A key role for nectin-1 in the ventral hippocampus in contextual fear memory

Nectins are cell adhesion molecules that are widely expressed in the brain. Nectin expression shows a dynamic spatiotemporal regulation, playing a role in neural migratory processes during development. Nectin-1 and nectin-3 and their heterophilic trans-interactions are important for the proper formation of synapses. In the hippocampus, nectin-1 and nectin-3 localize at puncta adherentia junctions and may play a role in synaptic plasticity, a mechanism essential for memory and learning. We evaluated the potential involvement of nectin-1 and nectin-3 in memory consolidation using an emotional learning paradigm. Rats trained for contextual fear conditioning showed transient nectin-1—but not nectin-3—protein upregulation in synapse-enriched hippocampal fractions at about 2 h posttraining. The upregulation of nectin-1 was found exclusively in the ventral hippocampus and was apparent in the synaptoneurosomal fraction. This upregulation was induced by contextual fear conditioning but not by exposure to context or shock alone. When an antibody against nectin-1, R165, was infused in the ventral-hippocampus immediately after training, contextual fear memory was impaired. However, treatment with the antibody in the dorsal hippocampus had no effect in contextual fear memory formation. Similarly, treatment with the antibody in the ventral hippocampus did not interfere with acoustic memory formation. Further control experiments indicated that the effects of ventral hippocampal infusion of the nectin-1 antibody in contextual fear memory cannot be ascribed to memory non-specific effects such as changes in anxiety-like behavior or locomotor behavior. Therefore, we conclude that nectin-1 recruitment to the perisynaptic environment in the ventral hippocampus plays an important role in the formation of contextual fear memories. Our results suggest that these mechanisms could be involved in the connection of emotional and contextual information processed in the amygdala and dorsal hippocampus, respectively, thus opening new venues for the development of treatments to psychopathological alterations linked to impaired contextualization of emotions.

Post-training administration of a synthetic peptide ligand of the neural cell adhesion molecule, C3d, attenuates long-term expression of contextual fear conditioning

Maria del Carmen Sandi Perez

The neural cell adhesion molecule (NCAM) plays a key role in synaptic plasticity and memory formation. We have recently developed a synthetic peptide, termed C3d, which, through the binding to the first, N-terminal immunoglobulin-like (Ig) module in the extracellular portion of NCAM, has been shown to promote neurite outgrowth and synapse formation in vitro, and to interfere with passive avoidance memory in rats in vivo. In this study, we investigated whether the i.c.v. administration of C3d, either 5.5 h after or 2 days before training, could be effective to modulate the strength at which emotional memory for aversive situations is established into a long-term memory. The effects of the peptide were evaluated in adult male Wistar rats trained in the contextual fear conditioning task. The results indicated that C3d significantly reduced the subsequent long-term retention of the conditioned fear response when administered 5.5 h post-training, as indicated by retention tests performed 2-3 and 7 days post-training. However, this treatment failed to influence conditioning for this task when injected 2 days pre-training. Additional experiments showed that C3d did not influence the emotional or locomotor behaviour of the animals, when tested in the open field task. Furthermore, hippocampal levels of microtubule-associated protein 2 (MAP2), Synaptophysin and NCAM were found unchanged when evaluated by enzyme-linked immunosorbent assay in crude synaptosomal preparations 2 days after peptide i.c.v. injection. Therefore, post-training injection of this synthetic peptide was efficient to attenuate the strength at which memory for contextual fear conditioning was enduringly stored, whilst it did not affect the acquisition of new memories. In addition to further support the view that NCAM is critically involved in memory consolidation, the current findings suggest that the NCAM IgI module is a potential target for the development of therapeutic drugs capable to reduce the cognitive impact induced by exposure to intensive stress experiences.

2003

Effects of P2, a peptide derived from a homophilic binding site in the neural cell adhesion molecule on learning and memory in rats

Maria del Carmen Sandi Perez

The neural cell adhesion molecule (NCAM) plays a pivotal role in neural development, regeneration, synaptic plasticity, and memory processes. P2 is a 12-amino-acid peptide derived from the second immunoglobulin-like (Ig) module of NCAM mediating cis-homophilic interactions between NCAM molecules present on the same cell. P2 is a potent NCAM agonist, capable of promoting neuronal differentiation and survival in vitro. The aim of this study was to assess the effect of P2 on learning and memory. Rats treated with P2 intracerebroventricularly (1 h prior to test) performed significantly better than controls in the reinforced T-maze, a test of spatial working memory. Further, rats treated with P2 exhibited decreased anxiety-like behavior while learning the T-maze task. In the social recognition test, both intracerebroventricular (1 h prior to test) and systemic (1 and 24 h prior to test) P2 treatment enhanced short-term social memory and counteracted (administration 24 h prior test) scopolamine-induced social memory impairment. In contrast, P2 (1 h prior to test) did not significantly improve long-term (24 h) retention of social memory, nor did it have any significant effects on long-term memory evaluated by the Morris water maze (administration between 2 days before training and 5.5 h posttraining). In the open field test, P2 (1 h prior to test) decreased general locomotion and rearing, but did not influence any other anxiety-related behaviors, indicating only a minimal influence on baseline anxiety levels. Taken together, these data indicate that in vivo P2 enhances short-term memory and protects against the amnestic effects of scopolamine, while modulating emotional behavior in a learning or novelty-related task

