Estrogen receptor α drives pro-resilient transcription in mouse models of depression

Zachary S. Lorsch, Yong Hwee Eddie Loh, Immanuel Purushothaman, Deena M. Walker, Eric M. Parise, Marine Salery, Michael E. Cahill, Georgia E. Hodes, Madeline L. Pfau, Hope Kronman, Peter J. Hamilton, Orna Issler, Benoit Labonté, Ann E. Symonds, Matthew Zucker, Tie Yuan Zhang, Michael J. Meaney, Scott J. Russo, Li Shen, Rosemary C. BagotEric J. Nestler

Research output: Contribution to journalArticlepeer-review

66 Scopus citations


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.

Original languageEnglish
Article number1116
JournalNature Communications
Issue number1
StatePublished - 1 Dec 2018


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