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  3. Neural mechanism underlying depressive-like state associated with social status loss

Neural mechanism underlying depressive-like state associated with social status loss

  • Cell. 2023 Feb 2;186(3):560-576.e17. doi: 10.1016/j.cell.2022.12.033.
Zhengxiao Fan 1,  Jiarui Chang 2,  Yilan Liang 2,  Hong Zhu 2,  Chaoyi Zhang 2,  Diyang Zheng 2,  Junying Wang 2,  Ying Xu 2,  Qi-Jing Li 3,  Hailan Hu 4
Affiliations

Affiliations

  • 1 Department of Neurobiology, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou 311121, China.
  • 2 Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou 311121, China.
  • 3 Institute of Molecular and Cell Biology (IMCB) & Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A(∗)STAR), Singapore 138668, Singapore.
  • 4 Department of Neurobiology, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China; Liangzhu Laboratory, MOE Frontier Science Center for Brain Science and Brain-Machine Integration, State Key Laboratory of Brain-Machine Intelligence, Zhejiang University, Hangzhou 311121, China; Center for Brain Science and Brain-Inspired Intelligence, Guangdong-Hong Kong-Macao Greater Bay Area, Guangzhou 510515, China; Research Units of Brain Mechanisms Underlying Emotion and Emotion disorders, Chinese Academy of Medical Sciences, Beijing 100730, China. Electronic address: huhailan@zju.edu.cn.
PMID: 36693374 DOI: 10.1016/j.cell.2022.12.033
Abstract

Downward social mobility is a well-known mental risk factor for depression, but its neural mechanism remains elusive. Here, by forcing mice to lose against their subordinates in a non-violent social contest, we lower their social ranks stably and induce depressive-like behaviors. These rank-decline-associated depressive-like behaviors can be reversed by regaining social status. In vivo fiber photometry and single-unit electrophysiological recording show that forced loss, but not natural loss, generates negative reward prediction error (RPE). Through the lateral hypothalamus, the RPE strongly activates the brain's anti-reward center, the lateral habenula (LHb). LHb activation inhibits the medial prefrontal cortex (mPFC) that controls social competitiveness and reinforces retreats in contests. These results reveal the core neural mechanisms mutually promoting social status loss and depressive behaviors. The intertwined Neuronal Signaling controlling mPFC and LHb activities provides a mechanistic foundation for the crosstalk between social mobility and psychological disorder, unveiling a promising target for intervention.

Keywords

burst; depression; ketamine; lateral habenula; reward prediction error; social competition; social hierarchy; social status.

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