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 5

Propensity to habitual behavior predicts binge- and anorexia-like phenotypes in VAChTcKO mice.

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Propensity to habitual behavior predicts binge- and anorexia-like phenot...
(A–D) Matrices show P values of the associations between behavioral data in control (Ctrl) male mice (A), VAChTcKO male mice (B), control female mice (C), and VAChTcKO female mice (D). (E and F) Estimates of the structural equation model representing the association between habits (devaluation scores), motivation (breaking point during PR test), anorexia-like phenotype (food intake during ABA model), and binge-like phenotype (H0–H1 sucrose intake during binge-like sucrose overconsumption test) for control mice or VAChTcKO mice. These associations were adjusted by sex. Solid lines represent significant effects, whereas dashed lines represent nonsignificant ones. The effect sizes (β estimates) presented in the figure were fully standardized and therefore may be compared. Estimates were derived from a model that fit the data well (root mean square error of approximation = 0.0, standardized root mean square residual = 0.00, comparative fit index = 1.000, Akaike information criterion = 639.918, and Bayesian information criterion = 650.888) and show that habits correlate to maladaptive eating only in VAChTcKO mice. (G) ROC curves based on probabilities generated from logistic regression analyses. The logistic regression model that generated these probabilities included valuation scores, devaluation scores, motivation scores, genotype, and sex to predict binge. The logistic regression model showed 83.3% sensitivity and 94.4% specificity in predicting vulnerability to binge-like behavior. The significant predictors were the valuation scores and sex. Devaluation scores were approaching significance. The area under the ROC curve (diagnostic power) is 94.4%. (H) The logistic regression model that generated the probabilities included valuation scores, devaluation scores, motivation scores, genotype, and sex to predict anorexia. The model exhibited 76.9% sensitivity and 88.6% specificity in identifying vulnerability to anorexia-like behavior. The only significant predictor was the devaluation scores. The area under the ROC curve (diagnostic power) is 92.1%.