Journal of Molecular Neuroscience Copyright © 2004 Humana Press Inc. All rights of any nature whatsoever reserved. ISSN0895-8696/04/22:159–166/$25.00
ORIGINAL ARTICLE
Characterization of Neuropeptide Y, Y2 Receptor Knockout Mice in Two Animal Models of Learning and Memory Processing John Paul Redrobe,1 Yvan Dumont,1 Herbert Herzog,2 and Rémi Quirion*,1 1
Douglas Hospital Research Centre, Department of Psychiatry, McGill University, Montreal, Quebec, H4H 1R3, Canada; and 2Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW 2010, Australia Received October 1, 2003; Accepted November 1, 2003
Abstract Neuropeptide Y (NPY) and, in particular, the Y2 receptor subtype, has been suggested to be involved in learning and memory processing. However, the precise role of Y2 receptors in learning and memory remains unclear. In the present study, mice lacking NPY Y2-type receptors were assessed in two animal models of learning and memory processing. We found that NPY Y2–/– mice displayed a deficit on the probe trial in the Morris water maze task, whereas acquisition performance, swim speed, and visible platform performance did not differ significantly between groups. In addition, NPY Y2–/– mice exhibited a marked deterioration in object memory 6 h, but not 1 h, following initial exposure in the object recognition test. Both groups of mice showed similar locomotor activity profiles in a low-stress, open field test. These data support the hypothesis that Y2 receptors are involved in the regulation of learning and memory processing. Index Entries: Neuropeptide Y; Y2 receptors; learning; water maze; object recognition; mice.
Introduction Neuropeptide Y (NPY) is a 36-amino-acid peptide that is widely distributed in the central nervous system. The biological actions of NPY are mediated by the activation of at least five molecularly defined classes of receptors known as the Y1, Y2, Y4, Y5, and y6 receptor subtypes (Michel et al., 1998). Intracerebroventricular administration of NPYhas been shown to stimulate food intake (Stanley and Leibowitz, 1984), inhibit neuronal excitability (Colmers and Bleakman, 1994), and display anticonvulsant effects (Vezzani et al., 1999). Neuropeptide Y is also thought to play a role in the pathophysiology of certain mood disor-
ders, including depression (Stogner and Holmes, 2000; Redrobe et al., 2001, 2002) and anxiety (Heilig et al., 1989, 1992; Kask et al., 2002). Moreover, one of the biological actions of NPY, which has received little attention in recent years, is believed to be its regulatory role in learning and memory processing (Flood et al., 1987; Redrobe et al., 1999). Initial studies demonstrated that NPY displayed antiamnesic effects in mice treated with the protein synthesis inhibitor, anisomycin, or the muscarinic receptor antagonist, scopolamine (Flood et al., 1987). More recently, NPY also attenuated learning impairments induced by the noncompetitive NMDA receptor channel antagonist, dizocilpine (MK-801)
*Author to whom all correspondence and reprint requests should be addressed. E-mail:
[email protected]
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160 (Bouchard et al., 1997). Further support for a physiological role of NPY in cognitive behaviors is found in studies in which passive immunization with NPY antibodies, injected into the hippocampal region, induced amnesia (Flood et al., 1989). Additional experiments have demonstrated that the effects of NPY on cognitive function are region specific (Flood et al., 1989). Injection of NPY into the rostral hippocampus and the septal area was shown to enhance memory retention, whereas NPYinjection into the amygdaloid body and the caudal hippocampus induced amnesia (Flood et al., 1989). Most recently, the development of an NPY transgenic rat has offered an attractive model for study of the effects of this peptide on learning and memory processing (Thorsell et al., 2000). Anatomical mapping studies of these animals have revealed restricted, but highly significant, hippocampal NPY overexpression in NPY transgenic subjects (Thorsell et al., 2000). Surprisingly, NPYtransgenic rats were shown to display deficits in both the acquisition and retention of a spatial memory task (Thorsell et al., 2000). The identity of the specific receptor subtype(s) involved in NPY-induced effects on learning and memory processing remain unclear, although some evidence suggests that the ability of NPY to enhance learning and memory might be linked to activation of NPY Y2 receptor subtypes (Morley and Flood, 1990; Heilig, 1993; Nakajima et al., 1994). In situ hybridization studies have shown that Y2 receptor mRNAis discretely localized in the rat brain, including comparatively high levels in the hippocampus (Dumont et al., 1997, 2000; Gustafson et al., 1997). In addition, radioligand binding experiments have demonstrated that Y2 receptors seem to be the predominant NPY receptor subtype in hippocampal formation (Dumont et al., 1997, 2000), in which they have generally been assumed to be presynaptic receptors that negatively modulate glutamatergic neurons (Colmers and Bleakman, 1994) and possibly NPY release (King et al., 2000; Weiser et al., 2000). Despite previous attempts, the precise role of NPY (and, in particular, the role of the Y2 receptor subtype) in learning and memory processing remains to be established clearly. Hence, we decided to test NPY Y2 receptor knockout mice (Baldock et al., 2002; Sainsbury et al., 2002; Smith-White et al., 2002), in two animal models often used for the study of learning and memory: the Morris water maze task (Morris et al., 1982); and the object recognition test (Ennaceur et al., 1988; Vaucher et al., 2002a, 2002b).
