Mol Neurobiol DOI 10.1007/s12035-017-0516-4

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Exercise as a Positive Modulator of Brain Function Karim A. Alkadhi 1

Received: 29 October 2016 / Accepted: 4 April 2017 # Springer Science+Business Media New York 2017

Abstract Various forms of exercise have been shown to prevent, restore, or ameliorate a variety of brain disorders including dementias, Parkinson’s disease, chronic stress, thyroid disorders, and sleep deprivation, some of which are discussed here. In this review, the effects on brain function of various forms of exercise and exercise mimetics in humans and animal experiments are compared and discussed. Possible mechanisms of the beneficial effects of exercise including the role of neurotrophic factors and others are also discussed. Keywords Electrophysiology . Long-term potentiation . BDNF . Human aerobic and anaerobic exercise . Animal voluntary and forced exercise . Meditation

Introduction Human and animal studies have reported that regular physical activity such as running or bicycling facilitates functional recovery from brain injury and improves learning and memory in various conditions, including age-related neurodegenerative disorders such as various forms of dementia [1–4] and psychiatric and neurological diseases [5–8]. Exercise can be a potent nonpharmacological approach for preventing or treating cognitive impairment. Animal experiments have shown that exercise enhances cognitive function, and prevents memory decline in the aged brain [9, 10], Alzheimer’s disease, Parkinson’s disease, and sleep deprivation [6, 11, 12]. * Karim A. Alkadhi [email protected] 1

Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX 77204, USA

Epidemiological studies suggest that regular exercise can prevent cognitive disorders inexpensively and with minimal adverse effects [13]. Remarkably, however, findings from my laboratory consistently show that regular exercise in normal adult rat does not show beneficial effects on behavioral, electrophysiological, or molecular parameters, except brain-derived neurotrophic factor (BDNF) level, which is invariably markedly elevated [6, 11, 14, 15], suggesting a neuroprotective effect of exercise. The neuroprotective effects of exercise are mediated by a diversity of molecular mechanisms including upregulation of molecules associated with learning and memory functions, which leads to improved performance in memory tasks. It has been shown that exercised animals achieved better results in the spatial memory tasks such as Morris water maze (MWM) or radial arm water maze (RAWM) compared to unexercised animals [9, 16–18]. Exercise can also modify nonspatial memory in the passive avoidance paradigm and object recognition tasks [9, 10, 17, 19–22]. Additionally, regular exercise can prevent or restore memory impairment in rats treated with alcohol [23], streptozocin [24], or reserpine [25]. There are several variables including type, intensity, and frequency of exercise that may influence the effectiveness of exercise as a neuroprotective procedure in humans. Similar factors are also known to impact the results of exercise in animal experimental models of exercise. These are discussed in the sections that follow.

Forced and Voluntary Exercise in Animal Research Animal research utilizes either voluntary exercise where individually housed animals have access to running wheels ad libitum, or forced exercise, which involves running on a treadmill or forced to swim in an enclosed pool. Both paradigms

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resemble human exercise patterns in certain ways. Voluntary exercise may represent individuals who exercise at their own convenience. Forced exercise, on the other hand, represents those who must exercise for preventative or therapeutic measures for certain disorders (e.g., poststroke training, dementia prevention program). Although forced exercise (treadmill running) allows better quantification and lessens isolation stress, several reports suggest that voluntary exercise (wheel running) seems to be more beneficial in rats [26] and Tg2576 mouse model of AD [27]. Interestingly, both voluntary wheel running and forced motorized wheel running, but not forced treadmill running, are effective in reducing uncontrollable stress-induced learning deficits in Fischer344 rats [28]. Nonetheless, both forced and voluntary forms of exercise modulate processes associated with synaptic plasticity as well as learning and memory. These effects include increasing neurogenesis in the dentate gyrus [26], modulating metabolic proteins [29], and inducing hippocampal mossy fiber sprouting [30]. Forced swimming in mice recovering from stroke fails to enhance survival of nascent neurons in the dentate gyrus or to improve spatial memory, whereas voluntary wheel running enhances nascent cell survival and upregulates phosphorylation of cAMP response element binding protein (CREB) in the dentate gyrus (DG) and reverses ischemia-induced spatial memory impairment [16]. Under similar conditions, Toldy et al. report that diet containing 1% nettle leaves combined with regular swimming training in rats ameliorates the severity of brain injury by reducing the DNA binding activity of inflammatory transcription factors NF-κB and activated protein-1 (AP-1) [31]. Even though findings regarding the benefits of voluntary and forced exercise may vary probably because of the species of animal and the type of exercise used, the essential conclusion is that moderate exercise in all forms is invariably beneficial for brain health.

Aerobic and Anaerobic Human Exercise Typically, human exercise has been categorized into aerobic (swimming, running, bicycling) and anaerobic (resistance training, toning) types, which yield different positive consequences on brain function. However, only a limited number of reports in the literature have compared the outcome of the two types. An early report in healthy older adult humans (65– 75 years old) shows that the aerobic (walking) exercise group exhibits higher rate of oxygen consumption, improves reaction time, and enhances performance in tests of executive functioning than the anaerobic (stretching and toning) exercise group [3]. Furthermore, a pilot study shows that in poststroke individuals, stationary bicycle aerobic training exercise results in improved information processing speed compared to the stretching exercise group [32]. In other studies, forced bicycle

training improves motor function in mentally depressed Parkinson’s disease patients [33, 34]. While both types singly improve cognition, analysis of previous studies shows that combining the two types of exercise results in markedly better improvements in cognition than aerobic exercise alone [35]. This has been corroborated by more recent studies. For example, in poststroke patients, combined aerobic and anaerobic training results in significant improvement in working memory [36]. Combining the two types of exercise training causes improvement of cognitive function that led to reduction in the proportion of stroke patients reaching the threshold criteria for mild cognitive impairment (MCI) [37]. Furthermore, studies in human subjects show that aerobic exercise per se or in combination with anaerobic exercise can contribute to cognitive improvement in the aged or demented individuals [38] and in Alzheimer’s disease patients [39]. The conclusion that can be drawn from these studies is that both aerobic and anaerobic exercise singly or in combination are neuroprotective.

