changes) represents such a formidable computational feat that it is widely assumed to be unique to primates. Such an assumption has restricted the investigation of its neuronal underpinnings to primate studies, which allow only a limited range of experimental approaches. In recent years, the increasingly powerful array of optical and molecular tools that has become available in rodents has spurred a renewed interest for rodent models of visual functions. However, evidence of primate-like visual object processing in rodents is still very limited and controversial. Results: Here we show that rats are capable of an advanced recognition strategy, which relies on extracting the most informative object features across the variety of viewing conditions the animals may face. Rat visual strategy was uncovered by applying an image masking method that revealed the features used by the animals to discriminate two objects across a range of sizes, positions, in-depth, and in-plane rotations. Noticeably, rat recognition relied on a combination of multiple features that were mostly preserved across the transformations the objects

underwent, and largely overlapped with the features that a simulated ideal observer deemed optimal to accomplish the discrimination task. Conclusions: These results indicate that rats are able to process and efficiently use shape information, in a way that is largely tolerant to variation in object appearance. This suggests that their visual system may serve as a powerful model to study the neuronal substrates of object recognition. Responses to black and white stimuli in the primary visual cortex explained by a model that combines luminance and contrast Zurawel G. 1*, Ayzenshtat A. 1, Shapley RM. 2, Slovin H. 1 1 The Leslie and Susan Gonda (goldschmied) Multidisciplinary Brain Research center,Bar-Ilan Univ. 2 Center for Neural Science, New York Univ. A key feature of V1 neurons is their responses to stimulus contrast. Recently, it was shown that neurons responding to black stimuli (negative contrast) substantially outnumber neurons responding to white stimuli (positive contrast) in the upper layers of monkey primary visual cortex. However, the exact spatio-temporal patterns of the activity evoked by black and white stimuli are not fully understood yet. To study these exact activity patterns, we trained monkeys to fixate while presented with 2x2 degree squares. Using voltage-sensitive dye imaging (VSDI), we measured V1 population responses to a white square on a gray uniform background and to a black square (of equal contrast) on the same background. V1 responses were as expected from retinotopic mapping, but showed marked spatial modulations over the evoked pattern. Cortical regions corresponding to corners and edges of the square stimulus exhibited significantly higher activity than regions corresponding to the center. Moreover, two of the squares' edges showed higher activation in regions corresponding to the corners than in regions corresponding to the edge's middle. Furthermore, patterns evoked by black and white were substantially different: activation at the region corresponding to the center of the black square was significantly higher than for the white, while along the squares' edges activation by black was only slightly higher. We propose a simplified model to explain all key observations, incorporating local contrast that accounts for edge processing, gain control that accounts for modulations along the edges, and signed luminance components that represent the different surface processing for black and white. The model performs well in predicting the measured spatial response, as well as the different responses evoked by the black and white stimuli and the black/white activation ratio at various regions.

J Mol Neurosci

Edge dominated responses for chromatic surfaces without filling-in in the primary visual cortex Zweig S 1*, Shapley R 2, Slovin H 1 1 The Gonda Multidisciplinary Brain Research Center, BarIlan Univ., Ramat Gan, Israel 2Center for Neural Science, New York Univ., New York, New York 10003 Background: Most neurons in primary visual cortex (V1) respond to spatial contrast. However recent evidence suggests there are also V1 responses to uniform surfaces. Previously, investigators have studied the dynamics of V1 responses to achromatic targets. We asked how edge vs. surface dynamics for colored targets compare with those of achromatic targets. Results: To investigate edge vs. surface dynamics, we presented two fixating monkeys with square patches of different sizes. The patches were either chromatic squares (CS) isoluminant to the surrounding gray background or black and white achromatic squares (AS) with equivalent contrast to the CS. Using voltage-sensitive dyes, we imaged the evoked neuronal population response at high spatial and temporal resolution. Early responses (within 40-100 ms) evoked by CS and AS had similar spatial characteristics. Both AS and CS evoked a "square" like spatial pattern in the imaged cortical area, with high responses in regions corresponding to the edges of the square and weaker responses in regions corresponding to its center. The responses to CS and AS, at later times were different. The population response at the center of the AS showed a slow response increase. Its amplitude at late times (>150ms) was close to the edge response amplitude. Additional analysis suggested that the late ASresponse increase progressed from edges to center as if there were a neural filling-in effect. The time required for the center to fill-in increased with the square size. The CS-response in the center, however, did not fill-in; it was edge-dominated at all times for all square sizes. Conclusions: During early times the spatial patterns of V1 population responses evoked by both CS and AS surfaces were edge dominated. However while the center of AS gradually filled-in later, the responses to CS were maximal at the edge-projections throughout. That is, we observed no color filling-in in V1.

Categorisation of discrete emotions in a new emotional picture database – the Nencki Affective Picture System (NAPS) Żurawski Ł. 1, Michałowski J. 2, Moslehi A. 2, Klocek Ł 2, Horvat M. 3, Grabowska A. 1, Jednoróg K. 1, Marchewka A. 4* 1 Dept. of Neurophysiology, Nencki Institute of Experimental Biology, Warsaw, Poland 2Faculty of Psychology, Warsaw Univ., Poland 3 Univ. of Zagreb, Faculty of Electrical Engineering and Computing, Zagreb, Croatia 4 Neurobiology Centre, Nencki Institute of Experimental Biology, Warsaw, Poland Background: Selection of static visual stimuli inducing emotional states in affective research is mostly based on valence and arousal ratings gathered according to dimensional theories of emotion. However, it was shown, using neuroimaging methods that neuronal mechanisms underlying processing of emotionally charged stimuli differ between discrete emotional categories. So far, only the International Affective Picture System (IAPS; Lang et al., 1997) provides behavioural norms (Mikels et al., 2005) which allow scientists to appropriately select stimuli for research aimed to modulate discrete emotions. The purpose of this project was to evaluate the subjective emotional experience induced by pictorial materials included in the Nencki Affective Picture System database (NAPS; Marchewka et al., 2013) using discrete emotional categories (happiness, surprise, fear, sadness, disgust and anger). Methods: 510 images of the NAPS database were rated by English-speaking European subjects (N=76) using computerized valence and arousal scales as well as discrete emotions scales of happiness, surprise, fear, sadness, disgust and anger. In the second step, images were classified on the basis of confidence intervals overlap of discrete emotions ratings (Mikels et al., 2005). Results: The preliminary data allowed distinguishing 360 images inducing one basic emotion, 55 images inducing several basic emotions and 95 images with undifferentiated emotional content. Conclusion: Provided data on dimensional and discrete emotional content of NAPS images will allow scientific community to select appropriate visual stimuli for affective research. The ratings freely available at http://naps.nencki.gov.pl/.