Estrogen Receptor α Drives Pro-Resilient Transcription in Mouse Models of Depression. Estrogen Receptor α 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 α (ERα) 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 ERα protein levels are altered by stress in male and female mice. Further, overexpression of ERα in the NAc promotes stress resilience in both sexes. Subsequent RNA sequencing reveals that ERα overexpression in NAc reproduces the transcriptional signature of resilience in male, but not female, mice. These results indicate that NAc ERα 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

多数暴露于应激刺激的个体并不会罹患抑郁症。动物模型研究表明，应激抵抗（stress resilience）是一种需要广泛转录调控适应的主动状态，但目前对该稳态过程的调控机制仍知之甚少。本研究分析了慢性社交挫败应激后差异表达基因的上游调控因子，鉴定出雌激素受体α（estrogen receptor α, ERα）是伏隔核（nucleus accumbens, NAc）中促抵抗性转录变化的首要调控因子——伏隔核是与抑郁症密切相关的关键脑奖赏区域。与上述发现一致，雌雄小鼠的核内ERα蛋白水平均会因应激刺激发生改变。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测序结果显示，伏隔核内ERα过表达可重现雄性小鼠的抵抗性转录特征，但无法在雌性小鼠中实现该效果。上述结果表明，伏隔核ERα是调控促抵抗性转录变化的重要因子，但其下游靶点存在性别特异性差异。整体实验设计：解析雌雄小鼠伏隔核内ESR1过表达后基因表达的变化。