Neural Mechanisms of Habit Formation for Behaviors Motivated by Drugs of Abuse and Natural Reward

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7. Project Summary/Abstract The overall objective of this proposal is to shed light on neural circuits underlying the transition from recreational to compulsive drug use, and, in doing so, to provide the candidate with training in advanced techniques to study the neural circuitry involved in drug use and abuse. Substance use disorders are characterized by compulsive drug use in spite of negative consequences, which might arise from the development of strong drug-taking “habits.” These habits consist of rigid, inflexible drug- seeking behavior, and they stand in contrast to “goal-directed” drug-seeking, which is more flexible and driven by pursuit of a desired outcome (e.g. a euphoric state or relief from withdrawal). Habits can arise from behavior motivated by either natural reward (e.g. food) or drugs, and behavior that is initially goal-driven can transition to habitual control. Studies have shown that the shift from goal-driven behavior to habit is accompanied by a shift in behavioral control from the ventral to the dorsal striatum, and recent evidence suggests that this intra-striatal shift is “downstream” of a shift from the basolateral amygdala (BLA), to the central amygdala (CeA). However, direct evidence for this theory is lacking, especially in the form of a signaling mechanism. Moreover, although there is evidence that dopaminergic input to the BLA and CeA is essential for the maintenance of cued drug- seeking, it is unclear how dopamine receptors in the amygdala are involved in the initiation of drug-taking or the formation of drug-seeking habits. Therefore, the candidate will pursue three sets of experiments, each examining the transition from goal-directed to habitual behavior in the context of both natural reward and cocaine self-administration: (1) recording neural activity simultaneously in the BLA and CeA, (2) using an optogenetic strategy to stimulate or inhibit dopaminergic input to the BLA or CeA, and (3) using a chemogenetic strategy (DREADDs) to inhibit specific projections from the medial prefrontal cortex (mPFC) to the BLA or CeA. In this way, the proposed experiments will elucidate the signaling mechanism, the role of dopamine, and the role of divergent mPFC inputs in BLA/CeA control of goal- directed vs. habitual behavior. During the award period, the candidate will undergo rigorous training in the techniques and theory underlying self-administration studies of substance use and addiction. The candidate will also gain training and experience in advanced techniques for neural circuit dissection, including optogenetics and chemogenetics. This work will take place in both the candidate’s dedicated lab space and the labs of the candidate’s unique cross-departmental advisory committee, all within the flourishing neuroscience community of the University of Pittsburgh. In addition, training will focus on publishing, grantsmanship, and job search skills, effectively preparing the candidate to apply for larger grants and a tenure-track position within five years.