Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset

Zhiwei Zheng; Chen Guo; Min Li; Liang Yang; Pengyang Liu; Xuliang Zhang; Yiqin Liu; Xiaonan Guo; Shuxia Cao; Yiyan Dong; Chunlei Zhang; Min Chen; Jiamin Xu; Hailan Hu; Yihui Cui

doi:10.1016/j.neuron.2022.01.011

Hypothalamus-habenula potentiation encodes chronic stress experience and drives depression onset

Neuron. 2022 Apr 20;110(8):1400-1415.e6. doi: 10.1016/j.neuron.2022.01.011. Epub 2022 Feb 2.

Authors

Zhiwei Zheng¹, Chen Guo¹, Min Li¹, Liang Yang¹, Pengyang Liu², Xuliang Zhang³, Yiqin Liu², Xiaonan Guo², Shuxia Cao², Yiyan Dong⁴, Chunlei Zhang⁵, Min Chen⁴, Jiamin Xu⁶, Hailan Hu⁴, Yihui Cui⁷

Affiliations

¹ Department of Neurobiology, Department of Neurology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058 Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, 311121 Hangzhou, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, 310058 Hangzhou, China.
² Department of Neurobiology, Department of Neurology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058 Hangzhou, China.
³ Laboratory Animal Center, Zhejiang University, 310058 Hangzhou, China.
⁴ Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, 311121 Hangzhou, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, 310058 Hangzhou, China.
⁵ NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, 310058 Hangzhou, China.
⁶ East China Normal University, Key Laboratory of Brain Functional Genomics, 200062 Shanghai, China.
⁷ Department of Neurobiology, Department of Neurology of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 310058 Hangzhou, China; Liangzhu Laboratory, Zhejiang University Medical Center, 1369 West Wenyi Road, 311121 Hangzhou, China; NHC and CAMS Key Laboratory of Medical Neurobiology, MOE Frontier Science Center for Brain Research and Brain-Machine Integration, School of Brain Science and Brain Medicine, Zhejiang University, 310058 Hangzhou, China. Electronic address: yihuicui@zju.edu.cn.

PMID: 35114101
DOI: 10.1016/j.neuron.2022.01.011

Abstract

Chronic stress is a major risk factor for depression onset. However, it remains unclear how repeated stress sculpts neural circuits and finally elicits depression. Given the essential role of lateral habenula (LHb) in depression, here, we attempt to clarify how LHb-centric neural circuitry integrates stress-related information. We identify lateral hypothalamus (LH) as the most physiologically relevant input to LHb under stress. LH neurons fire with a unique pattern that efficiently drives postsynaptic potential summation and a closely followed LHb bursting (EPSP-burst pairing) in response to various stressors. We found that LH-LHb synaptic potentiation is determinant in stress-induced depression. Mimicking this repeated EPSP-burst pairings at LH-LHb synapses by photostimulation, we artificially induced an "emotional status" merely by potentiating this pathway in mice. Collectively, these results delineate the spatiotemporal dynamics of chronic stress processing from forebrain onto LHb in a pathway-, cell-type-, and pattern-specific manner, shedding light on early interventions before depression onset.

Keywords: Hebbian rule; chronic stress; depression onset; emotional status; lateral habenula; lateral hypothalamus; synaptic potentiation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Depression / etiology
Habenula* / physiology
Hypothalamic Area, Lateral
Hypothalamus
Mice
Synapses / physiology