How Much Exercise Is Beneficial? It is well recognized that regular exercise can have substantial positive effect on cognitive abilities in various brain conditions including aging brain or pathological brain [6, 9–12]. The positive effects of exercise on cognitive function can be described by an inverted U-shape curve, suggesting that too much or too little exercise is not advantageous [40] and may even be harmful. For example, intense exercise impairs spatial memory acquisition in mice [41], inasmuch as high-intensity exercise leads to fatigue and excessive accumulation of harmful reactive oxygen species (ROS) that may overwhelm the natural antioxidant system. On the other hand, too little exercise does not upregulate the antioxidant capacity enough to counter the effects of exercise-generated ROS. However, regular exercise of moderate intensity can substantially improve cognitive function in children with cerebral palsy and counteract the development of dementia in various chronic diseases (e.g., [5, 42]).

Potential Cellular and Molecular Mechanisms of the Neuroprotective Actions of Exercise Several potential mechanisms have been proposed to explain the neuroprotective effects of exercise including increases in the levels of neurotrophic factors, particularly BDNF [4, 43, 44], reduction of oxidative stress [45], curtailment of neuroinflammation [46, 47], improvement of cerebral blood perfusion, or combinations thereof. These processes are mediated by various neurophysiological pathways in which alterations in cellular and molecular signaling pathways may positively

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influence angiogenesis, synaptogenesis, and neurogenesis and eventually leading to memory improvement that can be detected at the behavioral level. How does skeletal muscle activity influence the brain? Although there is widespread agreement on the beneficial effect of exercise in a diversity of brain disorders, it is unclear how muscle activity translates into a positive effect for the brain. The active muscles may communicate with the brain either via sensory nerve impulses originating from the active muscles (wired communication) or through blood-conveyed exercise-generated messenger. A wired messaging, however, seems unlikely as experiments in individuals with severed spinal cord or in those under epidural anesthesia (no afferent or efferent nerve impulses), contraction of paralyzed muscles by direct electrical stimulation generates physiological changes similar to those seen in active muscles of normal individuals [48, 49]. The alternative, therefore, is that contracting skeletal muscles communicate with the central nervous system (CNS) and other organs by discharging chemical messengers into the circulation [50, 51]. Since it is known that muscles produce BDNF during exercise, an obvious candidate for a messenger that communicates skeletal muscle activity to the CNS is BDNF; however, experiments have shown otherwise. A significant amount of BDNF is released during prolonged exercise in healthy male volunteers, which is thought to be the main source for increased plasma BDNF during exercise [52–54]. However, this muscleoriginating BDNF is not released into the circulation [55] but stays in the muscle, conceivably to function in an autocrine and/ or paracrine capacity [56]. What then is the source of the heightened BDNF levels in the circulation during exercise? The enhanced blood levels of BDNF during exercise may be, at least in part, due to discharge of BDNF from activated platelets [55], which are known to store and release BDNF [57, 58]. This has been confirmed by a report of substantial increases in BDNF levels in serum, plasma, and platelet following exercise in healthy individuals [59]. Another likely messenger that can communicate skeletal muscle activity to the brain is the cytokines. The cytokines are a group of low molecular weight glycoprotein molecules, which can function as pro-inflammatory and antiinflammatory agents and may even act as intercellular messengers. The levels of the cytokine interleukin-6 (IL-6) are significantly increased in response to exercise [56, 60]. Interestingly, it has been shown that labeled IL-6 reaches the brain via a saturable transport system, which may be sufficient to produce biological effects [61, 62]. It is reasonable to hypothesize that cytokines released during muscle activity may trigger the release of BDNF from platelets thus boosting its levels in the cerebral blood circulation and cerebrospinal fluid (CSF) (Fig. 1). Support of this possibility comes from reports showing that BDNF expression in the CSF is strongly correlated with IL-6 levels in the CSF and with blood platelet counts [63, 64].

