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.

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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.

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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.