Neurobiology of Learning and Memory 80 (2003) 123–129 www.elsevier.com/locate/ynlme
Pre-training prevents context fear conditioning deficits produced by hippocampal NMDA receptor blockade Matthew J. Sanders* and Michael S. Fanselow UCLA Psychology Department, 1285 Franz Hall, Los Angeles, CA 90095-1563, USA Received 15 January 2003; revised 7 March 2003; accepted 10 March 2003
Abstract These experiments explore parallels between the neurobiological substrates of spatial and context learning. Male Long–Evans rats were employed in a context fear conditioning protocol that involved sequential acquisition and testing in two distinct contexts. Rats received three unsignaled footshocks in one context and were tested for context fear, measured as freezing, the next day. Four days later, the procedure was repeated in a different, distinct context. Rats received a hippocampal infusion of either the NMDA receptor antagonist 5-amino-phosphonovaleric acid (APV, 10 lg) or vehicle prior to training in each context. NMDA receptor blockade was effective in impairing context learning only in the first context. Context fear acquisition was not impaired by APV in the second context, indicating that pre-training (in the first context) mitigated the effects of APV. These data agree with those seen previously in the water maze, where pre-training prevented learning deficits produced by NMDA receptor blockade. The data thus suggest that the neurobiological substrates of context learning and place learning overlap. Ó 2003 Elsevier Science (USA). All rights reserved. Keywords: Learning and memory; Pavlovian conditioning; Context fear; Hippocampus; APV
1. Introduction The behavioral, neurochemical, and neuroanatomical substrates of Pavlovian context fear conditioning are remarkably similar to those of spatial navigation. Spatial exploration and learning likely play large roles in the abilities of animal to learn about the safety of specific environments and to learn about avoidance of predation. Not surprisingly, spatial learning and context learning employ many of the same anatomical and transmitter systems. Substantial evidence implicates the rodent hippocampal formation in learning about spatial relations and in performance of spatial tasks. Many cells in the hippocampal formation respond to spatial stimuli (OÕKeefe & Dostrovsky, 1971; OÕKeefe & Nadel, 1978) and lesions of the hippocampal formation impair spatial learning (Morris, Garrud, Rawlins, & OÕKeefe, 1982; OÕKeefe, Nadel, Keightley, & Kill, 1975). Hippocampal lesions impair Pavlovian
* Corresponding author. Fax: 1-310-206-5895. E-mail address:
[email protected] (M.J. Sanders).
context fear conditioning as well (Kim, Rison, & Fanselow, 1993; Phillips & LeDoux, 1992; Young, Bohenek, & Fanselow, 1994). Additionally, spatial navigation in the rat is affected by manipulations of glutamatergic transmission. NMDA receptor blockade, through intracerebroventricular infusion of 5-aminophosphonovaleric acid (APV), impairs acquisition in the water maze (Cain, Saucier, Hall, Hargreaves, & Boon, 1996; Morris, 1989; Morris, Anderson, Lynch, & Baudry, 1986). NMDA receptor blockade, induced by intracerebroventricular APV (Fanselow, Kim, Yipp, & DeOca, 1994; Kim, DeCola, Landeira-Fernandez, & Fanselow, 1991; Young et al., 1994), impairs acquisition of Pavlovian context fear. Thus it appears that the processes of water maze and context learning may be served by similar substrates. Importantly, the function of these transmitter processes and their specificity to spatial learning per se remain a matter of debate. In fact, recent data indicate that the role of glutamatergic transmission in water maze learning may be much more complicated than thought previously. The function of NMDA receptormediated processes may extend beyond spatial learning
1074-7427/$ - see front matter Ó 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S1074-7427(03)00040-6
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to include at least motor learning and strategy learning (Cain et al., 1996; Saucier, Hargreaves, Boon, Vanderwolf, & Cain, 1996; Whishaw & Petrie, 1988; Whishaw & Tomie, 1987). The specificity of the role of these processes has been examined with the use of detailed behavioral protocols that examine the subtle non-spatial behavioral effects of drug manipulations. NMDA receptor blockade, via administration of APV, prevents acquisition of the hidden version of the water maze task. However, non-spatial pre-training in the water maze can reduce or prevent the behavioral abnormalities and acquisition deficit that normally is produced by NMDA receptor blockade (Bannerman, Good, Butcher, Ramsay, & Morris, 1995; Cain et al., 1996; Saucier et al., 1996). Pre-training may allow the acquisition of some non-spatial component of the task or may attenuate a sensory or motor deficit caused by the drug (Bannerman et al., 1995; Cain et al., 1996). While a number of obvious differences exist between context fear and spatial water maze navigation, we see a number of parallels between the two. The current studies were undertaken to further examine the parallels between context and space learning and to investigate possible non-context, sensorimotor explanations for the context learning deficit produced by NMDA receptor blockade. We undertook an examination of pre-training effects on context fear acquisition under receptor blockade. Our method involved context pre-training in one distinct conditioning chamber and then acquisition in a separate chamber under the influence of APV. Our design allowed us to investigate the context deficits produced by APV during the pre-training phase and the effect of the pretraining phase on later acquisition under the influence of APV.