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Materials and Methods Animals Adult male NPYY2–/– (receptor knockout) and NPY +/+ Y2 (wild-type control) mice (weighing 28–30 g at time of testing; C57/Bl6-129SvJ background) were used throughout this study. Animals were developed as mice described previously (Baldock et al., 2002; Sainsbury et al., 2002; Smith-White et al., 2002). They were singly housed under standard laboratory conditions (12-h light/12-h dark cycle, lights on at 0700, food, and water ad libitum). Each experimental group consisted of eight mice, and animal care was provided according to protocols and guidelines approved by McGill University and the Canadian Council of Animal Care. Morris Water Maze Task The water maze test was performed as described previously (Morris et al., 1982). The experimental apparatus consisted of a circular pool (diameter: 120 cm) filled with tap water, made opaque with powdered milk, and maintained at 24 ± 1°C. The escape platform (diameter: 8 cm) was hidden 0.5 cm below the surface of the water and remained in a fixed position throughout acquisition training. NPY Y2–/– and Y2+/+ mice were given 4 trials per day over 4 consecutive days (16 trials in all). For each trial, the mouse was placed in the pool (facing pool wall) at one of four selected starting points (north, south, east, or west pole). On locating the platform, the mouse was allowed to remain there for 15 s before being returned to its home cage. If the mouse did not find the platform within 60 s, it was set on the platform by hand and allowed to remain there for 15 s. Mice were gently restrained so as to avoid them jumping back into the water. An intertrial period of 10 min was employed throughout the study. The escape latency and swim speed were measured by a video tracking system connected to a computer equipped with the commercially available HVS image system (HVS, Buckingham, UK) for the analysis of Morris water maze performance. On the fifth day, a probe trial (60 s) was performed with the platform removed from the pool. The number of crossings through the original platform position (target area), the heading direction relative to an ideal path to the original platform position, and the Gallagher Proximity Measure were recorded. The proximity measure is not only sensitive to how long the animal swims to find a target but also to where it is in relation to the target during swimming. This measure
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Y2 Receptors and Learning Memory Processing has been shown to better separate spatial and nonspatial strategies over a given time period (Gallagher et al., 1993). Afterward, mice were subjected to another trial in which the platform (placed in its original position) was made visible above the water surface.
Object Recognition Test The test employed was essentially similar to that described elsewhere (Ennaceur et al., 1988; Vaucher et al., 2002a, 2002b). NPY Y2–/– and Y2+/+ mice were tested for object recognition in clear plastic small animal cages (36 × 22 × 25 cm). For each animal, one pair of objects was selected at random from a set of four objects that differed in shape, surface color, contrast, and texture. The four objects were selected from a larger pool of objects based on the criterion that mice would spend approximately equal time exploring each of the objects. Mice were habituated to the test chamber/environment over four daily sessions of 15 min. On the test day, two identical objects were placed on the center line of the long axis of the chamber floor, 5 cm from each cage end. Mice were allowed to explore the two objects for 5 min, and exploratory activity (i.e., the time spent exploring each object) was recorded. After a delay of 1 or 6 h, mice were re-exposed to a familiar object (from acquisition phase), together with a novel object (not used in acquisition phase). Once again, the time that each animal spent exploring each object was measured. A mouse was considered to be engaging in exploratory behavior if the animal touched the object with its forepaw or nose, or sniffed at the object within a distance of 1.5 cm. Testing was performed by an observer who was unaware of the genotype of the mice. The choice of object for novel or familiar was counterbalanced, and the position of each object was also alternated between trials to avoid any misinterpretation of data. After each exposure, the objects and test chamber were cleaned with 70% ethanol to eliminate odor cues. Separate groups of mice were used for each recognition/retention interval (i.e., 1 or 6 h postacquisition phase). A memory index (MI) was calculated for each mouse, where to represented time exploring the familiar object (from acquisition phase), and tn, the time exploring the novel object (from recognition phase): MI = (tn – to)/(tn + to) (Ennaceur et al., 1988; Vaucher et al., 2002a, 2002b). Locomotor Activity To test locomotor activity, NPY Y2–/– and Y2+/+ mice were tested in the open field (Gray and
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161 Lalljee, 1974). Mice were habituated to the test chamber over 4 daily sessions of 10 min (low stress environment). On the test day, each animal was placed into the center of the apparatus, which consisted of a square base (70 × 70 cm) surrounded by a 75-cm-high wall. Illumination was provided by a 40 W bulb, positioned 90 cm above the floor of the apparatus. Horizontal ambulation was measured, over a 10-min period, by a video tracking system connected to a computer equipped with the commercially available HVS image system for the analysis of open field activity.
