Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating
Mathieu Favier, … , Vania F. Prado, Salah El Mestikawy
Mathieu Favier, … , Vania F. Prado, Salah El Mestikawy
Published November 9, 2020
Citation Information: J Clin Invest. 2020;130(12):6616-6630. https://doi.org/10.1172/JCI138532.
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Research Article Neuroscience

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

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.

Authors

Mathieu Favier, Helena Janickova, Damian Justo, Ornela Kljakic, Léonie Runtz, Joman Y. Natsheh, Tharick A. Pascoal, Jurgen Germann, Daniel Gallino, Jun-II Kang, Xiang Qi Meng, Christina Antinora, Sanda Raulic, Jacob P.R. Jacobsen, Luc Moquin, Erika Vigneault, Alain Gratton, Marc G. Caron, Philibert Duriez, Mark P. Brandon, Pedro Rosa Neto, M. Mallar Chakravarty, Mohammad M. Herzallah, Philip Gorwood, Marco A.M. Prado, Vania F. Prado, Salah El Mestikawy

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Figure 3

Acetylcholine or glutamate released from striatal cholinergic interneurons differentially regulates transition from goal-directed behaviors to habits.

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Acetylcholine or glutamate released from striatal cholinergic interneuro...
(A) Diagram showing the training for sucrose self-administration and devaluation test. (B) Number of sucrose pellet deliveries for VGLUT3cKO mice (n = 11) versus controls (n = 13) during FR1 training. (C) Devaluation test for VGLUT3cKO mice (n = 11) versus controls (n = 12) after FR1 training. (D) Number of sucrose pellet deliveries for VGLUT3cKO mice (n = 11) versus controls (n = 13) during the 2 last sessions of FR1 training, followed by 8 sessions of random interval (RI) training to bias mice toward habits. (E) Devaluation after RI training presented in log10 and in raw number of nosepokes. (F) Number of sucrose pellet deliveries for VAChTcKO male mice (n = 12) versus controls (n = 12) during FR1 training. (G) Devaluation test of VAChTcKO male mice after FR1 training. (H) Progressive ratio (PR) test to assess the motivation of VAChTcKO male mice (n = 12) and littermate controls (n = 12). (I) Number of sucrose pellet deliveries for VAChTcKO female mice (n = 13) versus controls (n = 11) during FR1 training. (J) Devaluation test of VAChTcKO mice (n = 13) versus respective controls (n = 11). (K) PR test of VAChTcKO female mice (n = 13) and littermate controls (n = 11). Two-way repeated-measures ANOVA (B, D, F, and I) and post hoc comparison with the method of contrasts; paired 2-tailed t test (C, E, G, and J); unpaired 2-tailed t test (H and K). *P < 0.05, **P < 0.01, ***P < 0.001.