2. Method 2.1. Subjects Twenty-four female Long–Evans rats, weighing 300– 350 g at the time of surgery, served as subjects. All rats were bred and housed in the psychology department vivarium at UCLA. Animals were housed under a 14:10 day:night cycle (lights on 7 AM) with ad libitum access to food and water. All surgical and behavioral procedures were conducted during the day portion of the cycle. Rats were handled daily for 5 days prior to surgery and for 5 days preceding behavioral procedures. All procedures were conducted in accordance with the UCLA ChancellorÕs Animal Research Committee, the US Public Health Service ‘‘Policy on Humane Care and use of Laboratory Animals,’’ and the National Institutes of Health ‘‘Guide for the Care and Use of Laboratory Animals.’’
2.2. Surgery Each animal was anesthetized with 50 mg/kg sodium pentobarbital and treated with 0.4 mg/kg atropine sulfate. Once anesthetized, each rat was placed in a stereotaxic frame. The scalp was incised and the skin and fascia were retracted. Two holes were made in the skull overlying the dorsal hippocampus. A stainless steel guide cannula (26 gauge; Plastics One, Roanoke VA) was lowered into each hemisphere (coordinates 3.5 mm posterior, and 2:5 mm lateral from bregma, and 3.2 mm ventral from skull surface). Three jewelerÕs screws were implanted in the skull and served as anchors. Dental acrylic was poured around the guide cannulae and screws. Antibiotic ointment was applied to the wound and animals were allowed to recover on a water-circulating heating pad until awake. Dummy cannulae were placed in the guide cannulae to prevent the entry of foreign materials. Beginning 48 h after surgery, the dummy cannulae were changed daily with clean cannulae. Behavioral procedures began 7 days after surgery. 2.3. Apparatus The design of the study entailed two phases, a PreTraining Phase and an Experimental Phase. During each phase, animals were trained in a Pavlovian context fear conditioning task in a unique context. Within each phase, context fear was assessed 24 h after training. Training and testing during the Pre-Training Phase took place in four cubical chambers (28 cm 21 cm 21 cm) labeled Context A. Context A was characterized by a flat grid floor, bright lights, background noise produced by a box fan (60 dB), and a distinct ammonia odor (5% ammonium hydroxide used to clean the chambers and line the waste pans below the chambers). The floor of Context A consisted of 18 stainless steel rods, spaced 15 mm center to center. Training and testing during the Experimental Phase took place in four triangular prism-shaped chambers labeled Context B. These chambers had a square floor (21 cm 21 cm) and a triangular insert that altered the overall shape and volume of the chamber (walls at approximately 60°). Context B was characterized by a staggered grid floor, low light (red lights provided the only illumination), background noise provided by a white noise generator (55 dB), and a distinct acetic odor (1% acetic acid solution used to clean the chambers and line the waste pans below the chambers). The floor of Context B consisted of two staggered rows of stainless steel rods, spaced 25 mm center to center within each row. Drug administration was performed in a room separate from both Context A and Context B. Animals were transported from the vivarium to the drug room in their home cages. After drug administration, animals were carried to the conditioning chambers by the experimenters.
