Mesopontine cholinergic inputs to midbrain dopamine neurons drive stress-induced depressive-like behaviors

Sebastian P. Fernandez (), Loïc Broussot, Fabio Marti, Thomas Contesse, Xavier Mouska, Mariano Soiza-Reilly, Hélène Marie, Philippe Faure and Jacques Barik ()
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Sebastian P. Fernandez: Université Côte d’Azur
Loïc Broussot: Université Côte d’Azur
Fabio Marti: Université Pierre et Marie Curie
Thomas Contesse: Université Côte d’Azur
Xavier Mouska: Université Côte d’Azur
Mariano Soiza-Reilly: Université Pierre et Marie Curie
Hélène Marie: Université Côte d’Azur
Philippe Faure: Université Pierre et Marie Curie
Jacques Barik: Université Côte d’Azur

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06809-7

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