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 6

VAChT in the dorsomedial striatum regulates dopamine efflux and maladaptive eating.

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VAChT in the dorsomedial striatum regulates dopamine efflux and maladapt...
(A) Targeting of the dorsomedial subcompartment of the striatum (DMS) by voltammetric electrodes. NAc, nucleus accumbens. (B and C) DA release (B) and maximum level of DA release (C) in the DMS of VAChTcKO mice (n = 16) and controls (n = 11). (D) Putative model for dual regulation of striatal DA efflux by ACh/Glu released by ChIs varicosities in the DMS. DA efflux is stimulated by ACh through nicotinic receptors (nAChRs) and inhibited by glutamate through metabotropic glutamate receptors (mGluRs). (E) Targeting of the dorsolateral subcompartment of the striatum (DLS) by voltammetric electrodes. (F and G) DA release (F) and maximum level of DA release (G) in the DLS of VAChTcKO mice (n = 16) and controls (n = 17). (H) The absence of regulation of DA release by ACh/Glu released by ChI varicosity in the DLS. (I) Quantification of VAChT (left) and VGLUT3 (right) protein expression following infusion of AAV-Cre or AAV-GFP viruses in the DMS of VAChTfl/fl mice (VAChTcKO-DMS, n = 11) or control mice (n = 11). (J–L) VAChTcKO-DMS mice and controls in the binge-like sucrose overconsumption model. (J) Daily sucrose consumption during the total duration of access (H0–H4) for VAChTcKO-DMS mice and controls. (K) Similar to J but for H0–H1. (L) Similar to J but for H1–H4. (M) ABA model. Percentage of VAChTcKO-DMS mice and controls that reached a critical level of less than 75% baseline BW compared with controls during ABA. Two-way repeated-measures ANOVA (B, F, and J) and post hoc comparison with the method of contrasts; unpaired 2-tailed t test (C, G, and I); Kaplan-Meier test (M) and post hoc comparison with log-rank Mantel-Cox and Gehan-Breslow-Wilcoxon tests. *P < 0.05, **P < 0.01, ***P < 0.001.