SUMMARY
Compulsive behavior is a defining feature of disorders such as substance use disorder and obsessive-compulsive disorder. Current evidence suggests that corticostriatal circuits control the expression of established compulsions, but little is known about the mechanisms regulating the development of compulsions. We hypothesized that dopamine, a critical modulator of striatal synaptic plasticity, could control alterations in corticostriatal circuits leading to the development of compulsions (defined as continued reward-seeking in the face of punishment). We used dual-site fiber photometry to measure dopamine axon activity in the dorsomedial striatum (DMS) and the dorsolateral striatum (DLS) as compulsions emerged. Individual variability in the speed with which compulsions emerged was predicted by DMS dopamine axon activity. Amplifying this dopamine signal accelerated animals’ transitions to compulsion, whereas inhibition led to learning delays. In contrast, amplifying DLS dopamine signaling had no effect on the emergence of compulsions. These results establish DMS dopamine signaling as a key controller of the development of compulsive reward-seeking.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
↵5 Lead Contact
We increased the "n" in our initial behavior and fiber photometry experiments. Including these additional mice resulted in better-powered analyses and allowed at least some insight into the role of sex differences in our results. We now show recordings from the RI30 stage of training. These recordings help show how dopamine axon activity evolves across training stages and better motivate the optogenetic experiments performed. We performed two new optogenetics experiments - one inhibiting DMS dopamine terminals, and the other stimulating DLS dopamine terminals. These experiments add context to the previous results highlighting the role of DMS dopamine in provoking compulsive behavior and add robustness to the findings.