Differential effects of predator stress and the antidepressant tianeptine on physiological plasticity in the hippocampus and basolateral amygdala

Stress can profoundly affect memory and alter the functioning of the hippocampus and amygdala. Studies have also shown that the antidepressant tianeptine can block the effects of stress on hippocampal and amygdala morphology and synaptic plasticity. We examined the effects of acute predator stress and tianeptine on long-term potentiation (LTP; induced by 100 pulses in 1 s) and primed burst potentiation (PB; a low threshold form of LTP induced by only five physiologically patterned pulses) in CA1 and in the basolateral nucleus (BLA) of the amygdala in anesthetized rats. Predator stress blocked the induction of PB potentiation in CA1 and enhanced LTP in BLA. Tianeptine blocked the stress-induced suppression of PB potentiation in CA1 without affecting the stress-induced enhancement of LTP in BLA. In addition, tianeptine administered under non-stress conditions enhanced PB potentiation in the hippocampus and LTP in the amygdala. These findings support the hypothesis that acute stress impairs hippocampal functioning and enhances amygdaloid functioning. The work also provides insight into the actions of tianeptine with the finding that it enhanced electrophysiological measures of plasticity in the hippocampus and amygdala under stress, as well as non-stress, conditions.     

Transfer of spatial behavior between different environments: implications for theories of spatial learning and for the role of the hippocampus in spatial learning

In 3 experiments, rats were required to find a submerged platform located in 1 corner of an arena that had 2 long and 2 short sides; they were then trained to find the platform in a new arena that also had 2 long and 2 short sides but a different overall shape. The platform in the new arena was easier to find if it was in a corner that was geometrically equivalent, rather than the mirror image, of the corner where it had previously been located. The final experiment revealed that hippocampal lesions impaired rats' ability to find the platform in these arenas. The results suggest that rats did not use the overall shape of the arena to locate the platform but relied on more local cues and that the hippocampus plays a role in navigation based on these cues.     

Dorsal hippocampus function in learning and expressing a spatial discrimination

Learning to discriminate between spatial locations defined by two adjacent arms of a radial maze in the conditioned cue preference paradigm requires two kinds of information: latent spatial learning when the rats explore the maze with no food available, and learning about food availability in two spatial locations when the rats are then confined in one arm with food and the other with no food. Previous research showed that a functional dorsal hippocampus is not required for latent learning. The present experiments show that it is required for learning about food availability, and during retrieval of both types of information.     

The hippocampus and amygdala mediate the locomotor stimulating effects of corticotropin-releasing factor in mice

We have previously demonstrated that both stress manipulations and corticotropin-releasing factor (CRF) elevate locomotor activity in mice primarily in the center region of an open field. In the present study, other than confirming these findings, we have further examined the roles of the dentate gyrus of the hippocampus, the amygdala, and the caudate nucleus in mediating the locomotor-stimulating effect of CRF. Results indicate that among the areas examined, the hippocampus is the most important neural substrate of the action of CRF. The amygdala is also partly responsible for the behavioral effect produced by CRF. The caudate nucleus, however, although is important in the expression of gross motor activity, is not involved in the effect of CRF on locomotion in mice. The results are compared with those obtained in rats and are discussed in terms of the interactions between CRF and stress.     

Involvement of hippocampal nitric oxide in spatial learning in the rat

Nitric oxide (NO) is thought to be involved in synaptic plasticity contributing to learning and memory in several brain areas including the hippocampus. The hippocampus is believed to have a critical role in the processing of spatial information. But, data on the role of hippocampal NO in spatial learning are not consistent. So the effect of NO synthase (NOS) inhibition in the CA1 region of rat hippocampus on spatial localization was investigated in the Morris water maze (MWM). Male albino Wistar rats cannulated in their CA1 region received bilateral injections of vehicle (saline) or N(omega)-nitro-L-arginine methyl ester (L-NAME), a NOS inhibitor (50, 100 and 200 microg/0.5 microl) through the cannulae 30 min before training each day. Animals were subjected to 5 days of training in the MWM; 4 days with the invisible platform to test spatial learning and the 5th day with the visible platform to test motivation and sensorimotor coordination. The results showed dose-dependent increases (p<0.001) in escape latency, traveled distance, heading angle, and dose-dependent decreases (p<0.01) in target quadrant entries in L-NAME-received groups as compared to the control group. This impairment was reversed by co-administration of mole-equivalent doses of L-arginine (L-Arg), the NO precursor. L-Arg alone at the dose of 129.2 microg, increased heading angle (p<0.01) with no effect on other parameters. On the basis of the present data, it is concluded that processes mediated by NO synthesis in the hippocampus are essentially involved in spatial learning.     

