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 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.