SEX-SPECIFIC EFFECTS OF CHRONIC NON-DISCRIMINATORY SOCIAL DEFEAT STRESS (CNSDS) ON VENTRAL HIPPOCAMPAL PLASTICITY AND BEHAVIORAL VULNERABILITY

Depression is a complex disorder shaped by environmental, neurobiological, and immune factors, with chronic stress and systemic inflammation playing a central role in its pathophysiology. Among the brain regions involved, the ventral hippocampus is critically implicated, as it exhibits increased inflammation, altered synaptic plasticity, and disrupted connectivity with other structures. Despite the higher prevalence of depression in women, the mechanisms underlying sex-dependent differences in stress susceptibility remain poorly understood. This project aimed to investigate sex-specific responses to chronic psychosocial stress in a murine model and to identify potential biomarkers associated with differential stress vulnerability. Male and female mice were exposed for 10 days to a Chronic Non-discriminatory Social Defeat Stress (CNSDS) protocol. Behavioral outcomes were evaluated using standardized tests measuring anhedonia, anxiety-like behavior, and social interaction, alongside liquid intake and body weight monitoring. Synaptic plasticity in the ventral hippocampus was assessed ex vivo through electrophysiological field recordings of Long-Term Potentiation (LTP). Transcriptomic analyses were performed on ventral hippocampal tissue to evaluate inflammatory, synaptic and resilience-related markers. Male and female mice displayed distinct susceptibility profiles in response to CNSDS. In particular, susceptible females exhibited increased LTP in the ventral hippocampus, a change not observed in males or in non-susceptible females. These alterations were associated with greater social avoidance in females, while only males showed increased anxiety-like behavior compared to controls. Taken together, these findings highlight sex-dependent mechanisms linking chronic stress, hippocampal plasticity, and depressive-like phenotypes, underscoring the importance of considering sex as a biological variable in stress-related mood disorders research.