Flavor-illness aversions: potentiation of odor by taste is disrupted by application of novocaine into amygdala

Taste and odor have different properties in toxiphobic conditioning. When each is used alone, taste becomes aversive when followed by immediate or delayed poison, while odor becomes aversive only if followed by immediate poison. However, if odor and taste are presented as a compound and followed by delayed poison, then odor does become aversive when tested alone. It is as if taste has potentiated the odor signal. Several experiments assessed the role of the amygdala in this potentiation effect by anesthetizing the amygdala with 10% novocaine. Novocaine applied 30 min before presentation (Pre-CS) of an odor-taste compound disrupted the potentiated odor aversion but not the taste aversion. In contrast, novocaine applied 1 min after the compound odor-taste or 1 min prior to LiCl poison did not dissociate odor and taste aversions; both odor and taste aversions were facilitated. Novocaine applied 30 min before an odor alone also disrupted an odor aversion induced by immediate LiCl. But identical treatment did not disrupt odor avoidance conditioned by immediate foot-shock, suggesting that amygdala anesthesia does not simply produce anosmia. Pre-CS novocaine treatment also disrupted flavor neophobia prior to conditioning. The results suggest that novocaine applied to the amygdala disrupts the integration of odor with taste and illness during toxiphobic conditioning.     

Knockdown of Nurr1 in the rat hippocampus: implications to spatial discrimination learning and memory

Nurr1 expression is up-regulated in the brain following associative learning experiences, but its relevance to cognitive processes remains unclear. In these studies, rats initially received bilateral hippocampal infusions of control or antisense oligodeoxynucleotides (ODNs) 1 h prior to training in a holeboard spatial discrimination task. Such pre-training infusions of nurr1 antisense ODNs caused a moderate effect in learning the task and also impaired LTM tested 7 d later. In a second experiment, ODN infusions were given immediately after the animals had received two sessions of training, during which all animals showed normal learning. Although antisense treated rats were significantly impaired during the post-infusion stages of acquisition of the task, no group differences were observed during the LTM test given 7 d later. These animals were subjected 3 d later to reversal training in the same maze in the absence of any additional treatments. Remarkably, rats previously treated with antisense ODNs displayed perseveration: The animals were fixated with the previously learned pattern of baited holes, causing them to be significantly impaired in the extinction of acquired spatial preferences and future learning. We postulate that Nurr1 function in the hippocampus is important for normal cognitive processes.     

Rescue of synaptic plasticity and spatial learning deficits in the hippocampus of Homer1 knockout mice by recombinant Adeno-associated viral gene delivery of Homer1c

Homer1 belongs to a family of scaffolding proteins that interact with various post-synaptic density proteins including group I metabotropic glutamate receptors (mGluR1/5). Previous research in our laboratory implicates the Homer1c isoform in spatial learning. Homer1 knockout mice (H1-KO) display cognitive impairments, but their synaptic plasticity properties have not been described. Here, we investigated the role of Homer1 in long-term potentiation (LTP) in the hippocampal CA1 region of H1-KO mice in vitro. We found that late-phase LTP elicited by high frequency stimulation (HFS) was impaired, and that the induction and maintenance of theta burst stimulation (TBS) LTP were reduced in H1-KO. To test the hypothesis that Homer1c was sufficient to rescue these LTP deficits, we delivered Homer1c to the hippocampus of H1-KO using recombinant adeno-associated virus (rAAV). We found that rAAV-Homer1c rescued HFS and TBS-LTP in H1-KO animals. Next, we tested whether the LTP rescue by Homer1c was occurring via mGluR1/5. A selective mGluR5 antagonist, but not an mGluR1 antagonist, blocked the Homer1c-induced recovery of late-LTP, suggesting that Homer1c mediates functional effects on plasticity via mGluR5. To investigate the role of Homer1c in spatial learning, we injected rAAV-Homer1c to the hippocampus of H1-KO. We found that rAAV-Homer1c significantly improved H1-KO performance in the Radial Arm Water Maze. These results point to a significant role for Homer1c in synaptic plasticity and learning.     

