Neuronal dynamics underlying depressive-like states

Chronic stress induces neurobiological adaptations that can lead to depressive-like states, yet their temporal dynamics remain poorly understood. The lateral habenula (LHb) –a key node for aversion– shows stress-induced hyperactivity, but when these adaptations emerge and become behaviorally relevant is unclear. Here, we identify a temporally-defined onset of stress consequences in mice across behavioral, functional, and molecular levels using chronic corticosterone (CORT) administration. Using spatial transcriptomics, we generated an LHb molecular atlas that revealed topographically and temporally organized gene expression remodeling during CORT. Longitudinal two-photon calcium imaging revealed progressively enhanced LHb neuronal responses to aversive stimuli, with stable excitatory or inhibitory clusters alongside dynamic populations that increased their responses over CORT exposure, with distinct spatial patterns. These changes paralleled behavioral alterations, including reduced active coping and increased apathy-like behaviors. Ketamine reversed LHb remodeling and behavioral alterations when given at remodeling onset, and chemogenetic inhibition of LHb hyperactivity during this window normalized depression-related behaviors. Together, these findings identify shared spatiotemporal signatures across LHb neuronal ensembles, molecular landscape, and behavioral states, revealing a critical time window when antidepressant interventions can reverse stress-induced adaptations.