Obviously, the mechanism of the communication between contracting muscle and the brain is not well understood, and more work is necessary to unravel this mystery. Clarifying the molecular mechanism of this pathway will be valuable for the discovery of exercise-mimicking medications that would be of immense benefit in physically challenged individuals. Angiogenesis Exercise increases brain oxygen perfusion by improving cerebral blood supply through angiogenesis and by promoting vasodilation particularly in brain areas essential for task execution [65]. For example, Kramer et al. [3] report that aerobic exercise (walking) increases the maximum rate of oxygen usage, improves reaction time, and enhances performance in tests of executive functioning in older individuals. Exercise upregulates angiogenic factors including vascular endothelial growth factor (VEGF), angiopoietins, and insulinlike growth factor 1 (IGF-1), which are concerned with vascular growth [66–68], thus promoting cerebral perfusion leading to better cognitive performance [69, 70]. Regular exercise in rats and monkeys [71, 72] and even acute exercise in human [73] increases cerebral blood flow and volume and improves brain vasculature in various areas of the brain in healthy young and aged brains [68, 74] as well as in Alzheimer’s and Parkinson’s diseases [69, 75–77]. Synaptogenesis and Neurogenesis Ample evidence indicates the beneficial effect of exercise on synaptic architecture. For example, voluntary exercise increases the number of dendritic spines [78] and boosts dendritic density and length in cognition-related areas of the brain including dentate gyrus [79–82], cornu ammonis (CA1), and entorhinal cortex ([83, 84], for review see [85]). Neurogenesis induced by aerobic exercise in adult subjects is accompanied by enhanced synaptic plasticity, spatial memory, and pattern separation [86]. At the subcellular level, regular exercise increases the amount of synaptophysin, a vesicular protein that regulates synaptic transmission, and calcium/calmodulindependent protein kinase II (CaMKII) [87], both of which play important roles in synaptic plasticity. Further study is needed to show whether the exercise-induced morphological changes of the synapses are permanent, since the effects have been reported to be transient after spatial learning [88]. Neurogenesis in the hippocampus continues to occur even during advanced age in humans [89, 90]. That exercise increases hippocampal cell proliferation has been reported in a variety of conditions including menopause in women [91, 92], brain insults [80, 93, 94], stressed aged mice [95, 96], and ovariectomized mice [97]. In the subgranular layer of the dentate gyrus, nascent cell survival, proliferation, and maturation rates are markedly enhanced in exercised mice compared to

Mol Neurobiol Fig. 1 A simplified diagram representing an hypothesis that explains how skeletal muscle activity may translate to positive effects on the brain through increases in levels of brainderived neurotrophic factor (BDNF) in the central nervous system (CNS)

their matched sedentary controls [93, 98, 99]. The increase in the formation of new neurons has been correlated with the degree of neuroprotection [26, 100]. Moreover, rodent maternal exercise during gestation, which promotes hippocampal cell survival, can also strengthen the pups’ cognitive function [101]. In addition to effects on neurogenesis, exercise has been shown to cause generation of new oligodendrocytes in the spinal cord of mice [102]. It is unclear how neurogenesis can be beneficial to the brain. It has been suggested that the new neurons may integrate into existing operational circuits and function along with other neurons [103]. The presumed steady supply of new neurons serves to replace dysfunctional neurons, thus maintaining normal cognitive function. Exercise and Mitochondrial Energy Numerous early reports have shown that aerobic exercise increases mitochondrial oxidation efficiency, mass, and enzyme activity ([104, 105]; see [106] for review). Mitochondria, the major powerhouse of the cell, are dynamic organelles important in the regulation of calcium homeostasis and apoptosis [107, 108]. Exercise training and mitochondrial function seem to be mutually beneficial [109]. It has been shown that physical exercise decreases oxidative stress and apoptotic related markers in the cortex and cerebellum. Exercise also improves mitochondrial respiratory activity and increases the expression of proteins involved in mitochondrial biogenesis, autophagy, and fusion [110]. Moreover, regular exercise increases the production of mitochondrial ATP, a potent vasodilator that can increase oxygen supply to the local tissues [111, 112].

Exercise is known to have a positive effect on mitochondrial population and function. For example, exercise-induced mitochondrial biogenesis occurs extensively in human skeletal muscles [113, 114] and mice brains [115] making exercise an appealing target for novel treatment of CNS diseases, which are usually accompanied by mitochondrial dysfunction.

Role of Brain-Derived Neurotrophic Factor BDNF has become an increasingly important candidate as a modulator of effects of exercise on synaptic plasticity and its signaling cascades. Regular exercise increases and sustains BDNF protein levels in the hippocampus thereby improving cognitive function [116–119]. Several characteristics make BDNF an attractive molecule for this function: it can (1) be stored and discharged in the dendrites and axons of hippocampal neurons, (2) control activity-dependent protein synthesis, and (3) stimulate its own release at synaptic sites allowing for regenerative signaling for extended periods [120]. BDNF is a vital growth factor that works through activation of tropomyosin kinase B (TrkB) receptors, which are expressed in brain tissue as well as in skeletal muscle [55, 121]. The levels of BDNF are diminished in a variety of cases of impaired brain function. In fact, BDNF plasma levels have been suggested as a biomarker of impaired cognitive function [122]. BDNF regulates growth and preservation of neurons [123] and is widely believed to be important for cognitive function as indicated by its inadequate brain levels in neurodegenerative diseases including Huntington’s, Alzheimer’s, and Parkinson’s diseases [124].