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2.4. Drug administration For the Pre-Training Phase, rats were assigned randomly to receive either 5-amino-phosphonovaleric acid (APV; Sigma, St. Louis, MO) or Artificial Cerebrospinal Fluid vehicle (ACSF; Harvard Apparatus, Holliston, MA). APV was dissolved in ACSF vehicle. On the training day, animals were brought from the vivarium into the laboratory in their home cages. In squads of 4, they were placed in holding containers (15 cm 25 cm 35 cm). The dummy cannulae were removed and injection cannulae (33 gauge, Plastics One, Roanoke, VA) were inserted. Injection cannulae extended 0.5 mm beyond the guide cannulae. The injection cannulae were connected to 10-ll Hamilton syringes mounted in a Harvard Infusion Pump (Harvard Apparatus, Holliston, MA). ACSF or APV (2.5 lg/ll) was infused over 5 min at a rate of 0.4 ll/min (resulting in a final dose of 10 lg of APV per rat). Injection cannulae were left in place for 1 min after the infusion. After removal of the injection cannulae, the dummy cannulae were replaced and the rat was transferred immediately to the conditioning chamber. For the Experimental Phase, animals were re-assigned randomly to either the ACSF or APV groups, creating a 2 2 factorial design for the Experimental Phase (Pre-Training Phase Drug Experimental Phase Drug). The drug administration protocol for the Experimental Phase was identical to that of the Pre-Training Phase. 2.5. Behavioral procedure The Pre-Training Phase began 7 days after surgery. After drug administration, animals were placed in Context A. Three minutes after placement, animals received a series of three footshocks (1 mA, 1 s shocks with a 20 s inter-shock interval). Thirty seconds after the final footshock, animals were returned to their home cages. Twenty-four hours later, each animal was returned to the exact chamber where it received footshock for a context fear test. For 8 min, each subject was scored for freezing behavior, a species-specific defense response of the rat that serves as a reliable indicator of fear. Each animal was scored every 8 s in an instantaneous timesampling procedure. Freezing was defined as absence of all movement (including movement of vibrissae) save that required for respiration. The observer was blind to the treatments received during the conditioning session. Four days after the Pre-Training context test, the Experimental Phase of the experiment began. Animals were pair-matched for their performance in the context test of the Pre-Training Phase. Within each pair, animals were randomly assigned to receive either APV or ACSF during the conditioning session of the Experimental Phase. Animals were returned to the drug administration room and given either ACSF or APV in a manner
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identical to that of the Pre-Training Phase. After drug infusion, animals were placed in Context B for conditioning. After 3 min, animals received a series of three footshocks (again 1 mA, 1 s shocks with a 20 s intershock interval). Thirty seconds later, animals were removed from the chambers and placed in their home cages. The next day, animals were returned for the context fear test. Again, observations of each animal were made every 8 s for a period of 8 min. During all phases of the study, behavior was recorded on VHS tape. Later, freezing observations were made of the preshock and post-shock periods of the conditioning phase. 2.6. Histology After the completion of the Experimental Phase, all animals were sacrificed with an overdose of sodium pentobarbital. At the time of sacrifice, cresyl violet was infused through injection cannulae placed in the same location as those used for drug delivery. This procedure was used only to clarify the injection site, as no assumptions were made concerning the similarity of diffusion by cresyl violet and the drugs used in the study. 2.7. Analysis For all measurements in the Pre-Training Phase, a two-tailed t test was used to test statistical significance, with a set at 0.05. Results from the Experimental Phase initially were analyzed with a two-way Analysis of Variance with a set at 0.05.
3. Results Histological examination resulted in the removal of two animals from the data set. One animal showed abnormal enlargement of the ventricles. The cannula placement on the other animal was well dorsal to the hippocampus. All data and figures represent results obtained from the remaining 22 animals. Fig. 1 depicts
Fig. 1. Cannula placement. The figure depicts a representative histological section. Cannulae were placed successfully in 23 of the 24 animals.
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cannula placement in an animal that is representative of the remaining 21 rats. 3.1. Pre-Training Phase On the conditioning day of the Pre-Training Phase, freezing was measured during the 30-s post-shock period as a measure of conditioned fear of the context (Fanselow, 1980). Fig. 2A depicts the freezing during the post-shock period. Both the ACSF and APV groups showed significant context fear during the training session. The groups did not differ significantly during the training session ½F ð1; 20Þ ¼ 0:48. Twenty-four hours after the training session, animals were returned to the conditioning chamber for an 8 min test. Fig. 2B depicts the freezing during this context test. During this test, both groups showed some fear of the context. However, APV animals showed significantly reduced amounts of freezing compared to ACSF animals [F ð1; 20Þ ¼ 5:98, p < :05]. This pattern of results, with intact post-shock fear but impaired long-term fear, is identical to those that we have achieved before with a similar design (Young et al., 1994).
