Stress dynamically modulates Neuronal Autophagy to gate depression onset

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. RNA-sequencing was performed with fresh LHb, vHippo, mPFC, VTA, LH and NAc samples from chronic restraint stress (CRS) and naïve mice tested using FST 2 days prior to sacrifice. We divided CRS and naïve mice into two groups, respectively. Namely, CRS mice with high FST scores (FST immobility>110 s, n = 3), CRS mice with low FST scores (50 s