Estrogen receptor α drives pro-resilient transcription in mouse models of depression
Open accessAbstract
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.
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In both male and female mice, NAc ERα overexpression increases sucrose preference and promotes CSDS-resilience in males.
“In both male and female mice, NAc ERα overexpression increases sucrose preference and promotes CSDS-resilience in males [133].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [133]
NAc ERα overexpression in male mice induces a transcriptional profile similar to that of resilient mice.
“NAc ERα overexpression in male mice also induces a transcriptional profile similar to that of resilient mice [133].”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [133]
In female mice subject to chronic variable stress, NAc ERα is decreased in the nuclear fraction of both D1- and D2-MSNs.
“In female mice subject to chronic variable stress, NAc ERα is decreased in the nuclear fraction of both D1-and D2-MSNs.”
From The molecular and cellular mechanisms of depression: a focus on reward circuitry (2019) · cites this paper as [133]
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- Authors
- Lorsch, Z. S., Loh, Y.-H. E., Purushothaman, I., Walker, D. M., Parise, E. M., Salery, M., Cahill, M. E., Hodes, G. E., Pfau, M. L., Kronman, H., Hamilton, P. J., Issler, O., Labonté, B., Symonds, A. E., Zucker, M., Zhang, T. Y., Meaney, M. J., Russo, S. J., Shen, L., Bagot, R. C., & Nestler, E. J.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- University of Wisconsin–Madison (US)
- Virginia Tech (US)
- Ludmer Centre for Neuroinformatics and Mental Health (CA)
- Corresponding author
- Nestler, Eric J.
- ORCID
- Venue
- Nature Communications
- Published
- 2018-03-16
- Volume
- 9
- Issue
- 1
- Pages
- 1116-1116
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC5856766
- OpenAlex
- W2790925227
- Cited by
- 104
- References
- 52
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 10 · 2023: 9 · 2022: 11 · 2021: 17 · 2020: 18 · 2019: 20 · 2018: 4
- FWCI
- 8.47
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship@McGill (McGill) (submittedVersion, cc-by)
- VTechWorks (Virginia Tech) (submittedVersion, cc-by)
- Funders
- Hope for Depression Research Foundation
- Vanderbilt University
- National Alliance for Research on Schizophrenia and Depression
- National Institutes of Health
- National Institute of Mental Health (R01MH090264, F30MH110073, P50MH096890, T32MH096678, R01MH051399)
- National Institute of General Medical Sciences (T32GM007280)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Social Sciences › Psychology › Clinical Psychology › Resilience and Mental Health
- Keywords
- estrogen receptor alpha, depression, stress resilience, chronic social defeat stress, nucleus accumbens, transcriptional regulation, sex differences, gene expression, reward systems
- MeSH terms
- Adaptation, Psychological, Animals, Behavior, Animal, Depression, Female, Male, Mice, Inbred C57BL, Nucleus Accumbens, Sex Factors, Stress, Psychological, Gene Expression Profiling, Models, Animal, Estrogen Receptor alpha, Mice, Transcriptome
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