Stress during puberty boosts metabolic activation associated with fear-extinction learning in hippocampus, basal amygdala and cingulate cortex

Adolescence is characterized by major developmental changes that may render the individual vulnerable to stress and the development of psychopathologies in a sex-specific manner. Earlier we reported lower anxiety-like behavior and higher risk-taking and novelty seeking in rats previously exposed to peri-pubertal stress. Here we studied whether peri-pubertal stress affected the acquisition and extinction of fear memories and/or the associated functional engagement of various brain regions, as assessed with 2-deoxyglucose. We showed that while peri-pubertal stress reduced freezing during the acquisition of fear memories (training) in both sexes, it had a sex-specific effect on extinction of these memories. Moreover hippocampus, basal amygdala and cingulate and motor cortices showed higher metabolic rates during extinction in rats exposed to peri-pubertal stress. Interestingly, activation of the infralimbic cortex was negatively correlated with freezing during extinction only in control males, while only males stressed during puberty showed a significant correlation between behavior during extinction and metabolic activation of hippocampus, amygdala and paraventricular nucleus. No correlations between brain activation and behavior during extinction were observed in females (control or stress). These results indicate that exposure to peri-pubertal stress affects behavior and brain metabolism when the individual is exposed to an additional stressful challenge. Some of these effects are sex-specific.     

Kindling-induced changes in plasticity of the rat amygdala and hippocampus

Temporal lobe epilepsy (TLE) is often accompanied by interictal behavioral abnormalities, such as fear and memory impairment. To identify possible underlying substrates, we analyzed long-term synaptic plasticity in two relevant brain regions, the lateral amygdala (LA) and the CA1 region of the hippocampus, in the kindling model of epilepsy. Wistar rats were kindled through daily administration of brief electrical stimulations to the left basolateral nucleus of the amygdala. Field potential recordings were performed in slices obtained from kindled rats 48 h after the last induced seizure, and in slices from sham-implanted and nonimplanted controls. Kindling resulted in a significant impairment of long-term potentiation (LTP) in both the LA and the CA1, the magnitude of which was dependent on the number of prior stage V seizures. Saturation of CA1-LTP, assessed through repeated spaced delivery of high-frequency stimulation, occurred at lower levels in kindled compared to sham-implanted animals, consistent with the hypothesis of reduced capacity of further synaptic strengthening. Furthermore, theta pulse stimulation elicited long-term depression in the amygdala in nonimplanted and sham-implanted controls, whereas the same stimulation protocol stimulation caused LTP in kindled rats. In conclusion, kindling differentially affects the magnitude, saturation, and polarity of LTP in the CA1 and LA, respectively, most likely indicating an activity-dependent mechanism in the context of synaptic metaplasticity.     

High-fat diets impair spatial learning in the radial-arm maze in mice

It has been suggested that hyperglycemia and insulin resistance triggered by energy-dense diets can account for hippocampal damage and deficits of cognitive behaviour. We wonder if the impairment of learning and memory processes detected in diet-induced obese (DIO) mice is linked to diet composition itself. With this purpose we have evaluated learning performance in mice undergoing a short-term high-fat (HF) treatment, which leads to a pre-obese state characterized by increased adiposity without significant changes of glucose and insulin plasma levels. C57BL/6J mice were fed either a HF (45 kcal% from fat) or control diet (10 kcal% from fat) during 8 weeks. Learning performance was evaluated by using the four-arm baited version of the eight-arm radial maze test (RAM). Mice were trained to learn the RAM protocol and then memory was tested at different time-points. Time spent to consume food placed in baited arms and errors committed to find them were measured in all sessions. DIO mice significantly spent more time in learning the task and made a greater number of errors than controls. Moreover, retention tests revealed that both working and total memory errors were also more numerous in DIO mice. The current results show that short-term DIO impairs spatial learning and suggest that impairment of hippocampal learning elicited by HF diets might be perceptible before metabolic alterations linked to obesity develop.     

Excitotoxic lesions restricted to the dorsal CA1 field of the hippocampus impair spatial memory and extinction learning in C57BL/6 mice

Recent studies in patients with hippocampal lesions have indicated that the degree of memory impairment is proportional to the extent of damage within the hippocampus. Particularly, patients with damage restricted to the CA1 field demonstrate moderate to severe anterograde amnesia with only slight retrograde amnesia. Comparable results are also seen in other species such as non-human primates and rats; however, the effect of selective damage to CA1 has not yet been characterized in mice. In the present study, we investigated the effects of excitotoxic (NMDA) lesions of dorsal CA1 on several aspects of learning and memory performance in mice. Our data indicate that dorsal CA1 lesioned mice are hyperactive upon exposure to a novel environment, have spatial working memory impairments in the Y-maze spontaneous alternation task, and display deficits in an 8-arm spatial discrimination learning task. Lesioned mice are able to acquire an operant lever-press task but demonstrate extinction learning deficits in this appetitive operant paradigm. Taken together, our results indicate that lesions to dorsal CA1 in mice induce selective learning and memory performance deficits similar to those observed in other species, and extend previous findings indicating that this region of the hippocampus is critically involved in the processing of spatial information and/or the processing of inhibitory responses.     

