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 1

The balance between goal-directed behaviors and habits is altered in a subgroup of restrictive-type anorexia nervosa patients.

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The balance between goal-directed behaviors and habits is altered in a s...
(A and B) Instrumental learning stage. Eating disorder (ED) patients showed similar instrumental learning performances compared with healthy controls (HCs); accuracy was increased across blocks of trainings for all groups. (C and D) Outcome devaluation stage. In the second phase, accuracy of ED patients to direct their choices toward still-valued outcomes was not modified in comparison with HCs, suggesting that knowledge of response-outcome associations was not affected by the pathology. (E) Slip-of-action stage. During phase 3, the percentage of responses for valued outcome was not modified for ED patients. Together, these data suggest that ED patients performed similarly to controls in response to devalued outcome, but performance of ED patients was highly heterogeneous compared with controls. Dividing between restrictive anorexia nervosa (AN-R) and binge eating/purging ED patients (ED-BP) revealed that the AN-R subgroup responded significantly more to devalued items in phase 3. (F) Baseline stage of inhibitory control. No difference was found between HCs, AN-R, and ED-BP in the percentage of responses to valued or devalued stimuli. (G–I) Correlation analyses between cognitive flexibility as evaluated by the Trail Making Test B-A (TMTB-A) and the percentage of responses to devalued outcome measured in phase 3. (G) The rate of responses for devalued outcome of ED patients was correlated with a deficit of cognitive flexibility. (H and I) This correlation was specific to the AN-R group (H) but was not seen with the ED-BP subgroup (I). Two-way repeated-measures ANOVA (A and B) and post hoc comparison with the method of contrasts; unpaired 2-tailed t test (C); 1-way ANOVA (D); 2-way ANOVA (E and F) and post hoc comparison with Dunnett’s test. Dimensional analyses were performed by parametric simple linear regressions for G–I. **P < 0.01.