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BDNF is essential for neuronal development, survival and migration, neurogenesis, cell differentiation, growth of axons and dendrites, synapse formation, and synaptic plasticity [99, 125–130]. It is widely believed that BDNF has an important role in memory and its putative cellular models [131–133]. BDNF can work pre- or postsynaptically to regulate various signaling pathways including its own, which are important in the process of learning and memory [134–136]. In addition to the role of encouraging growth, differentiation, and survival of new neurons and synapses during development [137], BDNF is now recognized as a crucial modulator of synaptic plasticity in the adult brain [138]. For instance, BDNF can act presynaptically by enhancing quantal release of glutamate and postsynaptically by enhancing NMDA receptor subunit functionality, thus regulating calcium entry and promoting actin polymerization to improve structural plasticity [50, 139]. Synthesis of mature BDNF requires enzymatic cleavage of proBDNF, a precursor protein that exists in the endoplasmic reticulum at both pre- and postsynaptic terminals. BDNF is packaged in vesicles that are moved to the membrane where some of which constantly release their contents into the extracellular space, but the majority stay at the membrane until exocytosis is initiated by synaptic activity [140, 141]. Mature BDNF binds the extracellular domain of its receptor, TrkB, which can exist either pre- or postsynaptically at glutamate synapses and influence various downstream signaling molecules involved in synaptic plasticity such as the scaffolding protein synapsin-I and the transcription factor CREB [142]. Various events including exercise, introduction to novel environments, and even learning have been reported to boost hippocampal BDNF levels [119, 143, 144] and enhance performance in hippocampus-dependent memory tasks [145, 146]. In the hippocampus, exercise-induced upregulation of BDNF may be responsible for enhanced activation of CaMKII and CREB [6, 11, 14, 15, 147], probably by a mechanism that involves the release of Ca2+ from the intracellular stores through tyrosine kinase B receptor/phospholipase Cγ (TrkB/PLCγ) pathway [148–150]. Exercise can produce persistent increases in phosphorylated (P)-CREB and BDNF levels that last well past the end of exercise period. It seems that the CREB-mediated BDNF expression serves a positive feedback to continue the elevated CREB levels throughout and beyond the exercise period [118, 119, 151]. Exercise improves BDNF transcription [152] and levels [11, 15, 147, 153] in hippocampi of experimental animals and increases its plasma levels in healthy humans [154–156]. A study in a rat model of vascular dementia suggests that exercise delays cognitive decline by enhancing neurogenesis and increasing BDNF expression [157]. Exercise has been reported to increase the availability of key signaling molecules important for learning and memory by increasing CaMKII availability and activity while decreasing levels of the phosphatase calcineurin [6, 14, 118, 158,

159], probably through increasing BDNF levels. For instance, we and others have shown that voluntary or forced exercise stimulates an increase in BDNF gene expression [160–162] and enhanced BDNF protein expression in rat brain cognitionrelated areas [11, 14, 15]. By increasing the BDNF levels, exercise boosts the expression of key presynaptic molecules implicated in synaptic transmission such as synapsin-I and synaptophysin, which are concerned with vesicular function in the presynaptic nerve terminals [163]. These findings are important because they suggest that exercise-induced enhanced BDNF levels support hippocampal neurons in such a way as to allow them to withstand various insults including sleep deprivation, Alzheimer’s disease, and chronic psychological stress [11, 14, 15]. Strangely, the acute aerobic exercise-induced elevated serum levels of BDNF, which originates from human platelets [164–166], does not correlate with changes in neuropsychological and neurophysiological performances of human young adults [167]. Role of Other Neurotrophins The positive effect of exercise on cognitive function may also involve other neurotrophic factors such as the nerve growth factor (NGF), glial cell line-derived neurotrophic factor (GDNF), IGF-1, and VEGF. NGF preferentially binds to transmembrane TrkA receptors [168] and is the principal neurotrophic supporter of cholinergic neurons in the basal forebrain, a brain region essential for learning and memory, which is severely impacted in Alzheimer’s disease [169]. Exercise increases the level of NGF and TrkA proteins [170, 171], which is suggested to improve motor performance in a model of brain ischemia [168] and restore cognitive deficits in aged and streptozotocin-diabetic rats [162, 172–174]. The levels of GDNF are increased during exercise training in both young and aged animals [175]. The exercise-induced enhancement of GDNF levels may be responsible for the neuroprotection seen in rodent models of Parkinson’s disease [176, 177]. Additionally, human mesenchymal stem cells, transfected with GDNF, are able to protect cerebral ischemic rats from injuries, which suggests a novel potential treatment of stroke [178, 179]. However, further functional studies about GDNF are needed before concluding that GDNF may play a role in exercise-induced memory performance. IGF-1 is a potent trophic factor that can act peripherally and centrally [180, 181]. IGF-1 can interact with VEGF to mediate angiogenesis. Both IGF-1 and VEGF levels are known to increase during exercise [182]. At the same time, IGF-1 can modulate the action of exercise-induced BDNF [136]. Thus, it is postulated that IGF-1 maybe the mediator enabling the effect of exercise on brain health via BDNF-related mechanism [66].

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Moderate exercise induces upregulation of VEGF [183]. The angiogenesis that occurs during exercise is stimulated by the upsurge of blood flow to the muscle. This large increase of blood flow substantially increases shear stress in blood capillaries, which increases the release of vasodilators including nitric oxide (NO) and promotes angiogenesis [184]. In addition to causing vasodilatation, NO enhances the expression of VEGF [185]. As expected, however, high-intensity exhaustive types of exercise may compromise VEGF levels [186]. Support for the critical role of VEGF in angiogenesis comes from studies using VEGF-knockout mice where skeletal muscle angiogenesis fails to occur in reaction to prazosinmediated shear stress [187] or muscle overload stretch [188].

Exercise as a Physical Stressor The hypothalamic-pituitary-adrenal (HPA) axis is a critical regulator of the stress response. Both physical and psychological stressors activate the HPA by initiating secretion of the corticotrophin-releasing hormone (CRH) from neurons in the hypothalamus paraventricular nucleus. This hormone is carried by the blood directly to the anterior pituitary to cause discharge of the adrenocorticotropic hormone (ACTH) into the blood circulation. ACTH is transported by the blood to the adrenal cortex where it causes the release of the glucocorticoid cortisol in humans (corticosterone in rodents), which feeds back to inhibit the hypothalamus and pituitary secretions and moderates stress-induced excitability of the amygdala [189] thereby restoring the homeostasis. The site of action for glucocorticoid-mediated termination of the HPA axis activity after exposure to stress has been identified in the medial prefrontal cortex (mPFC) [190]. Glucocorticoids can occur in the blood either free or bound to the corticosteroid-binding globulin (CBG) protein. When stress decreases CBG, which is produced in the liver, the levels of biologically active (free) corticosterone rapidly increase [191]. It has been shown that excessively high glucocorticoid levels are detrimental to memory [192, 193]. Additionally, there seems to be a sex difference in the response to stress/exercise regarding the levels of corticosterone and CBG in rats [194–197]. Both chronic and acute stress increase glucocorticoid blood levels [191, 198–201]. In experiments involving both male and female rats, total serum corticosterone is significantly increased after various exercise regimens [197]. However, we have seen no increase in corticosterone levels in rats after 14 days of daily sessions of treadmill exercise [199]. This suggests that the levels of corticosterone depend on the duration of exercise training, which may indicate adaptation of the HPA to long-term training. Forced treadmill exercise in rats generates both positive and negative physiological consequences. Compared to sedentary controls, exercised rats show less gain in body weight

