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. Bagot and Eric J. Nestler ()
Additional contact information
Zachary S. Lorsch: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Yong-Hwee Eddie Loh: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Immanuel Purushothaman: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Deena M. Walker: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Eric M. Parise: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Marine Salery: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Michael E. Cahill: University of Wisconsin-Madison
Georgia E. Hodes: Virginia Polytechnic Institute and State University
Madeline L. Pfau: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Hope Kronman: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Peter J. Hamilton: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Orna Issler: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Benoit Labonté: Laval University
Ann E. Symonds: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Matthew Zucker: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Tie Yuan Zhang: McGill University
Michael J. Meaney: McGill University
Scott J. Russo: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Li Shen: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai
Rosemary C. Bagot: McGill University
Eric J. Nestler: Friedman Brain Institute, Icahn School of Medicine at Mount Sinai

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-03567-4

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