Sex-Specific Stress Outcomes Following Acute and Chronic Social Defeat Stress

Stressful experiences are a major risk factor for the development of neuropsychiatric disorders in vulnerable individuals. Identifying features that can distinguish stress-susceptible from resilient individuals remains a central goal in stress neurobiology. Due to the routine exclusion of female subjects from stress research or the use of male-defined criteria in behavioral characterization of subjects post-stress, female stress responses and vulnerability profiles remain poorly understood. This work aimed to gain a better understanding of sex-specific stress responses to social defeat stress. Here, we used a novel paired male-female social defeat paradigm and tracked subjects longitudinally in a ''two-hit'' design to evaluate responses to both acute social defeat stress (ASDS) and chronic social defeat stress (CSDS), and to determine how prior stress exposure influences subsequent vulnerability. We found that both ASDS and CSDS induces changes in social avoidance/approach behavior in males but not females, as measured by a classic social interaction ratio. Prior ASDS exposure enhanced susceptibility to subsequent CSDS most clearly in males, with females displaying specific changes in corner zone occupancy. Furthermore, we observed divergent anxiety profiles between males and females in a post-stress behavioral battery. Finally, females exhibited specific stress-related locomotor responses following ASDS. Together, these findings suggest that females may adopt distinct behavioral strategies following social defeat stress.