Stress dynamically modulates neuronal autophagy to gate depression onset

• 成果类型: Article
• 署名作者: Yang, Liang; Guo, Chen; Zheng, Zhiwei; Dong, Yiyan; Xie, Qifeng; Lv, Zijian; Li, Min; Lu, Yangyang; Guo, Xiaonan; Deng, Rongshan; Liu, Yiqin; Feng, Yirong; Mu, Ruiqi; Zhang, Xuliang; Ma, Huan; Chen, Zhong; Zhang, Zhijun; Dong, Zhaoqi; Yang, Wei; Zhang, Xiangnan; Cui, Yihui
• 署名单位: Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang University; Zhejiang Chinese Medical University; Southeast University - China; Chinese Academy of Sciences; Shenzhen Institute of Advanced Technology, CAS; Capital Medical University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-2751
• DOI: 10.1038/s41586-025-08807-4
• 发表日期: 2025-05-08
• 关键词: lateral habenula; inhibition; deficits

摘要

Chronic stress remodels brain homeostasis, in which persistent change leads to depressive disorders1. As a key modulator of brain homeostasis2, it remains elusive whether and how brain autophagy is engaged in stress dynamics. Here we discover that acute stress activates, whereas chronic stress suppresses, autophagy mainly in the lateral habenula (LHb). Systemic administration of distinct antidepressant drugs similarly restores autophagy function in the LHb, suggesting LHb autophagy as a common antidepressant target. Genetic ablation of LHb neuronal autophagy promotes stress susceptibility, whereas enhancing LHb autophagy exerts rapid antidepressant-like effects. LHb autophagy controls neuronal excitability, synaptic transmission and plasticity by means of on-demand degradation of glutamate receptors. Collectively, this study shows a causal role of LHb autophagy in maintaining emotional homeostasis against stress. Disrupted LHb autophagy is implicated in the maladaptation to chronic stress, and its reversal by autophagy enhancers provides a new antidepressant strategy.