Spatiotemporal remodeling in the habenula marks the onset of depression

Chronic stress has lasting adverse consequences that can lead, over time, to depressive disorders1‑4 yet identifying the optimal timeframe for effective therapies remains an unmet challenge. Enhanced neuronal activity and disrupted aversion-encoding in lateral habenula (LHb) are important mediators of stress-related behavioral repercussions5‑10, although the precise timing of its contribution is not understood. Here, we identified an antidepressant-sensitive onset of stress consequences in mice, observable across multiple levels of biological complexity – behavioral, functional, and molecular. Using spatial transcriptomics11,12, we generated a spatially-resolved molecular atlas of the LHb, revealing a topographically-organized and temporally-defined remodeling of gene expression in chronic stress. Longitudinal in vivo two-photon calcium imaging to survey the encoding properties of individual LHb neurons revealed progressively heightened excitatory responses to aversive stimuli. These neuronal adaptations were reversed by the antidepressant ketamine and mirrored both the progression of transcriptional changes as well as the emergence of depression-related behavioral phenotypes. Finally, both chemogenetically limiting LHb neuronal activity and administering ketamine at the onset of the remodeling processes exerted antidepressant effects. Together, these findings associate shared spatiotemporal signatures of LHb neuronal ensembles and genetic landscape with the onset of stress-induced depression-related states. This has implications for temporally tailoring therapeutical interventions in clinical practice.