Spatiotemporal remodeling in habenula marks the onset of depression-related phenotypes
Patricia Molina, Denys Osypenko, Josep Garnica, Quentin Amossé, Farha Bouteldja, Léa Camelot, Sarah Mondoloni, Mauro Congiu, Claudia Kathe, Manuel Mameli
Nature Neuroscience October 19, 2026 DOI: 10.1038/s41593-026-02488-6 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Animal study (mouse model) using spatial transcriptomics, longitudinal in vivo two-photon calcium imaging, chemogenetics, and ketamine administration Peer reviewed |
|---|---|
| Population | Mice |
| Intervention | Ketamine |
| Topics | Depression |
| Key findings | Chronic stress in mice produced a temporally defined, topographically organized remodeling of gene expression in the lateral habenula, progressively heightened excitatory responses of LHb neurons to aversive stimuli, and depression-related behavioral phenotypes. Ketamine reversed the neuronal adaptations and, like chemogenetic limitation of LHb activity, exerted antidepressant effects when administered at the onset of the remodeling processes. |
Abstract
Abstract 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.
Comparable studies
Other preclinical and animal studies on depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Psychedelics, but Not Ketamine, Produce Persistent Antidepressant-like Effects in a Rodent Experimental System for the Study of Depression Rats | 2020 | Preclinical study | |
| A Single Subanesthetic Dose of Ketamine Relieves Depression-like Behaviors Induced by Neuropathic Pain in Rats Rats with spared nerve injury (neuropathic pain model), sham-operated rats, and control... | 2011 | Animal experimental study | |
| Effects of N,N-Dimethyltryptamine on Rat Behaviors Relevant to Anxiety and Depression Adult male Sprague-Dawley rats | 2018 | Experimental study | |
| A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Mice and cultured rat cortical neurons | 2023 | Preclinical study | |
| Comparison of (R)-ketamine and lanicemine on depression-like phenotype and abnormal composition of gut microbiota in a social defeat stress model Susceptible mice after chronic social defeat stress | 2017 | Preclinical animal study |
Citations in the library
Cites 4
- A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature 2021
- Sustained antidepressant effect of ketamine through NMDAR trapping in the LHb Nature October 18, 2023
- Brain region-specific action of ketamine as a rapid antidepressant. Science August 9, 2024
- Sustained rescue of prefrontal circuit dysfunction by antidepressant-induced spine formation Science April 12, 2019