Stress dynamically modulates neuronal autophagy to gate depression onset

Liang Yang, Chen Guo, Zhiwei Zheng, Yiyan Dong, Qifeng Xie, Zijian Lv, Min Li, Yangyang Lu, Xiaonan Guo, Rongshan Deng, Yiqin Liu, Yirong Feng, Ruiqi Mu, Xuliang Zhang, Huan Ma, Zhong Chen, Zhijun Zhang, Zhaoqi Dong, Wei Yang, Xiangnan Zhang () and Yihui Cui ()
Additional contact information
Liang Yang: Zhejiang University School of Medicine
Chen Guo: Zhejiang University School of Medicine
Zhiwei Zheng: Zhejiang University School of Medicine
Yiyan Dong: Zhejiang University School of Medicine
Qifeng Xie: Zhejiang University School of Medicine
Zijian Lv: Zhejiang University School of Medicine
Min Li: Zhejiang University School of Medicine
Yangyang Lu: Zhejiang University
Xiaonan Guo: Zhejiang University School of Medicine
Rongshan Deng: Zhejiang University School of Medicine
Yiqin Liu: Zhejiang University School of Medicine
Yirong Feng: Zhejiang University School of Medicine
Ruiqi Mu: Zhejiang University School of Medicine
Xuliang Zhang: Zhejiang University
Huan Ma: Zhejiang University
Zhong Chen: Zhejiang Chinese Medical University
Zhijun Zhang: Southeast University
Zhaoqi Dong: Capital Medical University
Wei Yang: Zhejiang University School of Medicine
Xiangnan Zhang: Zhejiang University
Yihui Cui: Zhejiang University School of Medicine

Nature, 2025, vol. 641, issue 8062, 427-437

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-025-08807-4

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