199 | Acetylcholine dynamics in depression

Disorders of the Nervous System

Author: Daiana Rigoni | Email: rigoni@ipmc.cnrs.fr

Daiana Rigoni , Lea Royón , Marion Violain , Fernandez Sebastián , Jacques Barik

1° Université Côte d’Azur. Institut de Pharmacologie Moléculaire & Cellulaire, CNRS UMR 7275, Valbonne, France.

Stressful life events are primary risk factors favoring depression. In mice, chronic social defeat (CSD) induces susceptibility and resilience to stress. Both phenotypes are causally linked to distinct cellular and synaptic adaptations of Ventral Tegmental Area (VTA). However, the underlying homeostatic mechanisms are far from solved. The cholinergic (ACh) transmission is key to modulate VTA homeostasis. CSD causes a marked hyperactivity of laterodorsal tegmemtum (LDTg) cholinergic cells projecting to the VTA, which is a prerequisite for the subsequent maladaptations in VTA dopamine neurons, and the appearance of a depressive-like symptoms. Resilient mice exhibit a diminished sensitivity of VTA nicotinic acetylcholine receptors (nAChRs) when exposed to the exogenous agonist nicotine, suggesting a key role of ACh transmission/sensitivity of nicotinic systems in delineating susceptibility and resilience to depression. Here, we address the temporal dynamics of ACh transmission in vivo using fiber photometry measures of endogenous ACh release and calcium transients to unravel pre- and post-synaptic VTA adaptations during CSD. We also investigate how ACh transmission impacts VTA subnetworks considering the cellular heterogeneity of VTA neurons and the sensitivity of nAChRs using ex vivo electrophysiology and pharmacological approaches. This project will give new precedent to understand the neurobiological mechanisms in vivo underlying the susceptibility and resilience to stress.