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

TitleCholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating.
Publication TypeJournal Article
Year of Publication2020
AuthorsFavier M, Janickova H, Justo D, Kljakic O, Runtz L, Natsheh JY, Pascoal TA, Germann J, Gallino D, Kang J-I, Meng XQi, Antinora C, Raulic S, Jacobsen JPr, Moquin L, Vigneault E, Gratton A, Caron MG, Duriez P, Brandon MP, Rosa-Neto P, Chakravarty MM, Herzallah MM, Gorwood P, Prado MAm, Prado VF, Mestikawy SEl
JournalJ Clin Invest
Volume130
Issue12
Pagination6616-6630
Date Published2020 12 01
ISSN1558-8238
KeywordsAcetylcholine, Adult, Animals, Corpus Striatum, Donepezil, Feeding and Eating Disorders, Feeding Behavior, Female, Glutamic Acid, Humans, Interneurons, Levodopa, Male, Mice, Mice, Knockout, Middle Aged, Vesicular Acetylcholine Transport Proteins
Abstract

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.

DOI10.1172/JCI138532
Alternate JournalJ Clin Invest
PubMed ID33164988
PubMed Central IDPMC7685731
Grant ListR01 MH079201 / MH / NIMH NIH HHS / United States
R37 MH073853 / MH / NIMH NIH HHS / United States
MOP 126000 / / CIHR / Canada
MOP 136930 / / CIHR / Canada
MOP 89919 / / CIHR / Canada
PJT 162431 / / CIHR / Canada
PJT 159781 / / CIHR / Canada