An acute social defeat stressor in early puberty increases susceptibility to social defeat in adulthood.

Syrian hamsters readily display territorial aggression. If they lose even a single agonistic encounter, however, hamsters show striking reductions in aggressive behavior and increases in submissive behavior, a distinct behavioral change that we have previously termed conditioned defeat. This acute social defeat stressor is primarily psychological and is effective in both males and females. Therefore, we maintain that this procedure presents an ideal model for studying behavioral and physiological responses to social stress. Here, we demonstrate that social avoidance following social defeat is a particularly useful dependent measure because of its sensitivity and stability between sexes and across the estrous cycle. In addition, we demonstrate that peripubertal hamsters exposed to a single, 15min social defeat exhibit significantly more social avoidance 24h later when compared with no-defeat controls. Later, defeated and non-defeated hamsters display similar agonistic behavior in adulthood indicating that the peripubertal defeat does not alter adult territorial aggression. After experiencing an additional social defeat in adulthood, however, the hamsters that experienced the pubertal defeat respond to the adult defeat with increased social avoidance when compared with hamsters that were defeated only in adulthood and with no-defeat controls. These data are the first to show that a single social defeat in puberty increases susceptibility to later social defeat in both males and females.

Using Translational Models of Fear Conditioning to Uncover Sex-Linked Factors Related to PTSD Risk.

Post-traumatic stress disorder (PTSD) is a debilitating neuropsychiatric disorder that follows exposure to a traumatic event; however, not every person who experiences trauma will develop PTSD. Women are more likely to be diagnosed with PTSD than men even when controlling for type and amount of trauma exposure. Circulating levels of gonadal hormones such as estradiol, progesterone, and testosterone may contribute to differential risk for developing PTSD. In this review, we briefly consider the influence of gonadal hormones on fear conditioning processes including fear acquisition, fear inhibition, extinction learning, and extinction recall within translational neuroscience models. We discuss findings from human studies incorporating samples from both community and traumatized clinical populations to further understand how these hormones might interact with exposure to trauma. Additionally, we propose that special attention should be paid to the specific measure used to examine fear conditioning processes as there is evidence that common psychophysiological indices such as skin conductance response and fear-potentiated startle can reveal quite different results and thus necessitate nuanced interpretations. Continued research to understand the influence of gonadal hormones in fear learning and extinction processes will provide further insight into the increased risk women have of developing PTSD and provide new targets for the treatment and prevention of this disorder.

Ingestion of probiotic (Lactobacillus helveticus and Bifidobacterium longum) alters intestinal microbial structure and behavioral expression following social defeat stress.

Social stress exacerbates anxious and depressive behaviors in humans. Similarly, anxiety- and depressive-like behaviors are triggered by social stress in a variety of non-human animals. Here, we tested whether oral administration of the putative anxiolytic probiotic strains Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 reduces the striking increase in anxiety-like behavior and changes in gut microbiota observed following social defeat stress in Syrian hamsters. We administered the probiotic at two different doses for 21 days, and 16S rRNA gene amplicon sequencing revealed a shift in microbial structure following probiotic administration at both doses, independently of stress. Probiotic administration at either dose increased anti-inflammatory cytokines IL-4, IL-5, and IL-10 compared to placebo. Surprisingly, probiotic administration at the low dose, equivalent to the one used in humans, significantly increased social avoidance and decreased social interaction. This behavioral change was associated with a reduction in microbial richness in this group. Together, these results demonstrate that probiotic administration alters gut microbial composition and may promote an anti-inflammatory profile but that these changes may not promote reductions in behavioral responses to social stress.

Transcriptomic Analysis Reveals Sex-Dependent Expression Patterns in the Basolateral Amygdala of Dominant and Subordinate Animals After Acute Social Conflict.

The basolateral amygdala (BLA) is a critical nucleus mediating behavioral responses after exposure to acute social conflict. Male and female Syrian hamsters both readily establish a stable dominant-subordinate relationship among same-sex conspecifics, and the goal of the current study was to determine potential underlying genetic mechanisms in the BLA facilitating the establishment of social hierarchy. We sequenced the BLA transcriptomes of dominant, subordinate, and socially neutral males and females, and using de novo assembly techniques and gene network analyses, we compared these transcriptomes across social status within each sex. Our results revealed 499 transcripts that were differentially expressed in the BLA across both males and females and 138 distinct gene networks. Surprisingly, we found that there was virtually no overlap in the transcript changes or in gene network patterns in males and females of the same social status. These results suggest that, although males and females reliably engage in similar social behaviors to establish social dominance, the molecular mechanisms in the BLA by which these statuses are obtained and maintained are distinct.

Brain-derived neurotrophic factor signaling mitigates the impact of acute social stress.

Brain-derived neurotrophic factor (BDNF) is known to promote fear learning as well as avoidant behavioral responses to chronic social defeat stress, but, conversely, this peptide can also have antidepressant effects and can reduce depressant-like symptoms such as social avoidance. The purpose of this study was to use a variety of approaches to determine whether BDNF acting on tropomyosin receptor kinase B (TrkB) promotes or prevents avoidant phenotypes in hamsters and mice that have experienced acute social defeat stress. We utilized systemic and brain region-dependent manipulation of BDNF signaling before or immediately following social defeat stress in Syrian hamsters, TrkBF616A knock-in mice, and C57Bl/6J mice and measured the subsequent behavioral response to a novel opponent. Systemic TrkB receptor agonists reduced, and TrkB receptor antagonists enhanced, behavioral responses to social defeat in hamsters and mice. In the neural circuit that we have shown mediates defeat-induced behavioral responses, BDNF in the basolateral amygdala, but not the nucleus accumbens, also reduced social avoidant phenotypes. Conversely, knockdown in the basolateral amygdala of TrkB signaling in TrkBF616A mice enhanced defeat-induced social avoidance. These data demonstrate that systemic administration of BDNF-TrkB drugs at the time of social defeat alters the behavioral response to the defeat stressor. These drugs appear to act, at least in part, in the basolateral amygdala and not the nucleus accumbens. These findings were generalizable to two rodent species with very different social structures and, within mice, to a variety of strains providing converging evidence that BDNF-TrkB signaling reduces anxiety- and depression-like symptoms following short-term social stress.

Histone deacetylase and acetyltransferase inhibitors modulate behavioral responses to social stress.

Histone acetylation has emerged as a critical factor regulating learning and memory both during and after exposure to stressful stimuli. There are drugs that we now know affect histone acetylation that are already in use in clinical populations. The current study uses these drugs to examine the consequences of acutely increasing or decreasing histone acetylation during exposure to social stress. Using an acute model of social defeat in Syrian hamsters, we systemically and site-specifically administered drugs that alter histone acetylation and measured subsequent behavior and immediate-early gene activity. We found that systemic administration of a histone deacetylase inhibitor enhances social stress-induced behavioral responses in males and females. We also found that systemic administration completely blocks defeat-induced neuronal activation, as measured by Fos-immunoreactivity, in the infralimbic cortex, but not in the amygdala, after a mild social defeat stressor. Lastly, we demonstrated that site-specific administration of histone deacetylase inhibitors in the infralimbic region of the prefrontal cortex, but not in the basolateral amygdala, mimics the systemic effect. Conversely, decreasing acetylation by inhibiting histone acetyltransferases in the infralimbic cortex reduces behavioral responses to defeat. This is the first demonstration that acute pharmacological manipulation of histone acetylation during social defeat alters subsequent behavioral responses in both males and females. These results reveal that even systemic administration of drugs that alter histone acetylation can significantly alter behavioral responses to social stress and highlight the importance of the infralimbic cortex in mediating this effect.