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Stress dynamically modulates Neuronal Autophagy to gate depression onset [snRNA-seq]

GSE287308 Mus musculus Expression profiling by high throughput sequencing 6 samples Submitted 2025/01/20 Platform GPL24247
Summary
Chronic stress remodels brain homeostasis, in which persistent change leads to depressive disorders. As a key modulator of brain homeostasis, 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). Remarkably, 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 via on-demand degradation of glutamate receptors. Collectively, this study reveals 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 novel antidepressant strategy.
Published in
Stress dynamically modulates neuronal autophagy to gate depression onset
Yang L, Guo C, Zheng Z et al. · Nature 2025 · PMID 40205038 · doi:10.1038/s41586-025-08807-4
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Also filed as BioProject PRJNA1212076 and SRA study SRP558173. Searching any of these in the dataset finder brings you back here.

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