Sex Differences in Behavioral Responses to Chronic Unpredictable Mild Stress in Swiss Mice

Chronic stress-induced behavioral changes are partly sex-dependent, but their temporal dynamics remain unclear. Only a few studies have made a direct, comprehensive comparison of sex differences in stress-induced behavioral responses, and most focus on isogenic mouse strains, overlooking the genetic variability inherent to the stress-related disorders. In this study, we applied the chronic unpredictable mild stress (CUMS) model in Swiss mice to elucidate the time course of sex-dependent maladaptive behavioral responses to stress. Adult males and females were exposed to 4, 6, or 8 weeks of CUMS, followed by behavioral assessment and quantification of serum corticosterone. Analysis of the thigmotaxis-related parameters in the open field (OF) revealed distinct temporal patterns between males and females. CUMS-exposed females showed an initial decrease in the OF center exploration (4 weeks), with no changes observed after 6 or 8 weeks. By contrast, males showed decreased OF center exploration only after 4 weeks of stress, with this effect shifting to a decrease after 6 and 8 weeks. Eight weeks of CUMS reduced latency and increased immobility during forced swimming. Moreover, only females showed increased corticosterone levels after 8 weeks of stress, and these levels were moderately correlated with forced-swimming immobility. In conclusion, our results indicate females are more sensitive to stress-induced maladaptive behavioral responses than males, consistent with clinical data showing that women are more prone to stress-induced adverse outcomes than men. Moreover, Swiss mice can be considered highly stress-resilient, requiring longer stress exposure to develop behavioral changes related to depressive-like symptomatology.