A2: Striosomal models of drug use and cost - Project Summary Our understanding of the mechanistic underpinnings of drug consumption and craving has been greatly aided by the development of numerous computational models focused on these behaviors. However, most of these models ignore the role of cost. To this end, our proposal seeks to experimentally validate a novel computational neurobiological model of costly drug-taking behavior centered on the striosomes of the dorsomedial striatum (DMS). Notably, the striosomes lie at the center of the cortico-striatal- dopaminergic circuit, which is critical for drug-seeking behavior and the evaluation of co- occurring cost and reward. While DMS striosomes have been implicated in behaviors such as locomotor sensitization to cocaine, no studies have investigated the computational and experimental role of striosomes in a cost-drug tradeoff during self- administration behavior. We recently developed a computational model of striosomal state-switching in cost/benefit decision-making. Using this model, we have shown that different neural ‘states’ such as stress and aging can, via striosomal circuitry, drive distinct patterns of cost/benefit decision-making. Here, we seek to develop an expanded version of this model to demonstrate a role for striosomal circuitry in driving drug-taking in the face of cost. We hypothesize that the prelimbic-striosomal-substantia nigra pars compacta circuit mediates the impact of craving on drug-cost tradeoffs and predicts vulnerable drug-taking phenotypes associated with cost. We will assess drug-taking using two distinct drug-taking paradigms that involve a cost: punished responding and effortful responding. These two types of costs differentially impact drug-taking, and we hypothesize that animals will form distinct patterns of vulnerability and resilience to drug-taking paired with these costs. Furthermore, the neurocircuitry underlying these two types of costs differs, and both sex and drug type (cocaine vs. opioids) differentially interact with cost type. In total, our goal is to validate a computational model of costly drug-taking during a craving state. Towards this goal, we will use electrophysiology, optogenetics, and advanced modeling techniques to determine the role of the prelimbic- striosomal (Aim 1) and striosomal-substantia nigra (Aim 2) circuits in vulnerability for punished and effortful drug-taking behavior. Collectively, these studies will move us towards our long-term goals of predicting individuals who are at-risk for relapse, and providing new targets for intervention to prevent relapse.