in a separate context. A 2 2 factorial ANOVA was employed to examine the influence of both the drug given during this phase of the experiment and the drug given during the Pre-Training Phase. Pre-shock freezing was measured as an indicator of context generalization. That is, the uniqueness of the second context was examined by assessing fear to the second context. Fig. 3A depicts the pre-shock freezing. The drug condition during pre-training had no effect on baseline freezing [F ð1; 18Þ ¼ 4:22, p > :05] and did not interact with the drug condition during the Experimental Phase [F ð1; 18Þ ¼ 2:63, p > :05]. Thus, when given at the time of training in the Experimental Phase, APV had no effect on generalization between Context A and Context B. Fig. 3B depicts the amount of post-shock freezing during the training session of the Experimental Phase. The ANOVA revealed that the APV-treated animals froze less after shock than did ACSF-treated animals [F ð1; 18Þ ¼ 4:55, p < :05]. Pre-training drug condition A
3.2. Experimental Phase Four days after the Pre-Training Phase, animals were given ACSF or APV and trained in an identical fashion
A
B
C B
Fig. 2. Freezing observed during the Pre-Training Phase. (A) Freezing levels in the immediate post-shock period during acquisition. APV animals and ACSF animals did not differ on this measure. (B) Freezing levels in the 24-h context test. In this test, APV animals showed a significant deficit in context fear.
Fig. 3. Freezing observed during the Experimental Phase. (A) Freezing during the pre-shock period. Animals did not show fear to the new context and the groups did not differ on this measure. (B) Freezing levels in the immediate post-shock period during acquisition. (C) Freezing levels in the 24-h context test. APV treatment during the Experimental Phase reduced post-shock freezing but had no effect on freezing at 24 h.
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had no significant effect [F ð1; 18Þ ¼ 1:16, p > :05] and did not interact with the drug condition in the Experimental Phase [F ð1; 18Þ ¼ 2:5, p > :05]. Twenty-four hours after training, the animals were returned to Context B for an 8 min test. Fig. 3C depicts the freezing scores during this test. ACSF and APV animals showed similar levels of fear during the context test [F ð1; 20Þ ¼ 0:60]. Drug condition in the Pre-Training Phase had no effect [F ð1; 18Þ ¼ 0:88] and did not interact with drug condition during the Experimental Phase [F ð1; 18Þ ¼ 0:84]. Thus, APV failed to affect context fear in animals that had been trained previously in a separate, distinct context.
4. Summary and discussion In the Pre-Training Phase, APV produced a deficit in context fear acquisition that was comparable to deficits seen previously in this laboratory. While post-shock fear remained in tact, long-term fear was impaired. However, training in a second context was not impaired by APV. Thus, context Pre-Training prevented the deficit in context fear normally produced by APV. The factorial analyses indicated that the pre-training treatment was effective in alleviating the deficit regardless of drug condition during that treatment. Context fear conditioning is similar to spatial learning in many respects. Both are dependent on the hippocampus (Kim et al., 1993; Morris et al., 1982; OÕKeefe et al., 1975; Phillips & LeDoux, 1992) and both involve NMDA receptor-mediated transmission (Morris et al., 1986; Young et al., 1994). Both are susceptible to the effects of pre-training. We discovered that context fear conditioning, like water maze learning, is impaired by APV only in the absence of previous conditioning. While fear conditioning demonstrates this surface similarity to spatial learning, we believe that the underlying mechanism of the pre-training effect may differ from that seen in spatial learning. NMDA receptor antagonism causes clear sensorimotor disturbances. In the water maze literature, investigators have argued that APV causes sensorimotor disturbances that impair the ability of the animal to learn the myriad non-spatial requirements of the task (Cain et al., 1996). We infused a total dose of 10 lg of APV into the hippocampi of each rat, in order to replicate conditions under which we previously have revealed an APV deficit in context fear conditioning (Young et al., 1994). Previous reports indicate that this dose (when given intracerebroventricularly), produces mild hyperactivity and mild ataxia (Cain et al., 1996). During the pre-shock period, we often observe APV-treated animals making foot faults or demonstrating slight ataxia. Thus, we must first rule out performance accounts of our deficit before making any strong conclusions about the role of NMDA re-
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ceptors in context fear acquisition per se. For at least two reasons, performance effects cannot account for the deficit that we see in context fear caused by NMDA receptor blockade. First, all animals demonstrated short-term memory for context fear in the Pre-Training Phase of the study regardless of NMDA receptor blockade. That is, post-shock freezing evidenced acquisition and performance of the conditional freezing response under NMDA receptor blockade. Thus, any sensorimotor deficit caused by NMDA receptor blockade failed to interfere with both the criterion behavior and the short-term retention of the fear memory. However, NMDA antagonism did interfere with the long-term storage of that fear memory. Second, all animals were tested free of NMDA antagonism during both phases of the study. During