Sex Difference in Stress Susceptibility and Resilience in a Restraint Stress-induced Depression Mouse Model: A Proteomic Investigation of the Hippocampal Dentate Gyrus

The sex differences in major depressive disorder are well-established, with women showing greater vulnerability and more severe symptoms than men. However, the underlying molecular mechanisms driving this disparity remain unclear. Chronic stress is a key trigger for depressive disorders, and the significant impact of stress on the neurogenic hippocampal dentate gyrus (DG) may be a critical factor in this link. The present study examined sex-specific responses to chronic stress in mice. Females exhibited depressive symptoms, including anhedonia and despair, while males showed resilience. Interestingly, upregulated corticotrophin-releasing hormone receptors in the DG were observed in both sexes. However, the observation of impaired neural progenitor cell proliferation and reduced dendritic spine density in the dentate gyrus of stress-induced depressive female mice exclusively suggested a potential sex-specific difference in resilience, with males exhibiting a greater capacity to withstand the negative consequences of chronic stress. This led us to use a proteomic approach to investigate the molecular basis of gender-specific responses to chronic stress in the hippocampal dentate gyrus of male and female mice. The present study identified 20 differentially regulated proteins associated with key cellular functions, including cell cycle regulation, Hippo signalling, PI3K/AKT signalling, and axon guidance. Notably, only a subset of 14-3-3 family proteins exhibited contrasting expression patterns between stressed male and female mice, suggesting a potential role in mediating stress resilience in males. Overall, the findings highlight gender-specific differences in the hippocampal dentate gyrus's response to chronic stress and shed light on the molecular mechanisms underlying gender-based differences in stress susceptibility.