[199]. However, forced treadmill running also causes potentially negative changes including decreased serum CBG, adrenal hypertrophy, and suppressed lymphocyte proliferation among other effects [202]. Ample evidence suggests that the endocannabinoid (eCB) system may be involved in directing the actions of glucocorticoids on mPFC neuronal activation. Anandamide, an endocannabinoid believed to be involved in psychological and physical types of stress, is inactivated by the enzyme fatty acid amide hydrolase. The concentration of anandamide decreases during prolonged psychological stress [203] as a result of an increase in the enzyme that inactivates anandamide [204]. In contrast, regular aerobic exercise evokes an increase in anandamide levels and elevates brain hippocampal endocannabinoid CB1 receptor density in rats [205, 206]. It has been reported that during a day of rest, there is greater inactivation of cortisol into cortisone in highly trained men compared to the untrained group [207]. Unlike physical stress, individuals with chronic psychological stress show increased cortisol response to awakening (an index of the adrenocortical activity), without increased inactivation of cortisol [208]. Therefore, efficient inactivation of the stress hormones in physically active individuals protects them against the harmful effects of prolonged release of cortisol ([207]; for review, see [209]). Regular exercise is shown by us to normalize the elevated corticosterone levels seen in sleep-deprived rats [210] and by others in aged transgenic mouse model of Alzheimer’s disease [211]. Although voluntary wheel running in C57BL/6J male mice increases BDNF levels and neurogenesis, it elevates corticosterone levels and increases anxiety in the open field, elevated O-maze, and dark-light tests [212]. In contrast, we have shown that regular treadmill exercise in healthy adult rats has no measurable effects on corticosterone levels and does not affect anxiety as measured in the open field, elevated plus maze, and light-dark tests [14, 199]. An important unanswered question is whether long-term regular exercise can increase plasma CBG levels to curtail the free circulating corticosteriods. The answer to this question will have to await future studies.

Exercise and Psychological Stress Psychological stress-induced elevated corticosteroid levels downregulate BDNF expression [213] and impair synaptic plasticity [214]. Animal experiments show that psychological stress markedly impaired spatial memory and LTP in the CA1 region [215] and reduced the basal levels of BDNF protein [216, 217] and adenosine monophosphate-activated protein kinase (AMPK) [217]. Regular exercise can relieve memory deficits and prevent stress-induced reduction of BDNF and AMPK levels [217]. Our experiments in single-prolonged stress (SPS) rat model of posttraumatic stress disorder

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(PTSD) have shown that the anxiety and depression-like behaviors and cognitive deficiency characteristic of this disorder are largely prevented by moderate physical exercise [199]. Likewise, exercise in humans has been reported to alleviate psychological stress, depression, and anxiety, an action that could involve a role for BDNF [218–220]. For example, isolation stress in human (e.g., in simulation of long-term space missions) results in increased salivary cortisol levels accompanied by a decrease in cortical activity. These effects were antagonized by moderate exercise [221].

Exercise and Anxiety The beneficial effects of exercise extend to anxiety and depressive disorders [222–224]. In rodents, exercise can also prevent anxiety-like and defensive behaviors [225, 226]. In rats treated with l-buthionine-(S,R)-sulfoximine (BSO) to induce anxiety-like behavior, moderate treadmill exercise is effective in preventing anxiety [227]. Furthermore, treadmill exercise reverses anxiety caused by social defeat in rats [200]. Interestingly, the beneficial effects of exercise can be realized even on fetuses in utero. Offspring of exercised pregnant mice can later have a positive effect on the ability of the pups to overcome anxiety-inducing situations. When mice pups are separated from their sedentary mothers, they show clear anxiety-like behaviors; however, mice pups separated from their mothers that are exercised during pregnancy show decreased anxiety-like behaviors [228]. The mechanism of anti-anxiety effect of running has been investigated in mice. Exercise seems to improve natural anxiety regulation by enhancing inhibitory GABAergic pathway in the hippocampus of runner mice thereby limiting the excitatory effects of stress on neuron involved in promoting/ maintaining anxiety [229].

The Effect of Regular Exercise on Oxidative Stress In a study that involved administration of BSO, an agent that increases oxidative stress markers, treadmill exercise prevents BSO-induced increase in oxidative stress markers in serum, urine as well as tissue homogenates from various brain regions [227]. Moreover, increased oxidative stress caused by social defeat in rats is reversed by treadmill exercise, most probably by strengthening antioxidant response in the body [200]. Accumulation of ROS is seen with aging, oxidative stressrelated diseases, and neurodegenerative diseases. Excessive amounts of ROS formation can interfere with DNA repair mechanisms and mitochondrial antioxidant defense systems. Moreover, ROS can alter nucleic acids, membrane phospholipids, and proteins, which eventually lead to oxidative stressinduced apoptosis.

