Major depressive disorder (MDD) is a devastating illness and the leading cause of disability worldwide [1]. Differences between men and women in the etiology and pathology of depression likely impact symptomatology, severity, and prevalence [2, 3]. Since depression prevalence remains higher in women across life stages and hormonal states, factors other than circulating gonadal hormones may contribute to these sex differences, including permanent organizational effects of gonadal hormones acting during sensitive developmental periods and/or genetic sex effects (i.e., XX/XY).

As genetic sex determines gonadal sex in standard laboratory mice, parsing the impact of developmental hormonal and genetic sex requires use of the unique Four Core Genotypes (FCG) mouse strain, in which gonadal sex determination is decoupled from sex chromosomes. In our study [4], we found males had lower depressive-like behavior than females. Since we used FCG mice, we were able to determine how both developmental gonadal hormone exposure and genetic sex independently contributed to this sex difference. We then used RNA-sequencing to examine potential molecular mechanisms driving sex differences in behavior within three nodes of mesocorticolimbic circuitry—prefrontal cortex (PFC), nucleus accumbens (NAc), and basolateral amygdala (BLA). We found significant sex differences in immune-related pathways that were driven by both developmental gonadal hormones and genetic sex. For example, genetic sex drove differences related to T- and B-cell signaling across brain regions. When we looked at the effect of stress on gene expression, we found very little overlap between males and females, consistent with recent findings by our group and others using human postmortem brains [5, 6]. For instance, in the BLA, stress altered the expression of dopamine- and serotonin-related genes in males, but EIF2 and mTOR signaling in females, both of which may be involved in stress-induced synaptic plasticity.

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