Sub‐Chronic Stress Induces Similar Depression and Anxiety‐Like Behavioral Alterations in Male and Female Mice

Women exhibit higher rates of post‐traumatic stress disorder, major depression, and anxiety disorders than men, but the biological basis for this sex difference remains largely unknown. Stress has been implicated in anxiety, depression, and other mental disorders, and it has been hypothesized that sex differences in stress susceptibility could underlie the clinically observed gender differences in the incidence of mental illness. Preclinical studies examining sex differences in vulnerability to stress have reported mixed findings, but several recent studies have found that females, but not males, exhibit depression‐ and anxiety‐like behavior following sub‐chronic variable stress (SCVS). These prior studies further suggested that the differential responses of males and females to SCVS result at least in part from sex differences in the expression of DNA methyltransferase 3a (Dnmt3a) and nuclear factor kappa B (NFKB) in the striatum. To evaluate the generalizability of these published findings, the current study examined sex differences in response to a modified version of the SCVS model. Our results reveal that SCVS significantly increases the expression of Dnmt3a and the p105 subunit of NFKB in the striatum of females but not males. However, in contrast to prior research, both sexes displayed increased depression‐ and anxiety‐like behavior following SCVS, suggesting that males are not entirely resilient to SCVS. The identification of SCVS‐induced behavioral disturbances in males in the absence of SVCS‐induced alterations in Dnmt3a or NFKB suggests that the molecular mechanisms leading to depression‐ and anxiety‐like behavior may differ in males and females. Future research elucidating the sex differences in stress‐induced molecular pathology could prove critical for improving our ability to design rational therapeutic interventions that counteract the effects of stress in males and females.