the Pre-Training Phase of the study, APV-treated animals demonstrated little long-term memory of context fear despite being tested in a drug-free state. Thus, the animals performed perfectly well under the influence of APV yet failed to demonstrate fear 24 h later. In the Experimental Phase of the study, animals demonstrated both short- and long-term memory for the context-shock association despite NMDA receptor blockade during acquisition. Therefore, only a mnemonic effect of NMDA receptor blockade can explain the dissociation between shortand long-term memory in our task and the elimination of that dissociation by pre-training. In short, the pretraining effect seen in fear conditioning mimics that seen in the water maze but the underlying mechanism must be fundamentally different. Others have discovered genetic distinctions between water maze and context fear learning that may entail differences at the sensory, motor, or mnemonic level (Owen, Logue, Rasmussen, & Wehner, 1997). There are some similarities and differences between our results and those of Lee and Kim (1998), who employed a similar design with APV infusion into the amygdala. In their study, animals were trained in one context drug-free and then in a different context under NMDA receptor blockade. This condition is mimicked in our group of animals that received ACSF infusion into the hippocampus during the Pre-Training Phase and then APV during the Experimental Phase. Their results showed that such animals still showed severe impairments in context fear acquisition during the subsequent training if APV was infused into the amygdala. In contrast, the present results indicate that NMDA receptor blockade in the dorsal hippocampus does not impair context fear acquisition if fear has been acquired previously to a different context. The challenge at hand obviously is to determine exactly what aspects of pre-training prevented the deficit in our APV-treated animals. Our APV-treated animals demonstrated the ability to learn a number of important things under NMDA receptor blockade. First, the
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short-term measure indicates that they were able to store, for at least a short time, information about the context and its association with shock. More importantly, the effect of pre-training on later acquisition demonstrates that APV-treated animals can form longterm memories for at least some aspects of our task. The sequential design of our study allowed us to look at the effects of NMDA receptor blockade on pre-training itself. Pre-training was beneficial to learning in the Experimental Phase regardless of whether the pre-training treatment took place under NMDA receptor blockade or not. In order for this to be the case, animals must have retained some crucial information from the PreTraining Phase despite showing no evidence of context fear 24 h after pre-training. As both APV-treated and ACSF-treated animals benefited from the pre-training, this crucial information must be stored by a mechanism other than NMDA receptor-mediated plasticity in the dorsal hippocampus. Two possibilities should be kept in mind, however. First, the completeness of NMDA receptor blockade in these studies is unknown. The possibility remains that hippocampal tissue, lying outside of the spread of our infusion, could have encoded some aspect of the pre-training event. Additionally, the blockade during the Experimental Phase may have been incomplete. Second, context generalization may have played a role in the benefit of pre-training. We saw very little evidence of generalization between our two contexts. However, the amount of generalization needed to attenuate the detrimental effects of APV remains unknown. The present results leave undetermined exactly which aspects of the Pre-Training Phase prevent APV deficits in later training. It would appear unlikely that simple context exposure could account for the pre-training effects. The contexts used during the two phases were dissimilar and animals in this study and others typically show very little generalization between the two. Our animals, despite their relatively impoverished existence, are exposed to many contexts before taking part in our experiments. Thus, some specific aspect of context fear acquisition, outside of the specific context-shock association, most likely enables the neural circuitry to acquire later associations despite NMDA receptor blockade. Two possibilities are obvious. First, pretraining could enable the hippocampus to function normally despite NMDA receptor blockade. Our working hypothesis is that the hippocampus, through an NMDA receptor-dependent process, forms a representation of the training context that is necessary for context fear acquisition. NMDA receptor-mediated plasticity is essential for this context encoding process. ‘‘Practice,’’ afforded to the hippocampus during pretraining, might enable the hippocampus to process contextual information despite NMDA receptor blockade during later training. Second, pre-training could
enable some other structure to process contextual information in the absence of normal hippocampal function. By this logic, ‘‘practice’’ afforded to some other structure during pre-training would allow it to compensate for the loss of the hippocampus during later training. Future studies must address these possibilities through systematic pre-training with particular aspects of the training situation and site-specific infusions in other structures that might compensate for the loss of hippocampal function.
