¹Mayo Clinic College of Medicine and Science, Pharmacology, Rochester, United States, ²Mayo Clinic College of Medicine and Science, Neurosurgery, Rochester, United States, ³Mayo Clinic College of Medicine and Science, Pharmacology and Psychiatry, Rochester, United States

Background: The dorsolateral striatum (DLS) is predominantly associated with movement and habitual behaviors while the dorsomedial striatum (DMS) is primarily recognized for regulating goal-directed reward-seeking behaviors. Notably, activating striatal direct-pathway medium spiny neurons (dMSN) enhances reinforcement learning, whereas stimulating striatal indirect-pathway MSN (iMSN) induces avoidance behaviors and inhibits reinforcement. Although extensive research has compared the functions of DMS versus DLS or iMSN versus dMSN in reward-seeking, it remains unclear whether iMSN may exhibit distinct roles in suppressing compulsive alcohol-seeking within each specific striatal subregion.

Aims & Objectives: In this study, we sought to address this by selectively ablating iMSN^DMS->GPe and iMSN^DLS->GPe and trained mice to exhibit goal-directed and habitual reward-seeking behaviors using random ratio (RR) and random interval (RI) operant conditioning, respectively. We also aim to investigate whether circuit-specific partial ablation alters compulsive alcohol-seeking and drinking behaviors.

Method: To ablate the circuit in a targeted fashion, we employed a genetically engineered caspase 3, in which activation results in apoptosis. We also investigated compulsive ethanol-seeking behaviors using nose-poke operant alcohol-drinking experiments in a two-bottle choice (water versus alcohol) paradigm with or without quinine adulteration.

Results: Interestingly, caspase 3-mediated ablation of iMSN^DMS->GPe resulted in an insensitivity to satiety-based reward devaluation in RR-trained mice, consistent with a shift toward habitual behavior. The ablation of iMSN^DLS->GPe did not influence locomotor function in the open field test and accelerated rotor rod or anxiety-related behaviors, nor did it affect the expression of habitual or goal-directed seeking behavior during the devaluation of a random interval or random ratio operant schedule. However, when subjected to quinine adulteration, mice with iMSN^DLS->GPe ablation exhibited increased compulsive alcohol-seeking behaviors in habitual and goal-directed operant conditioning paradigms. Consistently, in a separate cohort of mice, we found that the iMSN^DLS->GPe ablated mice showed higher preference and consumption of alcohol than control mice in a two-bottle choice experiment, with increasing quinine concentration and exhibiting more compulsive-like behavior. The iMSN^DLS->GPe ablated mice prefer more ethanol than control mice while still developing an aversion to seeking the reward.​

Discussion & Conclusions: Altogether, our findings reveal an essential role of iMSN^DLS->GPe in behavioral flexibility and inhibiting compulsive-like behavior, which may be a potential therapeutic target for alcohol and other addictive disorders. Our findings reveal a novel role of iMSN^DLS->GPe in behavioral flexibility and constraining habitual reward-seeking, which may be a potential therapeutic target for alcohol use disorder and other compulsive disorders.