Pré-Publication, Document De Travail Année : 2025

Adaptive changes of cholinergic projections to the nucleus accumbens bidirectionally mediate cocaine reinforcing effects

Laa Aguiar
R Bastos-Gonçalves
  • Fonction : Auteur
Tta Carvalho
Ac Faria
  • Fonction : Auteur
Nap Vasconcelos
B Coimbra
Aj Rodrigues

Résumé

Abstract The laterodorsal tegmentum (LDT) sends critical inputs to distinct reward circuit regions, including the nucleus accumbens (NAc), but their functional role in addiction-related behaviors remains underexplored. Here, we demonstrate that LDT-NAc cholinergic projections undergo cocaine-induced adaptations and modulate cocaine-related behaviors. Using cell type-specific tracing, we show that LDT neurons preferentially innervate NAc medium spiny neurons and cholinergic interneurons. Large-scale in vivo recordings reveal that cocaine pre-exposure induces persistent alterations in both LDT and NAc neuronal dynamics and modifies responses to subsequent cocaine challenge. Remarkably, pre-exposure to cocaine triggers population-specific adaptations in the LDT, selectively enhancing excitability of LDT-NAc-projecting cholinergic neurons while reducing that of non-projecting cholinergic cells. Behaviorally, optogenetic activation of LDT-NAc cholinergic projections enhances cocaine conditioning, whereas their inhibition diminishes cocaine’s reinforcing effects. Our findings identify LDT-NAc cholinergic inputs as key substrates of cocaine-induced plasticity, and critical mediators of cocaine’s rewarding properties, introducing a novel component to addiction circuitry.

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hal-05369298 , version 1 (17-11-2025)

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Laa Aguiar, L Royon, R Bastos-Gonçalves, Tta Carvalho, E Teixeira, et al.. Adaptive changes of cholinergic projections to the nucleus accumbens bidirectionally mediate cocaine reinforcing effects. 2025. ⟨hal-05369298⟩
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