References Bannerman, D. M., Good, M. A., Butcher, S. P., Ramsay, M., & Morris, R. G. M. (1995). Distinct components of spatial learning revealed by prior training and NMDA receptor blockade. Nature, 378, 182–186. Cain, D. P., Saucier, D., Hall, J., Hargreaves, E. L, & Boon, F. (1996). Detailed behavioral analysis of water maze acquisition under APV or CNQX: Contribution of sensorimotor disturbances to druginduced acquisition deficits. Behavioral Neuroscience, 110, 86–102. Fanselow, M. S. (1980). Conditional and unconditional components of postshock freezing. Pavlovian Journal of Biological Sciences, 15, 177–182. Fanselow, M. S., Kim, J. J., Yipp, J., & DeOca, B. (1994). Differential effects of N-methyl-D -aspartate antagonist D L -2-amino-5-phosphonovalerate on acquisition of fear of auditory and contextual cues. Behavioral Neuroscience, 108, 235–240. Kim, J. J., DeCola, J. P, Landeira-Fernandez, J., & Fanselow, M. S. (1991). N-Methyl-D -aspartate receptor antagonist APV blocks acquisition but not expression of fear conditioning. Behavioral Neuroscience, 105, 126–133. Kim, J. J., Rison, R. A., & Fanselow, M. S. (1993). Effects of amygdala, hippocampus, and periacqueductal gray lesions on short- and long-term contextual fear. Behavioral Neuroscience, 107, 1093–1098. Lee, H., & Kim, J. J. (1998). Amygdalar NMDA receptors are critical for new fear learning in previously fear-conditioned rats. Journal of Neuroscience, 18, 8444–8454. Morris, R. G. M. (1989). Synaptic plasticity and learning: Selective impairment of learning in rats and blockade of long-term potentiation in vivo by the N-methyl-D -aspartate receptor antagonist AP5. Journal of Neuroscience, 9, 3040–3057. Morris, G. G. M., Anderson, E., Lynch, G. S., & Baudry, M. (1986). Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D -aspartate receptor antagonist, AP5. Nature, 319, 774–776. Morris, R. G. M., Garrud, P., Rawlins, J., & OÕKeefe, J. (1982). Place navigation impaired in rats with hippocampal lesions. Nature, 297, 681–683. OÕKeefe, J., & Dostrovsky, J. (1971). The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely moving rat. Brain Research, 34, 171–175. OÕKeefe, J., & Nadel, L. (1978). The hippocampus as a cognitive map. Oxford: Clarendon. OÕKeefe, J., Nadel, L., Keightley, S., & Kill, D. (1975). Fornix lesions selectively abolish place learning in the rat. Experimental Neurology, 48, 152–166. Owen, E. H., Logue, S. F., Rasmussen, D. L., & Wehner, J. M. (1997). Assessment of learning by the Morris water task and fear conditioning in inbred mouse strains and F1 hybrids: Implications of genetic background for single gene mutations and quantitative trait loci analyses. Neuroscience, 80, 1087–1099.
M.J. Sanders, M.S. Fanselow / Neurobiology of Learning and Memory 80 (2003) 123–129 Phillips, R. G., & LeDoux, J. E. (1992). Differential contributions of amygdala and hippocampus to cued and contextual fear conditioning. Behavioral Neuroscience, 106, 274–285. Saucier, D., Hargreaves, E. L., Boon, F., Vanderwolf, C. H., & Cain, D. P. (1996). Detailed behavioral analysis of water maze acquisition under systemic NMDA or muscarinic antagonism: Nonspatial pretraining eliminates spatial learning deficits. Behavioral Neuroscience, 110, 103–116. Whishaw, I. Q., & Petrie, B. F. (1988). Cholinergic blockade in the rat impairs strategy selection but not learning and retention of
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nonspatial visual discrimination problems in a swimming pool. Behavioral Neuroscience, 102, 662–677. Whishaw, I. Q., & Tomie, J. (1987). Cholinergic receptor blockade produces impairments in a sensorimotor subsystem for place navigation in the rat: Evidence from sensory, motor, and acquisition tests in a swimming pool. Behavioral Neuroscience, 101, 603–616. Young, S. L., Bohenek, D. L., & Fanselow, M. S. (1994). NMDA processes mediate anterograde amnesia of contextual fear conditioning induced by hippocampal damage: Immunization against amnesia by context preexposure. Behavioral Neuroscience, 108, 19–29.