It may seem paradoxical that exercise effectively protects the brain while at the same time exercise increases the production of ROS. This paradox can be explained by the Bhormesis^ concept, which proposes that exposure to a low level of toxin may benefit the organism ([230]; for review, see [231]). Exercise of moderate intensity is thought to normalize the ROS levels and reduce oxidative stress [232], whereas intense exercise or a single bout of exercise may induce oxidative damage [233–235]. Aerobic and anaerobic training increase the natural antioxidant system capacity [236] by upregulating the expression of antioxidant enzymes that can counteract the oxidative damage caused by stress and neurodegenerative diseases. For example, the level of glutathione transferase, which degrades the lipid peroxidation product in cells, 4-hydroxynonenal (4HNE), is greatly increased during exercise training [237]. Another mechanism by which exercise can also counteract the detrimental effect of oxidative stress on the brain is by increasing the activity of proteasomal, mitochondrial antioxidant defense mechanisms (superoxide dismutases (SOD), glutathione peroxidase (GSH-Px), and catalase) and DNA-repair enzymes (8-oxoG-DNA glycosylase (OGG1)) whose primary function is the protein quality control. Antioxidant defense is significantly enhanced after exercise training in the brains of diabetic animals [238] or Alzheimer’s disease models [239]. Treadmill-exercised Tg mice reveal an increase in the expressions of antioxidant defense mechanisms SOD-1, SOD-2, and 70-kDa heat shock proteins (HSP-70) [211]. The brain antioxidant system is differentially regulated in various brain areas. For example, SOD activity is notably increased in the corpus striatum and brainstem regions with exercise, whereas hippocampal SOD activity stays low. However, GSH-Px activity is highly enhanced in the hippocampus [240]. Moreover, other studies have shown that exercise decreases oxidative markers such as reactive carbonyl derivatives (RCDs) [235, 241] and free radical elements [21]. Recently, it has been reported that a single bout of exercise significantly increases the activities of SOD and catalase in hypertensive rats [242].

Exercise and Sleep Deprivation Sleep deprivation and circadian rhythm disturbances have been associated with adverse effects on brain function (for review, see [243, 244]). Sleep loss disrupts the efficient consolidation and restructuring of information saved in earlier activated synaptic networks resulting in memory disturbances. This impairment is particularly damaging to the cognition-related hippocampal areas of the brain [243]. Sleep deprivation blocks the acquisition and consolidation of new information causing impairment of situational alertness, which often results in inaccurate decisions [245–248]. Psychostimulants can alleviate the

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effects of sleep loss only for limited periods of time before dose-limiting adverse effects become apparent [249, 250]. Sleep-deprived individuals can easily incorporate exercise into their daily routine, since exercise is a relatively innocuous, nonaddictive activity that is generally beneficial to overall mental, cardiovascular, and metabolic health [4, 251, 252]. Sleep deprivation causes impairment of learning and shortterm and long-term memory in sedentary rats [11, 15, 250, 253–256], which is reversed in treadmill-exercised rats [11, 15, 265]. Human studies have shown that exercise training is invariably beneficial in countering various deleterious effects of sleep deprivation (e.g., [257–260]). Sleep restriction in healthy young adults contributes to somatic symptoms including pain, fatigue, cognitive dysfunction, and negative mood, which are prevented by exercise [257]. In a similar group of individuals, exercise reverses the sleep deprivation-induced diminished release of growth hormone (GH) [258]. Our electrophysiological experiments in anesthetized sedentary rats reveal that sleep loss causes severe impairment of early- (E-LTP) and late-phase long-term potentiation (L-LTP) in hippocampal CA1 and DG areas [11, 250, 253, 254, 261, 266]. However, sleep-deprived rats with prior training on treadmill show normal synaptic plasticity [11, 15, 126, 127]. Exercise produces positive alterations in synaptic plasticity and its causal molecular cascade, which is thought to be through boosting the availability of endogenous BDNF, a positive modulator of neuronal growth and plasticity [151, 159]. These changes improve neuronal networking that eventually leads to enhanced LTP expression and improved animal performance in hippocampus-dependent tasks such as the radial arm maze (RAM), Morris water maz (MWM), and radial arm water maze (RAWM) [6, 11, 15, 116, 139, 173, 262–264]. Interestingly, although sleep deprivation profoundly impacts neural plasticity, it does not seem to impair normal basal synaptic transmission in the hippocampal CA1 and DG areas of sleep-deprived rats [11, 250, 253, 254, 261, 266]. We studied the effect of exercise on cognitive functionrelated signaling molecules in a rat model of REM sleep deprivation (Table 1). In REM sleep-deprived rats in the modified multiple platform (columns in water), the levels of signaling m o l e c u l e s i n c l u d i n g C a M K I I , C a M K I V, C R E B , MAPK/ERK, and BDNF are investigated. Sleep loss causes marked reductions in the phosphorylated forms of these molecules in both CA1 and DG areas of the hippocampus, which are prevented by exercise (Table 1) [11, 15, 126, 128, 129, 265, 267]. Remarkably, we discovered that the levels of calcineurin, a protein phosphatase responsible for dephosphorylating P-CaMKII to its inactive form [268], are not affected by SD or exercise in this rat model (Table 1). Exercise training reduces the sleep deprivation-induced mRNA expression and/or protein content of proinflammatory TNF-α and IL-1β increases in the hippocampus [269]. Sleep deprivation in rats increases serum

corticosterone, causes oxidative damage in the brain, and increases anxiety behavior. Furthermore, sleep deprivation produces an upsurge in protein expression of antioxidant defense enzymes glyoxalase (GLO)-1 and glutathione reductase (GSR)-1 in the hippocampus, cortex, and amygdala. However, we have shown that these effects are not seen in the regularly exercised sleep-deprived group of rats [210]. Results from rodent studies as well as human trials suggest that exercise has the capacity for countering circadian rhythm disruption. This offers therapeutic potential for situations when sleep is not a feasible option, as with medical interns, soldiers, or pilots, where attention to detail, swift and precise actions are vitally required [270, 271].

