2. Academic Validation
  3. Stress dynamically modulates neuronal autophagy to gate depression onset

Stress dynamically modulates neuronal autophagy to gate depression onset

  • Nature. 2025 May;641(8062):427-437. doi: 10.1038/s41586-025-08807-4.
Liang Yang # 1 2 3,  Chen Guo # 1 2 3,  Zhiwei Zheng # 1 2 3,  Yiyan Dong # 1 4 5,  Qifeng Xie 1 2 3,  Zijian Lv 1 2 3,  Min Li 1 4 5,  Yangyang Lu 6 7,  Xiaonan Guo 1 4 5,  Rongshan Deng 1 4 5,  Yiqin Liu 1 2 3,  Yirong Feng 1 4 5,  Ruiqi Mu 1 2 3,  Xuliang Zhang 8,  Huan Ma 2 3,  Zhong Chen 9,  Zhijun Zhang 10 11,  Zhaoqi Dong 12,  Wei Yang 5,  Xiangnan Zhang 13 14,  Yihui Cui 15 16 17
Affiliations

Affiliations

  • 1 Department of Psychiatry of Sir Run Run Shaw Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China.
  • 2 MOE Frontier Science Center for Brain Science and Brain-Machine Integration, Zhejiang University, Hangzhou, China.
  • 3 NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou, China.
  • 4 International Institutes of Medicine, The Fourth Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, China.
  • 5 Department of Biophysics and Department of Neurology of the Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 6 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, China.
  • 7 Jinhua Institute of Zhejiang University, Jinhua, China.
  • 8 Laboratory Animal Center, Zhejiang University, Hangzhou, China.
  • 9 Zhejiang Key Laboratory of Neuropsychopharmacology, Zhejiang Chinese Medical University, Hangzhou, China.
  • 10 Department of Neurology, Affiliated Zhongda Hospital, School of Medicine, Institute of Neuropsychiatry, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing, China.
  • 11 Department of Mental Health and Public Health, Faculty of Life and Health Sciences, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China.
  • 12 Department of Neurobiology, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
  • 13 Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, State Key Laboratory of Advanced Drug Delivery and Release Systems, Zhejiang University, Hangzhou, China. [email protected].
  • 14 Jinhua Institute of Zhejiang University, Jinhua, China. [email protected].
  • 15 Department of Psychiatry of Sir Run Run Shaw Hospital and School of Brain Science and Brain Medicine, Zhejiang University School of Medicine, Hangzhou, China. [email protected].
  • 16 MOE Frontier Science Center for Brain Science and Brain-Machine Integration, Zhejiang University, Hangzhou, China. [email protected].
  • 17 NHC and CAMS Key Laboratory of Medical Neurobiology, Zhejiang University, Hangzhou, China. [email protected].
  • # Contributed equally.
PMID: 40205038 DOI: 10.1038/s41586-025-08807-4
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.

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