Cholinergic dysfunction in the dorsal striatum promotes habit formation and maladaptive eating
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
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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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 4

VAChTcKO mice develop binge- and anorexia-like phenotypes.

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VAChTcKO mice develop binge- and anorexia-like phenotypes. (A) Diagram s...
(A) Diagram showing the binge-like sucrose overconsumption model. Mice alternated daily between 20-hour food restriction and 4-hour simultaneous access to food and to a highly concentrated sucrose solution. (B) Daily sucrose consumption by male VAChTcKO mice (n = 12) and littermate controls (n = 12) during access to sucrose solution (H0–H4). (C) Daily sucrose consumption by male VAChTcKO mice and controls during the first hour of access to sucrose solution (H0–H1). (D) Daily sucrose consumption by male VAChTcKO mice and controls during the last 3 hours of access to sucrose solution (H1–H4). (E) Daily sucrose consumption by female VAChTcKO mice (n = 13) and littermate controls (n = 11) during access to sucrose solution (H0–H4). (F) Daily sucrose consumption by female VAChTcKO mice and littermate controls during the first hour of access to sucrose solution (H0–H1). (G) Daily sucrose consumption by female VAChTcKO mice and controls during the last 3 hours of access to sucrose solution (H1–H4). (H) Diagram of the activity-based anorexia (ABA) model. During baseline, mice were habituated to cages with running wheel for 7 days receiving ad libitum food. Then, mice underwent a progressive time-restricted access to food for 8 days. (I and J) Percentage of male (I, n = 12) and female (J, n = 12) VAChTcKO mice and controls (n = 12) that reached a critical level of less than 75% baseline BW compared with controls during ABA. Note that male and female VAChTcKO mice were significantly more affected than control mice. Two-way repeated-measures ANOVA (B–G) and post hoc comparison with the method of contrasts; Kaplan-Meier test (I and J) and post hoc comparison with log-rank Mantel-Cox and Gehan-Breslow-Wilcoxon tests. *P < 0.05, **P < 0.01, ***P < 0.001.