Sex-specific behavioral, cardiac, and neuroendocrine responses to repeated witness social stress in adult rats

In humans, sex disparities exist in the prevalence of social stress-related disorders, yet our understanding of the predisposing factors and underlying mechanisms is still elusive. Also at the preclinical level, the investigation of sex differences in social stress responses is limited. In this study, adult male and female wild-type Groningen rats were repeatedly exposed to witness social defeat stress (WS) to assess sex-specific behavioral, neuroendocrine, and cardiac responses to the same social stress paradigm. Male and female rats bore witness to an aggressive social defeat episode between two males for nine consecutive days or were exposed to a control (CTR) procedure. Stress-related parameters were assessed in correspondence to the first and last WS/CTR exposure and also during subsequent exposure to the stress context alone in the absence of social defeat. During WS, rats of both sexes displayed larger amounts of burying behavior and smaller amounts of rearing and grooming behaviors, but with a greater extent in female witnesses. Cardiac autonomic responses to WS were similar between the sexes, yet only females displayed higher plasma corticosterone levels after the first WS exposure compared to CTRs, and had a larger corticosterone increase than male witnesses upon repeated WS. Exposure to the stress context alone (i.e., without the presence of the aggressive resident rat) elicited greater amount of burying behavior and more pronounced and persistent tachycardic responses in females than males with a history of WS. Our findings suggest sex-disparities in the response of adult rats to WS at multiple behavioral, cardiac, and neuroendocrine levels, highlighting the utility of this social stress paradigm for investigating predisposing factors and pathophysiological mechanisms underlying sex-specific vulnerabilities to stress-related pathologies.