Abstract
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.
Highlights
Most people exposed to stress do not develop depression
Women are more likely to suffer from major depressive disorder (MDD) than men[21], and periods during which estrogen levels are changing, such as postpartum and perimenopause, are associated with higher rates of depression[22,23]
While genetic alterations in estrogen receptor α (ERα) have been linked to MDD in humans in candidate gene studies[27,28], these findings are unique to females[28]
Summary
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. 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. The causal relationship between transcriptional alterations, changes in cellular function, and modulated circuit-level physiology has been established by studies examining viral-mediated gene transfer in key driver genes known to regulate a single transcriptional network[7,16]. These studies have been limited to individual networks implicated in stress susceptibility. There has to date been no comprehensive analysis of upstream genes that orchestrate the totality of these stressinduced transcriptional responses, those that mediate homeostatic resilience to stress
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