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
View: Text | PDF
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

×

Figure 7

Pharmacological modulation of ACh or DA neurotransmission reverses the self-starvation phenotype observed in VAChTcKO mice.

Options: View larger image (or click on image) Download as PowerPoint
Pharmacological modulation of ACh or DA neurotransmission reverses the s...
(A and B) Percentage of mice that reached critical weight threshold for control (n = 10) or VAChTcKO mice (n = 10) treated with saline or l-DOPA (15 mg/kg). A total of 9–10 were used in each group. (B and C) Chronic pharmacological treatment with donepezil (0.3 mg/kg). Percentage of mice that reached critical weight threshold for control (n = 10) or VAChTcKO mice (n = 10) treated with saline or donepezil. Note that donepezil was effective to reverse decreased food intake observed for VAChTcKO mice compared with saline-treated (NaCl-treated) VAChTcKO mice and had no effect on control mice. Kaplan-Meier test (A–D) and post hoc comparison with log-rank Mantel-Cox and Gehan-Breslow-Wilcoxon tests. *P < 0.05. (E) Hypothetical model. Subcompartments of the striatum: (i) nucleus accumbens (NAc), reward-guided behaviors; (ii) dorsomedial striatum (DMS; or caudate in human), goal-directed behaviors; and (iii) dorsolateral striatum (DLS; or putamen in human), habits. Transitions from the NAc to the DMS and then to the DLS parallel the transition from voluntary reward-seeking behavior to compulsive behaviors. These transitions are finely tuned by dopamine (12). In VGLUT3cKO mice, DA effluxes are increased in the NAc/DMS but unchanged in the DLS. VGLUT3cKO mice are resistant to habit formation and remain in goal-directed behaviors. In contrast, in VAChTcKO mice, DA transmission is reduced by about 50%–70% in the NAc/DMS but remains unaltered in the DLS. Imbalanced DA levels in the NAc/DMS versus the DLS lead to rapid transitions from goal-directed behaviors to habits. In control conditions, VAChTcKO mice feed normally. Stressful conditions (e.g., restricted access to food) precipitate maladaptive eating behaviors in VAChTcKO mice.