Estrogen Receptor a Drives Pro-Resilient Transcription in Mouse Models of Depression

Most people exposed to stress do not develop depression. Animal models have shown that stress resilience is an active state that requires broad transcriptional adaptations, but how this homeostatic process is regulated remains poorly understood. In this study, we analyze upstream regulators of genes differentially expressed after chronic social defeat stress. We identify estrogen receptor a (ERa) as the top regulator of pro-resilient transcriptional changes in the nucleus accumbens (NAc), a key brain reward region implicated in depression. In accordance with these findings, nuclear ERa protein levels are altered by stress in male and female mice. Further, overexpression of ERa in the NAc promotes stress resilience in both sexes. Subsequent RNA sequencing reveals that ERa overexpression in NAc reproduces the transcriptional signature of resilience in male, but not female, mice. These results indicate that NAc ERa is an important regulator of pro-resilient transcriptional changes, but with sex-specific downstream targets. Overall design: Understanding changes in gene expression upon ESR1 overexpression in males and females多数暴露于应激环境的个体并不会罹患抑郁症。动物模型研究证实，应激抵抗（stress resilience）是一种需要广泛转录适应性改变的主动状态，但目前学界对这一稳态过程的调控机制仍知之甚少。本研究针对慢性社交挫败应激后差异表达基因的上游调控因子展开分析，鉴定出雌激素受体α（ERα）是伏隔核（NAc，一个与抑郁症密切相关的关键脑奖赏区域）内促抵抗性转录变化的核心调控因子。与上述发现一致，应激可改变雌雄小鼠核内ERα的蛋白水平。进一步实验表明，在伏隔核中过表达ERα可提升雌雄小鼠的应激抵抗能力。后续RNA测序（RNA sequencing）结果显示，伏隔核内ERα过表达可在雄性小鼠中重现应激抵抗相关的转录特征，但在雌性小鼠中未观察到此现象。上述结果表明，伏隔核内的ERα是调控促抵抗性转录变化的关键因子，但其下游靶点存在性别特异性差异。整体实验设计：探究雌雄小鼠体内ESR1过表达后基因表达的变化情况。