Statistics Results are expressed as means ± S.E.M. of (1) escape latency in Morris maze (Fig. 1A), passes through target (Fig. 1B), heading direction (Fig. 1C), average proximity to target (Fig. 1D); (2) MI in the object recognition test (Fig. 1E); and (3) horizontal ambulation in low-stress, open field apparatus (Fig. 1F). Student t-tests were used to assess statistical differences between groups (p < 0.05 considered statistically significant; n = 8).
Results Morris Water Maze Task NPY Y2+/+ and Y2–/– mice showed similar escape latencies to find the hidden platform over 16 training trials. Although there was a tendency for Y2–/– mice to spend more time searching, this trend did not reach statistical significance (Fig. 1A). In a probe trial (conducted 24 h after the last training trial), NPY Y2–/– mice made significantly fewer passes through the original platform position (p < 0.01) when compared to NPY Y2+/+ animals (Fig. 1B). Analysis of the heading direction from the starting point, relative to an ideal path to the original platform position, revealed that NPY Y2–/– mice were significantly inferior to their NPY Y2+/+ counterparts (p < 0.05; Fig. 1C). In addition, NPY Y2–/– mice were found to spend significantly less time in the proximity of the original platform position, as measured by Gallagher’s Proximity Measure, than NPY Y+/+ mice (p < 0.001; Fig. 1D). The Gallagher Proximity Measure is a measure of the average distance of the test subject from the target area over the entire testing period (in this case, 60 s). Analysis of swim speed and visible platform performance did not reveal any significant differences between NPY Y2+/+ and Y2–/– mice (data not shown).
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Fig. 1. (A) Escape latency (s) to find hidden platform in Morris water maze; (B) number of passes through original platform position in the probe trial; (C) heading direction in the probe trial; (D) average proximity to target in the probe trial (cm); (E) MI in the object recognition test; (F) total crossings in a low-stress, open field apparatus. Results are expressed as mean± S.E.M. Student’s t-test was used to assess statistical differences between groups (p < 0.05 considered statistically significant; n = 8).
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Y2 Receptors and Learning Memory Processing Object Recognition Test Figure 1E shows a histogram of memory performance of NPY Y2+/+ and Y2–/– mice at 1 and 6 h after initial exposure to the objects in the object recognition task. Statistical analysis indicated that memory for a previously encountered object deteriorated in NPY Y2–/– mice between 1 and 6 h after the initial exposure (p < 0.01; Fig. 1E). These findings did not seem to be a result of procedural performance variables, as initial phase exploratory activity did not differ significantly between NPYY2–/– and Y2+/+ mice (data not shown). Locomotor Activity Locomotor activity scores, in a low-stress, open field apparatus, did not differ significantly between NPY Y2+/+ and Y2–/– mice (Fig. 1F).
Discussion The findings reported in the present study provide the first demonstration (to the best of our knowledge) of the potential involvement of NPY Y 2 receptors in mnemonic processes using transgenic mice. The experiments thus fill a gap in our current understanding of the role of NPY in learning and memory. This conclusion is drawn from experiments in which adult male mice, deficient in the Y2 receptor subtype, displayed learning deficits in the Morris water maze and the object recognition test. These findings did not seem to be a result of procedural performance variables, as swim speed, visual platform performance (water maze), initial phase exploratory activity (object recognition), and horizontal ambulation in a low-stress open field did not significantly differ between NPYY2–/– and Y2+/+ mice. The Morris water maze task is a behavioral model in which a rat or mouse uses spatial cues to find a hidden platform and is thought to be dependent on the integrative functioning of the hippocampal formation (Morris et al., 1982). The fixed platform version of the test, as used in the present study, is thought to assess the spatial reference memory abilities of the test animal (D’Hooge and De Deyn, 2001). NPY Y2–/– mice did not show any significant deficits in the acquisition of the hidden platform task, when compared to NPY Y2+/+ control groups. These animals were also capable of finding a visible platform, showing escape latencies and swim speeds similar to NPY Y2+/+ mice. However, NPY Y2–/– mice did show deficits in the probe trial, a measure of whether the trained subjects showed a spatial preference for
