Circuit mechanisms underlying inflexible habitual behaviors following chronic cocaine use

PROJECT SUMMARY/ABSTRACT K99 research: Habits are inflexible behaviors that occur independently of the outcome of a given action. In cocaine use disorder, habits are often discussed in the context of drug use; however, equally important is the impact of cocaine consumption on habitual behaviors that form in relation to non-drug stimuli. Indeed, clinical evidence suggests individuals suffering from cocaine use disorder rely on habits at the expense of goal- directed control in non-drug contexts. At the center of goal-directed and habitual control are the dorsomedial and dorsolateral striatum (DMS, DLS), respectively. Efficient action control depends on balanced activity between these two regions – a process that critically depends on dopamine modulation of D1- and D2- expressing spiny projection neurons (SPN). Importantly, repeated cocaine use in humans and animals results in deficits in dopamine release and striatal activity. Thus, both dopamine release and SPNs activity are necessary for adaptive behavioral control and are thought to be impaired in cocaine use disorder. I will ask: 1) Does a history of cocaine self-administration alter dopamine release to promote habitual behavior? Mice with a history of cocaine use will perform a sucrose-based operant task that generates both habitual and goal-directed behavior. Using fiber photometry and optogenetics, I will test the hypothesis that a history of drug use results in stronger dopamine deficits in DMS compared to DLS and that this imbalance promotes habits. 2) Does cocaine self-administration change neural activity patterns associated with habits differently than those related to goal-directed actions? Using cellular resolution in vivo calcium imaging, I will test the hypothesis that the cell-type specific activity related to habits in DLS is less variable than activity related to goal-directed movements and that these patterns are differentially affected by a history of cocaine. R00 research: I will transition into my independent research for the R00 phase of this award by asking: 3) What mechanisms allow specific behaviors to be differentially affected by a history of cocaine use? I will use video-triggered optogenetic stimulation of dopaminergic neurons to test the hypothesis that cocaine use affects how temporally precise dopamine release changes the encoding of specific actions. Training in applying optical tools to addiction research and in computational analysis during the K99 phase will be crucial to successfully carry out R00 experiments. Training: This proposal is designed to provide me with training in utilizing circuit neuroscience tools in the context of addiction models and with new skills in computational analysis. My mentorship team of Dr. Calipari, Wassum, Womelsdorf and Rubinov is well-suited to ensure success in the technical and theoretical aspects of my training. My plan also focuses on career development training, with a focus on writing and managing federal grants. These training goals are crafted to allow me to produce impactful contributions to addiction research in the short term and to rapidly acquire R01 funding upon transitioning to independence.