Fishberg Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave L Levy Place, New York, NY, 10029, USA.
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI, 53706, USA.
Nat Commun. 2018 Mar 16;9(1):1116. doi: 10.1038/s41467-018-03567-4.
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.
大多数接触压力的人不会患上抑郁症。动物模型表明，抗压能力是一种积极的状态，需要广泛的转录适应，但这种动态平衡过程是如何调节的仍知之甚少。在这项研究中，我们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。我们确定雌激素受体 α (ERα) 是伏隔核（NAc）中抗压力转录变化的主要调控因子，NAc 是与抑郁症相关的关键大脑奖励区域。与这些发现一致，应激会改变雄性和雌性小鼠 NAc 中的核 ERα 蛋白水平。此外，在 NAc 中过表达 ERα 可促进两性的抗压能力。随后的 RNA 测序表明，在 NAc 中过表达 ERα 可重现雄性小鼠的抗压转录特征，但不能重现雌性小鼠的转录特征。这些结果表明，NAc ERα 是抗压力转录变化的重要调节因子，但具有性别特异性的下游靶标。