Facilitation of learning spatial relations among locations by visual cues: Implications for theoretical accounts of spatial learning

Human participants searched in a real environment or interactive 3-D virtual environment open field for four hidden goal locations arranged in a 2 × 2 square configuration in a 5 × 5 matrix of raised bins. The participants were randomly assigned to one of two groups: cues 1 pattern or pattern only. The participants experienced a training phase, followed by a testing phase. Visual cues specified the goal locations during training only for the cues 1 pattern group. Both groups were then tested in the absence of visual cues. The results in both environments indicated that the participants learned the spatial relations among goal locations. However, visual cues during training facilitated learning of the spatial relations among goal locations: In both environments, the participants trained with the visual cues made fewer errors during testing than did those trained only with the pattern. The results suggest that learning based on the spatial relations among locations may not be susceptible to cue competition effects and have implications for standard associative and dual-system accounts of spatial learning.     

Microinjections of leupeptin in the frontal cortex or dorsal hippocampus block spatial learning in the rat

Adult male Long-Evans hooded rats were given bilateral microinjections of 18 mM leupeptin or saline through cannulae implanted with tips aimed at the frontal cortex or CA1 or CA3 hippocampal cell fields. Five minutes following injections animals were allowed to complete an eight-arm radial maze. The acquisition criterion required that the animal make 7 correct choices of the first 8, and 8 correct choices of the first 10, for five consecutive sessions. Leupeptin slowed acquisition of the eight-arm radial maze task when injected into the CA1 and CA3 hippocampal fields or the frontal cortex, but did not influence spontaneous activity. These results suggest that earlier reports of the amnestic effect of leupeptin when administered into the lateral cerebral ventricle may have been due to effects within the cortex and hippocampus. The present experiment represents the first attempt to identify behaviorally those brain areas in which leupeptin acts to alter learning.     

Social learning and acquired recognition of a predator by a marine fish

Predation is known to influence the distribution of behavioural traits among prey individuals, populations and communities over both evolutionary and ecological time scales. Prey have evolved mechanisms of rapidly learning the identity of predators. Chemical cues are often used by prey to assess predation risk especially in aquatic systems where visual cues are unreliable. Social learning is a method of threat assessment common among a variety of freshwater fish taxa, which incorporates chemosensory information. Learning predator identities through social learning is beneficial to na?ve individuals as it eliminates the need for direct interaction with a potential threat. Although social learning is widespread throughout the animal kingdom, no research on the use of this mechanism exists for marine species. In this study, we examined the role of social learning in predator recognition for a tropical damselfish, Acanthochromis polyacanthus. This species was found to not only possess and respond to conspecific chemical alarm cues, but na?ve individuals were able to learn a predators' identity from experienced individuals, the process of social learning. Fish that learned to associate risk with the olfactory cue of a predator responded with the same intensity as conspecifics that were exposed to a chemical alarm cue from a conspecific skin extract.     

Of mice and men: virtual Hebb-Williams mazes permit comparison of spatial learning across species

We developed a computer-generated virtual environment to test humans, for the first time, on the Hebb-Williams mazes. The goal was to provide a standardized test that could be used to directly compare human performance with that of C57BL/6J mice performing in real versions of the mazes. Such a comparison seems crucial if conclusions regarding genetic manipulations of rodents are to be mapped onto human cognitive disorders. The learning curves across species were strikingly similar, lending support to the rodent model of human spatial memory. Humans learned faster than rodents in both the acquisition and the test portions of the protocol, and females of both species were less efficient in solving these problems than males. These results represent the first modern comparison of human and rodent learning that uses the same test of spatial problem solving.     

Prolonged inactivation of the hippocampus reveals temporally graded retrograde amnesia for unreinforced spatial learning in rats

We investigated whether systems consolidation of spatial memory could be detected in a non-navigational, spatial-learning test that takes advantage of rats’ natural propensity to preferentially investigate an object that was displaced relative to spatial cues more than an object that remained stationary. Previous studies using navigational spatial-learning tests have generally failed to reveal temporally-graded retrograde amnesia, possibly because the hippocampus needs to be intact for the retrieval and/or processing of navigational information during the test. In the present study, the hippocampus of rats was kept inactivated, at two sites along its septo-temporal axis (dorsal and intermediate), for four consecutive days, beginning either 3 h or 5 days after familiarization to two identical objects in an open field. Rats that had their hippocampus inactivated beginning 5 days but not 3 h after familiarization showed evidence that they remembered the previous location of the displaced object. The results suggest that systems consolidation of spatial memories can be detected using a non-navigational test of spatial memory.