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163 a previously learned target location (Gerlai, 2001). The precise strategies used by an animal to find the hidden platform have been discussed elsewhere (Poucet, 1993; Whishaw et al., 1995; Gerlai, 2001). However, it is generally agreed that a rodent must use complex extra-maze cue associations (Gerlai, 2001) or path integration (Whishaw et al., 1995) to return to the original platform position on the probe trial. In the present study, analysis of probe trial performance showed that NPY Y2+/+ animals displayed a strong spatial bias to the target quadrant, in that these animals swam directly to, and spent more time in and around, the original platform position. Therefore, it is suggested that NPY Y2+/+ mice demonstrated a stronger cognitive representation for the former platform position. In contrast, deletion of the Y2 receptor in NPY Y2–/– mice seems to have interfered in one, or possibly more, of the cognitive abilities thought to be crucial in the probe trial (e.g., complex extra-maze cue associations or path integration). That is, the strategy used by NPY Y2–/– mice in acquisition training seems to fail in the probe trial, when the platform is no longer available for escape. The possibility that NPY Y2–/– mice employed strategies other than those requiring spatial navigation is also supported by analysis of heading direction. The Y2–/– animals exhibited significantly larger heading angles relative to an ideal path to the target area than did NPY Y2+/+ mice. These findings suggest that hippocampal function is compromised in NPYY2–/– mice and propose a facilitatory role for NPY Y2 receptors in spatial reference learning and memory processing. The object recognition test, on the other hand, is based on the spontaneous, differential exploration of familiar and novel objects and does not depend on spatial cues. This test is thought to allow assessment of subtle changes in nonspatial working memory (Ennaceur et al., 1988; Vaucher et al., 2002a, 2002b). NPY Y 2–/– mice were found to exhibit a marked deterioration in object memory 6 h, but not 1 h, after initial exposure in the object recognition test. This finding implies that NPY Y2–/– mice were unable to retain the memory acquired in the initial phase of the task, the familiar object. Indeed, there are numerous lines of evidence suggesting that NPY does enhance memory retention and that this effect is mediated via Y2 receptors (Morley and Flood, 1990; Heilig, 1993; Nakajima et al., 1994). A series of recent data from rodents with lesions of specific brain regions indicates a significant role for the hippocampus in spatial memory, whereas integrity of medial lobe structures, such as the perirhinal and
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164 entorhinal cortices, seems to be more critical for object recognition (Ennaceur et al., 1996; Ennaceur and Aggleton, 1997; Buckley and Gaffan, 1998; Steckler et al., 1998; Kornecook et al., 1999). Under normal physiological conditions, moderate levels of Y2 receptor binding sites and mRNAs are present in the entorhinal and perirhinal cortices, suggesting a role for Y2 receptors in the normal functioning of these structures (Dumont et al., 2000). Thus, deletion of the Y2 receptor subtype might elicit a detrimental influence on the functioning of medial temporal lobe structures, which leads to a deficit in long-term retention of object memory. A possible confounding factor of these data is that Y2 receptor knockout mice have been reported to display an anxiolytic-like phenotype in certain animal models (Redrobe et al., 2003). Considering that NPY exerts anxiolytic-like effects (Heilig et al., 1989, 1992; Kask et al., 2002) and the hypothesis that blockade/ deletion of the Y2 autoreceptor might increase NPY transmission (King et al., 2000; Weiser et al., 2000), motivational variables could play some part. Another limitation of these studies is the same problem that plagues all experiments involving transgenic animals: It is difficult to determine the precise role of a gene missing throughout development in a behavioral abnormality evident at a later point in life. A possible solution to this problem could be to test the recently developed conditional Y2 receptor knockout mice (Sainsbury et al., 2002) in animal models of learning and memory. Another concern, which is related to that described above, involves the inherent problems in interpreting any experimental manipulation that decreases performance in tests of learning and memory. There are a myriad of factors that might lead to impairments in the tests used that do not specifically involve learning or memory per se; therefore, the influence of other variables (e.g., motivational or attentional) cannot be ruled out. Indeed, selective serotonin reuptake inhibitors, which have been shown to be effective in treating certain anxiety disorders, have recently been shown to induce learning deficits in the Morris water maze task (Majlessi and Naghdi, 2002). On the other hand, the delay-dependent effect observed in the object recognition test provides some compelling evidence of a memory-specific effect. In addition, the number of passes through the target position, the heading direction, and the average proximity to the target position (in the Morris water maze) were all significantly affected by deletion of the Y2 receptor subtype. The motivation to complete the task in
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Redrobe et al. the Morris water maze is largely aversive, and altered sensitivity to stress might therefore affect outcome in this model. However, normal escape latencies were found in Y2–/– mice under visible platform conditions, demonstrating that neither the motivation nor the ability to find the platform was affected by deletion of the Y2 receptor gene. In conclusion, it has been shown that NPY Y2–/– mice exhibited deficits in the Morris water maze and object recognition task, strongly suggesting that Y2 receptors might play an integral role in spatial reference memory and nonspatial working memory processing.
Acknowledgments This work was supported by a grant from the Canadian Institutes for Health Research (CIHR) to R. Q.
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