Prolonged social isolation promotes depressive-like behavior in male and female mice, with sex-related differences in the stress response

Abstract Background Social isolation is a chronic psychological stressor with high translational relevance to depression in humans, particularly in the aftermath of the COVID-19 pandemic. However, few preclinical studies have evaluated its sex-dependent effects. Some studies have shown that after four weeks of social isolation, only males exhibit depressive-like behavior, without a comprehensive view of the underlying immune and neuroimmune alterations. Methods Here, we examined the impact of prolonged social isolation on depressive- and anxiety-like behaviors of adult male and female mice, using the forced swim, splash, open field, and light/dark box tests. We also analyzed peripheral immune profiles through flow cytometry, ELISA and qRT-PCR, and neuroimmune responses through qRT-PCR and immunofluorescence for astrocytes and microglia. Results After seven weeks of social isolation, both males and females exhibited depressive-like behavior and inflammatory signs such as elevated neutrophils in circulation, decreased IL-10 expression in the spleen, higher expression of IDO in the hippocampus, and higher microglia number. However, sex-related differences were also detected. Isolated males show lower body weight, with no changes in corticosterone levels, while isolated females exhibit increased corticosterone levels, higher IL-1β expression in the hippocampus, and higher microglia total area. Conclusions After seven weeks of social isolation, both sexes exhibit depressive-like behavior, with sex-related differences in body weight, corticosterone levels, and cellular and molecular signs of neuroinflammation. These findings highlight the importance of temporality and sex as key variables in the behavioral and physiological responses to chronic stress. Given the increased prevalence of depression in women, these results provide new insights into sex-specific susceptibility to chronic stress and may inform the development of tailored diagnostic and therapeutic strategies.