Exercise in Alzheimer’s Disease Behavioral and psychological symptoms of dementia have been shown to be reduced by exercise [272]. Exercise can enrich and condition the brain to resist neurodegenerative and ischemic insults [9, 20, 51]. The effect of exercise on Alzheimer’s disease (AD) in humans has garnered a considerable amount of attention inasmuch as exercise is able to reduce the negative cognitive effects and delay the onset of the disease [5, 69]. A primary impact of AD in the early stages is on mitochondrial function, which deteriorates further with the progression of the disease ([273–275]; for review, see [276]). In fact, mitochondrial dysfunction is also seen in blood cells and fibroblasts of AD patients [277–281] indicating extensive deterioration. Moreover, AD brains reveal impaired biogenesis and axonal transport of mitochondria [282, 283] as well as a decrease in the levels of mitochondrial uncoupling protein 2 (UCP2) and ubiquitous mitochondrial creatine kinase (uMtCK) molecules involved in energy-balancing mechanism [284, 285]. AD pathology severely compromises the integrity of the nucleus basalis of Meynert, a major site of production of the neurotransmitter acetylcholine (ACh) in the brain; hence, AD patients display substantial bilateral gray matter loss in the substantia innominata, which correlates with cognitive impairment [286]. Cerebral blood flow regulation, learning and memory, and synaptic plasticity are some of the important brain functions where ACh and its receptors play an important part. Exercise has been shown to improve ACh-induced vasodilation [242], which may in turn result in better behavioral performance [287]. It has been suggested that the well-known role of ACh in synaptic plasticity is linked to the action of BDNF and/or GDNF [288]. The hippocampus is essential for the ability to remember episodes and experiences known as Bepisodic memory^ (for review, see [289]). This vital brain structure is one of the earliest structures to succumb to Alzheimer’s disease and other types of dementias in humans and animal models of the

Mol Neurobiol Table 1 Summary of the effects of regular exercise and/or SD on the basal levels of signaling molecules important for neuroplasticity

Exercised/normal

Sedentary/sleep deprived

Exercised/sleep deprived

CA1 area

DG area

CA1 area

DG area

CA1 area

DG area

Phospho-CaMKII

Increased*

Normal

Decreased*

Decreased*

Normalized

Normalized

Total CaMKII

Normal

Normal

Decreased*

Decreased*

Normalized

Normalized

Calcineurin

Normal

Normal

Normal

Normal

Normal

Normal

Phospho-CREB Total CREB

Increased* Normal

Increased* Normal

Decreased* Decreased*

Decreased* Decreased*

Increased* Normalized

Increased* Normalized

CaMKIV Phospho MAPK/ERK

Normal Increased*

Normal Increased*

Decreased* Decreased*

Decreased* Normal

Normalized Increased*

Normalized Increased*

Total MAPK/ERK

Increased*

Increased*

Normal

Normal

Increased*

Increased*

BDNF

Increased*

Increased*

Decreased*

Decreased*

Increased*

Increased*

Protein levels of P-CaMKII, total CaMKII, calcineurin, BDNF, P-CREB, total CREB, CaMKIV, P-MAPK/ERK, and total MAPK/ERK in the CA1 or DG hippocampal areas of sleep-deprived, exercised, and exercised/sleepdeprived rats are compared to those of the sedentary control rats with significance (*) at p < 0.05–0.001. Adopted from [11, 15, 126–128, 263, 269, 275]

disease [263, 290, 291]. In a rat model of AD, we and others have reported that treadmill exercise regimen (4 weeks) prevents cognitive and noncognitive disturbances caused by 14day infusion of amyloid beta42 (Aβ1–42). In this model, learning and memory are tested in water mazes where the results show that Aβ1–42 treatment markedly impairs the ability of the animals to learn and remember, as both spatial short-term and long-term memory are severely compromised [263, 292–295]. Exercise alleviates memory impairment in these rats [263, 295, 296]. In the same rat model, in vivo electrophysiological experiments show severe impairment of the cellular correlates of memory, E-LTP and L-LTP, in hippocampal area CA1 [263, 295, 297], and dentate gyrus [6, 263]. Regular treadmill

Table 2 Summary of the effects of regular exercise on the basal levels of signaling molecules in a rat model of AD

exercise prior to and during the infusion of Aβ1–42 prevents these functional deleterious effects in AD rats [6, 263, 295]. In addition, exercise prevents impairment of basal synaptic transmission in these areas of the hippocampus of AD rats [6, 14]. Noncognitive functions such as emotions, olfactory function, gait, and balance are also negatively impacted at all stages of AD [298, 299]. Animal models of AD reveal profound disturbances of noncognitive functions that can be reversed or prevented by exercise. In the open field test, AD animals show marked deficiencies in performance; for example, rats show reduced time spent in the center area of the open field indicating increased anxiety. However, this increase in anxiety is not seen in exercised AD rats [14, 296]. Similar prevention of anxiety is seen in other tests including light-

