Abstract
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.
Highlights
Major depressive disorder (MDD) is a debilitating disease affecting ~6.7% of the US population and a leading cause of disability worldwide[1]
Sex differences in behavior are driven by both developmental gonadal sex and genetic sex Four Core genotypes (FCG) mice were run through anhedonia-/depressive-like behavioral assays under non-stress conditions, and exposed to unpredictable chronic mild stress (UCMS) and re-tested on the same behavioral assays
We find that the sex difference in latency to eat was recapitulated in both XX Males (XX Males vs. XX Females; t(77) = 2.97; p < 0.01) and XY Females (XY Females vs. XX Females; t(77) = 2.207; p < 0.01); this suggests that both developmental gonadal sex and genetic sex contribute to the sex difference in latency to eat in novelty-suppressed feeding (NSF)
Summary
Major depressive disorder (MDD) is a debilitating disease affecting ~6.7% of the US population and a leading cause of disability worldwide[1]. Symptoms of MDD include emotional dysregulation, cognitive deficits, and anhedonia. The reduced ability to experience pleasure and lack of interest in once “rewarding” activities, is present in ~37% of MDD patients, and often predicts poor treatment response[2]. The mesocorticolimbic system is a primary circuit of emotion and mood regulation, comprised of the prefrontal and anterior cingulate cortices, hippocampus, amygdala, dorsal striatum, and nucleus accumbens (NAc), along with other regions[3]. Evidence suggests dysfunction of the mesocorticolimbic system in MDD [e.g., refs. Neuroimaging studies reveal that individuals with MDD have sustained amygdala hyperactivity, altered prefrontal cortex (PFC) functionality, and reduced activity of the NAc in response to rewarding stimuli[7,8,9]
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