Stress dynamically modulates neuronal autophagy to gate depression onset
Chronic stress remodels brain homeostasis, in which persistent change leads to depressive disorders<sup>1</sup>. As a key modulator of brain homeostasis<sup>2</sup>, 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.
Authors
- Wei Yang (ORCID: https://orcid.org/0000-0003-3065-1843)
- Qifeng Xie (ORCID: https://orcid.org/0000-0001-7152-2461)
- Xiangnan Zhang (ORCID: https://orcid.org/0000-0002-7603-7403)
- Zhi-Wei Zheng (ORCID: https://orcid.org/0000-0002-9725-9566)
- Yiqin Liu
- Zijian Lv (ORCID: https://orcid.org/0000-0001-5176-6397)
- Xuliang Zhang (ORCID: https://orcid.org/0000-0002-8952-8009)
- Yiyan Dong (ORCID: https://orcid.org/0000-0002-4664-4579)
- Yihui Cui (ORCID: https://orcid.org/0000-0002-7362-6237)
- Huan Ma (ORCID: https://orcid.org/0000-0003-4359-8631)
- Zhaoqi Dong
- Zhijun Zhang (ORCID: https://orcid.org/0000-0001-5480-0888)
- Min Li (ORCID: https://orcid.org/0000-0002-3971-9130)
- Zhong Chen (ORCID: https://orcid.org/0000-0003-4755-9357)
- Xiaonan Guo (ORCID: https://orcid.org/0000-0002-0801-6133)
- Yangyang Lu (ORCID: https://orcid.org/0000-0002-2933-3461)
- Liang Yang (ORCID: https://orcid.org/0000-0002-1872-6083)
- Guo Chen (ORCID: https://orcid.org/0000-0002-5200-5802)
- Ruiqi Mu
- Rongshan Deng
- Yirong Feng
Institutions
- Zhejiang Chinese Medical University (CN)
- Allen Institute for Brain Science (US)
- Capital Medical University (CN)
- Chinese Academy of Sciences (CN)
- Sir Run Run Shaw Hospital (CN)
- Zhongda Hospital Southeast University (CN)
- Jinhua Academy of Agricultural Sciences (CN)
- Zhejiang Lab (CN)
- Shenzhen Institutes of Advanced Technology (CN)
- Zhejiang University (CN)
Publication Details
- Journal
- Nature
- Published
- 2025-04-09
- DOI
- https://doi.org/10.1038/s41586-025-08807-4
- Citations
- 36
- Primary Topic
- Autophagy in Disease and Therapy
- Type
- article
- Field-Weighted Citation Impact
- 48.75