Exercise/normal

Sedentary/AD

Exercise/AD

CA1 area

DG area

CA1 area

DG area

CA1 area

DG area

Phospho-CaMKII Total CaMKII

Normal Normal

Normal Normal

Decreased* Normal

Decreased* Normal

Normalized Normal

Normalized Normal

Calcineurin Phospho-CREB Total CREB CaMKIV Phospho MAPK/ERK Total MAPK/ERK BDNF APP BACE-1

Normal Normal Normal Normal Normal Normal Increased* Normal Normal

Normal Normal Normal Normal Normal Normal Increased* Normal Normal

Increased* Decreased* Normal Decreased* Normal Normal Decreased* Increased* Increased*

Increased* Decreased* Normal Decreased* Normal Normal Decreased* Increased* Increased*

Normalized Normalized Normal Normalized Normal Normal Increased* Normalized Normalized

Normalized Normalized Normal Normalized Normal Normal Increased* Normalized Normalized

Protein levels of signaling and AD-related molecules in the CA1 and DG hippocampal areas are compared to levels in sedentary normal control rats with significance (*) at p < 0.05–0.001 when increased or decreased. Adopted from [6, 274, 302, 314]

Mol Neurobiol

dark and elevated plus maze (EPM) tests. Interestingly, however, the reduced total activity or total time moving seen in AD rats in these tests is not prevented by exercise [14, 296]. The seemingly impaired locomotor activity in AD rats could be due to lack of motivation rather than motor dysfunction inasmuch as these rats ran well on the treadmill (forced exercise) with no obvious motor deficits [155, 300]. The impact of exercise on signaling molecules essential for cognitive functions is also investigated in my laboratory (in the Aβ1–42 rat model: Table 2). In the CA1 and DG areas of sedentary AD rats, the levels of signaling molecules including CaMKII, CaMKIV, CREB, and BDNF are markedly reduced but are normal in regularly exercised AD rats [6, 14, 292, 295, 301]. Furthermore, the phosphatase calcineurin level is increased in this rat model of AD but remains normal in exercised AD rats [155, 295] (Table 2). Regular physical activity in humans is correlated with lower brain Aβ levels, improved immediate recall, and enhanced visuospatial ability [302–305]. Experiments on mouse models of AD confirmed that exercise could reduce Aβ load ([306, 307]; for review, see [308]). Additionally, in the Aβ rat model of AD, the Aβ-induced increases in amyloid precursor protein (APP) and β-secretase (BACE-1) in the CA1 and DG area of the hippocampus were prevented by exercise (Table 2) [309]. Similar findings are reported in other rat models of enhanced Aβ load [310, 311]. In transgenic mice models of AD, treadmill exercise reduces Aβ1–42 deposition through inhibition of BACE-1 in the cortex and hippocampus [306, 312]. Regular exercise is known to increase the level of serotonin (5-HT) and dopamine [313]. At the same time, anandamide, an endocannabinoid that regulates dopamine release, is secreted during exercise training resulting in activation of the endocannabinoid system [314–316]. Thus, by improving the serotonin signaling exercise seems to ameliorate memory impairment associated with AD.

Exercise Mimetics and Brain Function The use of pharmacological agents to imitate the beneficial effects of exercise is very attractive as an alternative to physical exercise, particularly for individuals who are physically impaired. Unfortunately, however, exercise mimetics investigated so far seem to have predominantly local effects on the muscle itself, and in most cases, only when combined with physical exercise do they produce desirable effects such as improved mitochondrial biogenesis in skeletal muscle [317, 318]. The concept of an exercise mimetic that can provide an alternative to physical activity in fostering brain function in aging or neurodegenerative diseases has recently received ample attention. For example, initial reports present some promising results on the effects of agents such as GW501516 and AICAR in improving spatial memory and elevating dentate

gyrus neurogenesis and augmenting genes important for neuronal development and plasticity in the hippocampus [319, 320]. A more recent work from the same group reports that exercise or AICAR results in comparable changes in muscle of rodents; however, longer period of treatment with AICAR (14 days) results in negative effects on the brain including upregulation of markers of apoptosis and inflammation [321]. Nevertheless, exercise mimetics seem to be more promising in ameliorating certain peripheral conditions such as diabetes and skeletal muscle pathology [322–325].

Concluding Remarks There is general agreement that regular moderate exercise has a substantial neuroprotective/neurorestorative impact on brain function. Evidence from both human and animal experiments for the beneficial effects of exercise on brain function is overwhelmingly convincing. Numerous studies provide convincing evidence indicating that exercise can amend metabolic, structural, and functional aspects of the brain that preserve cognitive performance and may reverse impairment in those with cognitive impairments particularly older individuals. Thus, utilizing exercise to improve cognitive abilities has been successful in a variety of brain disorders including AD, sleep deprivation, stress, depression, and anxiety. Thus, exercise offers extensive mental health benefits that merit its regular use as a low-cost, low-risk intervention. Review of data presented in this review suggests that exercise programs that include both aerobic and anaerobic such as resistance training may produce better results for the neuroprotective action of exercise. However, a number of aspects of the effects of exercise remain unresolved. For example, the exact mechanism of the neuroprotective effect of exercise and how muscle activity is communicated to the brain are still uncertain and warrant further exploration. Additionally, the field of study of exercise mimetics is still in the nascent stages and will require further work to address a number of concerns that so far remain unresolved regarding high dosage requirement, untoward effects, and toxicity, which render them clinically unfeasible at this time.

Acknowledgements This work is supported by various University of Houston internal grants.

Compliance with Ethical Standards Conflict of Interest interest.

The author declares that he has no conflict of

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