Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating.

Journal Article (Journal Article)

Dysregulation of habit formation has been recently proposed as pivotal to eating disorders. Here, we report that a subset of patients suffering from restrictive anorexia nervosa have enhanced habit formation compared with healthy controls. Habit formation is modulated by striatal cholinergic interneurons. These interneurons express vesicular transporters for acetylcholine (VAChT) and glutamate (VGLUT3) and use acetylcholine/glutamate cotransmission to regulate striatal functions. Using mice with genetically silenced VAChT (VAChT conditional KO, VAChTcKO) or VGLUT3 (VGLUT3cKO), we investigated the roles that acetylcholine and glutamate released by cholinergic interneurons play in habit formation and maladaptive eating. Silencing glutamate favored goal-directed behaviors and had no impact on eating behavior. In contrast, VAChTcKO mice were more prone to habits and maladaptive eating. Specific deletion of VAChT in the dorsomedial striatum of adult mice was sufficient to phenocopy maladaptive eating behaviors of VAChTcKO mice. Interestingly, VAChTcKO mice had reduced dopamine release in the dorsomedial striatum but not in the dorsolateral striatum. The dysfunctional eating behavior of VAChTcKO mice was alleviated by donepezil and by l-DOPA, confirming an acetylcholine/dopamine deficit. Our study reveals that loss of acetylcholine leads to a dopamine imbalance in striatal compartments, thereby promoting habits and vulnerability to maladaptive eating in mice.

Full Text

Duke Authors

Cited Authors

  • Favier, M; Janickova, H; Justo, D; Kljakic, O; Runtz, L; Natsheh, JY; Pascoal, TA; Germann, J; Gallino, D; Kang, J-I; Meng, XQ; Antinora, C; Raulic, S; Jacobsen, JP; Moquin, L; Vigneault, E; Gratton, A; Caron, MG; Duriez, P; Brandon, MP; Neto, PR; Chakravarty, MM; Herzallah, MM; Gorwood, P; Prado, MA; Prado, VF; El Mestikawy, S

Published Date

  • December 1, 2020

Published In

Volume / Issue

  • 130 / 12

Start / End Page

  • 6616 - 6630

PubMed ID

  • 33164988

Pubmed Central ID

  • 33164988

Electronic International Standard Serial Number (EISSN)

  • 1558-8238

Digital Object Identifier (DOI)

  • 10.1172/JCI138532

Language

  • eng

Conference Location

  • United States