Mesopontine cholinergic inputs to midbrain dopamine neurons drive stress-induced depressive-like behaviors
Open accessAbstract
Stressful life events are primary environmental factors that markedly contribute to depression by triggering brain cellular maladaptations. Dysregulation of ventral tegmental area (VTA) dopamine neurons has been causally linked to the appearance of social withdrawal and anhedonia, two classical manifestations of depression. However, the relevant inputs that shape these dopamine signals remain largely unknown. We demonstrate that chronic social defeat (CSD) stress, a preclinical paradigm of depression, causes marked hyperactivity of laterodorsal tegmentum (LDTg) excitatory neurons that project to the VTA. Selective chemogenetic-mediated inhibition of cholinergic LDTg neurons prevent CSD-induced VTA DA neurons dysregulation and depressive-like behaviors. Pro-depressant outcomes are replicated by pairing activation of LDTg cholinergic terminals in the VTA with a moderate stress. Prevention of CSD outcomes are recapitulated by blocking corticotropin-releasing factor receptor 1 within the LDTg. These data uncover a neuro-circuitry of depressive-like disorders and demonstrate that stress, via a neuroendocrine signal, profoundly dysregulates the LDTg.
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Release of ACh from LDT projections directly modulates activity of VTA DA neurons, finely tuning their firing rate and burst properties.
“The release of ACh from LDT projections directly modulates activity of VTA DA neurons, finely tuning their firing rate and burst properties [73, 74].”
From Adolescent nicotine exposure and persistent neurocircuitry changes: unveiling lifelong psychiatric risks (2025) · cites this paper as [74]
The Discussion (Fig. 6; page not provided) says enhanced acetylcholine release directly increases VTA dopamine-neuron firing and that LDTg excitatory projections regulate firing and bursting. The Results (‘Silencing LDTg prevents maladaptations to chronic stress’; page not provided) show reduced firing and bursting after silencing the LDTg as a whole, but do not establish that acetylcholine release specifically tunes bursting. (LLM, conf=0.82)
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“The release of ACh from LDT projections directly modulates activity of VTA DA neurons, fi nely tuning their fi ring rate and burst properties [73, 74].”
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- Authors
- Fernandez, S. P., Broussot, L., Marti, F., Contesse, T., Mouska, X., Soiza-Reilly, M., Marie, H., Faure, P., & Barik, J.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- ORCID
- Venue
- Nature Communications
- Published
- 2018-10-25
- Volume
- 9
- Issue
- 1
- Pages
- 4449-4449
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6202358
- OpenAlex
- W2896041157
- Cited by
- 75
- References
- 58
- Citations by year
- 2026: 8 · 2025: 11 · 2024: 8 · 2023: 7 · 2022: 12 · 2021: 10 · 2020: 13 · 2019: 5
- FWCI
- 3.19
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas) (submittedVersion, cc-by-nc-sa)
- HAL (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- Americanae (AECID Library) (submittedVersion, cc-by-nc-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-13-JSV4-0004, ANR-16-CE16-0020, ANR-16)
- Fondation pour la Recherche Médicale
- Karolinska Institutet
- Centre National de la Recherche Scientifique
- Institut Universitaire de France
- Institut National Du Cancer
- Université de Lausanne
- Fédération pour la Recherche sur le Cerveau
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- depression, chronic social defeat stress, laterodorsal tegmentum, ventral tegmental area dopamine neurons, corticotropin-releasing hormone receptor 1, chemogenetic inhibition, anhedonia, social withdrawal
- MeSH terms
- CRF Receptor, Type 1, Acetylcholine, Animals, Behavior, Animal, Chronic Disease, Corticotropin-Releasing Hormone, Depression, Male, Mesencephalon, Mice, Inbred C57BL, Models, Biological, Pons, Stress, Psychological, Signal Transduction, Ventral Tegmental Area, Receptors, Corticotropin-Releasing Hormone, Glutamic Acid, Gene Silencing, Dopaminergic Neurons, Pontine Tegmentum
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