Women are twice as likely as men to be diagnosed with major depressive disorder (MDD). Recent studies report distinct molecular changes in depressed men and women across mesocorticolimbic brain regions. However, it is unclear which sex-related factors drive distinct MDD-associated pathology. The goal of this study was to use mouse experimental systems to investigate sex-specific mechanisms underlying the distinct molecular profiles of MDD in men and women. We used unpredictable chronic mild stress to induce an elevated anxiety-/depressive-like state and “four core genotypes” (FCG) mice to probe for sex-specific mechanisms. As predicted, based on previous implications in mood, stress impacted the expression of several dopamine-, GABA-, and glutamate-related genes. Some of these effects, specifically in the prefrontal cortex, were genetic sex-specific, with effects in XX mice but not in XY mice. Stress also impacted gene expression differently across the mesocorticolimbic circuit, with increased expression of mood-related genes in the prefrontal cortex and nucleus accumbens, but decreased expression in basolateral amygdala. Our results suggest that females are sensitive to the effects of chronic stress, partly due to their genetic sex, independent of gonadal hormones. Furthermore, these results point to the prefrontal cortex as the node in the mesocorticolimbic circuitry with the strongest female-specific effects.

Women are approximately two times as likely to be diagnosed with major depressive disorder (MDD) compared to men. While sex differences in MDD might be driven by circulating gonadal hormones, we hypothesized that developmental hormone exposure and/or genetic sex might play a role. Mice were gonadectomized in adulthood to isolate the role of developmental hormones. We examined the effects of developmental gonadal and genetic sex on anhedonia-/depressive-like behaviors under non-stress and chronic stress conditions and performed RNA-sequencing in three mood-relevant brain regions. We used an integrative network approach to identify transcriptional modules and stress-specific hub genes regulating stress susceptibility, with a focus on whether these differed by sex. After identifying sex differences in anhedonia-/depressive-like behaviors (female > male), we show that both developmental hormone exposure (gonadal female > gonadal male) and genetic sex (XX > XY) contribute to the sex difference. The top biological pathways represented by differentially expressed genes were related to immune function; we identify which differentially expressed genes are driven by developmental gonadal or genetic sex. There was very little overlap in genes affected by chronic stress in males and females. We also identified highly co-expressed gene modules affected by stress, some of which were affected in opposite directions in males and females. Since all mice had equivalent hormone exposure in adulthood, these results suggest that sex differences in gonadal hormone exposure during sensitive developmental periods program adult sex differences in mood, and that these sex differences are independent of adult circulating gonadal hormones.