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.

中文翻译：

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成人情绪的性别差异和压力引起的跨中脑边缘回路的转录连贯性差异。

与男性相比，女性被诊断患有重度抑郁症 (MDD) 的可能性大约是男性的两倍。虽然 MDD 的性别差异可能是由循环的性腺激素驱动的，但我们假设发育激素暴露和/或遗传性别可能发挥作用。小鼠在成年期进行性腺切除术以分离发育激素的作用。我们检查了发育性性腺和遗传性对非压力和慢性压力条件下快感缺乏/抑郁样行为的影响，并在三个与情绪相关的大脑区域进行了 RNA 测序。我们使用综合网络方法来识别转录模块和调节压力易感性的压力特异性中枢基因，重点关注这些是否因性别而异。在确定快感缺乏/抑郁样行为的性别差异后（女性 > 男性），我们表明发育激素暴露（性腺女性>性腺男性）和遗传性别（XX > XY）都会导致性别差异。以差异表达基因为代表的顶级生物学途径与免疫功能有关；我们确定了哪些差异表达的基因是由发育性性腺或遗传性别驱动的。男性和女性受慢性压力影响的基因几乎没有重叠。我们还确定了受压力影响的高度共表达的基因模块，其中一些在男性和女性中受到相反方向的影响。由于所有小鼠在成年期都有相同的激素暴露，这些结果表明，在敏感发育时期性腺激素暴露的性别差异会影响成年情绪的性别差异，