2007

Learning, Stress and the Role of Personality Profiles in Rats

Basira Salehi, Maria del Carmen Sandi Perez

Stress has been shown to modulate many aspects of physiology and behavior. In particular, substantial work has confirmed that stress is a strong modulator of learning and memory processes. It is more than a century that Yerkes and Dodson have shown that relationship between stress intensity and memory function follows an inverted-U-shaped curve; memory increases with stress to an optimal point, above or below which memory decreases. Despite the great popularity of the Yerkes-Dodson law, the validity of the law has been criticized due to significant methodological problems in the study performed by Yerkes and Dodson (1908) and their data being judged insufficient to substantiate conclusions, among other reasons. Moreover the existing evidence has not yet illustrated this phenomenon under the same experimental conditions for relational learning tasks. On the other hand, stress is not the only factor that modulates cognitive abilities. Different types of learning and memory might be affected by other factors such as individual differences in personality. While the relationship between personality and learning has been studied in human, animal studies addressed to understanding the relationship between personality and learning have been rare. In addition, exposure to stress during pregnancy can have deleterious emotional effects on women. However, the mechanisms underlying these emotional effects are not well understood, and the development of suitable animal models for stress-induced depression in females still remains scarce. The goal of this Thesis was to investigate how stress affects cognitive and emotional processes in different animal models, and to explore the importance of individual differences in the mediation of stress effects. On a first study, we investigated the relationship between stress intensity and memory function. For this purpose cognitive abilities of rats to learn a radial arm water maze were assessed under different stress intensities, using behavioural and endocrine approaches. Our results confirm, for the first time, the existence of an inverted-U-shape memory function according to stressor intensity during the early learning and memory phases in a hippocampus-dependent task. Furthermore, we present evidence that these stress effects are not shown uniformly by all individuals; rather, performance at either the high or the low stress intensities is differentially affected in individuals with different personality-like profiles. In a second study, we investigated whether different personality traits in the Wistar outbred strain of rats were associated with performance in specific types of learning and memory tasks that have been reported to depend on specific brain areas, such as the amygdala, hippocampus and prefrontal cortex (PFC). Using a wide variety of behavioral tests, we identified three personality factors: anxiety, exploration and locomotion. According to our results, the locomotion trait displayed no correlation with learning and memory. However curiosity trait predicted extinction of fear memories and spatial reversal learning, and the anxiety traits was related to extinction of fear. These results suggest that behavioral traits, anxiety and curiosity, might be linked to the functioning of specific brain areas (i.e. amygdala and PFC). Our findings are consistent with recent human studies showing that certain personality traits can predict academic achievement and point out the importance of constructing learning environments that could optimize individual strengths. In a third study, we used a model of stress during pregnancy in an attempt to mirror more closely than other experimental approaches based mainly on movement restraint procedures the human condition where stress is often persistently imposed by a male aggressive partner. For that purpose we used aggressive male rats that cohabitated with (and therefore can be considered a stressor) female rats during their pregnancy and, then, characterized the behaviour of these females after weaning. Similar to effects reported in humans, mother rats displayed anxiety-like and depressive-like behaviours, with the females presenting a high anxiety trait being the more vulnerable to the deleterious effects resulting from exposure to the aggressive male. These results propose an interesting animal model to study the effect of stress during pregnancy. Taken together, our results reinforce the view that stress has a strong impact on cognitive function and emotion. They also stress the importance of taking into account individual differences to characterize individuals with different vulnerability to be affected in both cognitive and emotional domain by exposure to stress. Our approach is novel and original in that it takes into account several behavioural (personality-like) traits simultaneously and shows the importance of different traits for different aspects of the relationship between stress, emotion and cognition. The approaches and findings provide valuable models to address the neurobiological mechanisms underlying stress effects on behavior.

EPFL2010

Post-training administration of a synthetic peptide ligand of the neural cell adhesion molecule, C3d, attenuates long-term expression of contextual fear conditioning

Maria del Carmen Sandi Perez

2003

Learning, Stress and the Role of Personality Profiles in Rats

Basira Salehi, Maria del Carmen Sandi Perez

EPFL2010