Contrasting hippocampal and amygdalar expression of genes related to neural plasticity during escape from social aggression

Abstract

Social subjugation has widespread consequences affecting behavior and underlying neural systems. We hypothesized that individual differences in stress responsiveness were associated with differential expression of neurotrophin associated genes within the hippocampus and amygdala. To do this we examined the brains of hamsters placed in resident/intruder interactions, modified by the opportunity to escape from aggression. In the amygdala, aggressive social interaction stimulated increased BDNF receptor TrK_B mRNA levels regardless of the ability to escape the aggressor. In contrast, the availability of escape limited the elevation of GluR₁ AMPA subunit mRNA. In the hippocampal CA₁, the glucocorticoid stress hormone, cortisol, was negatively correlated with BDNF and TrK_B gene expression, but showed a positive correlation with BDNF expression in the DG. Latency to escape the aggressor was also negatively correlated with CA₁ BDNF expression. In contrast, the relationship between amygdalar TrK_B and GluR₁ was positive with respect to escape latency. These results suggest that an interplay of stress and neurotrophic systems influences learned escape behavior. Animals which escape faster seem to have a more robust neurotrophic profile in the hippocampus, with the opposite of this pattern in the amygdala. We propose that changes in the equilibrium of hippocampal and amygdalar learning result in differing behavioral stress coping choices.

Introduction

Stress shapes individual experience, and individuals respond to the stress of social aggression differently, therefore potential neural and behavioral consequences that are derived from social stress vary by individual [1], [2]. Hamsters exhibit a marked territorial aggression that is influenced by social status, stress and/or defeat [3], [4], [5]. Exposing hamsters to social aggression alters their behavioral character in future social interactions. Specifically, if animals are defeated when they are juveniles they are more likely to attack non-threatening conspecifics later in life [5], [6]. Hamsters that were not allowed to escape defeat by a conspecific show significantly increased social avoidance of adults thereafter [7], [8]. Even limited social defeat experience in male adult hamsters influences subsequent social and aggressive behavior. It does this in such a way as to produce a conditioned defeat drastically inhibiting aggressive behavior [4], [9]. Acquisition and expression of this conditioned defeat requires the basolateral amygdala and glutamatergic potentiation [10], [11], [12].

Neural plasticity describes events associated with synaptic remodeling and learning. As such, this kind of synaptic flexibility plays an important role in the development and expression of behavior associated with adaptive coping in response to social stress [13], [14]. Conditioned defeat depends on a neurocircuitry that includes the amygdala, hippocampus, and prefrontal cortex modulated by glutamatergic (including NMDA), serotonergic, GABAergic, and corticotrophin releasing factor (CRF) systems [15], [16], [17], [18], [19]. Glutamate (via AMPA and/or NMDA receptors) and CRF stimulate CREB transcription factor and neurotrophic activity [20], [21], [22], [23], [24], [25], [26]. The behaviors associated with conditioned defeat are enhanced by overexpression of CREB in the basolateral amygdala (BLA) [27]. Neurotrophins such as brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin related kinase B (TrK_B) as well as the AMPA receptor subunit GluR₁ contribute to molecular mechanisms of neural plasticity such as long-term potentiation, synaptic remodeling, and changes in learning [23], [28], [29], [30]. What is more, BDNF and TrK_B in the hippocampus and amygdala appear to be important for social defeat conditioning [31], [32]. Neuroplastic changes in social and fear learning are especially prevalent in the hippocampus and amygdala [29], [33], [34], [35], [36]. Expression of the gene for BDNF is required for motivational aspects of social interaction, such that local knockdown in the nucleus accumbens eliminates the effects of repeated aggression, including social aversion [37]. Additionally, there appears to be a protective role for BDNF in early development. Knocking down the neurotrophin in the hippocampus of juveniles causes elevations in glucocorticoids [38]. Stress, and accompanying corticosteroids, typically inhibits hippocampal BDNF [39], [40], as is the case in animals that display social avoidance [41]. A mutation of the human BDNF gene (Val66Met; G196A) is correlated with a higher susceptibility to stress-induced affective disorders in addition to heightened anticipatory stress responses [42], [43].

The integrated relationships between social aggression, neuroendocrine stress responses, neuroplasticity, and the learning of adaptive coping strategies led to the development of a new conceptual model to help understand the decision-making process that occurs under stressful conditions [14]. This stress–choice model compares two adaptive behavioral responses to social aggression, submission, and escape, and allows examination of the neural and behavioral events that lead to each one. As neuroplastic changes in hippocampus promote improved spatial and operant learning [44], [45] and changes in amygdala enhance fear learning [33], [46], our hypothesis was that neural plasticity in the hippocampus and amygdala is important for producing adaptive social behavior. We also postulate that gene expression in the hippocampus and amygdala is counterbalanced, and the relative activity of those regions produce different kinds of behavioral adaptation. More specifically, we hypothesize that animals that actively make use of escape opportunities from aggressive interactions will have more BDNF expression in the hippocampus and less in the amygdala. On the other hand, animals that remain in the presence of aggressively dominant territorial opponents (do not escape) will exhibit the opposite pattern. As the BDNF protein stimulates numerous mechanisms that produce neural plasticity, we extend these hypotheses to the molecular elements involved in BDNF's mechanism of action. Therefore, we hypothesize that expression of the BDNF receptor TrK_B, its downstream 2nd messenger ERK, and the AMPA receptor subunit GluR₁ will be modulated in a similar fashion to BDNF given that these genes are associated with learning and act downstream of BDNF [47], [48].