Experience-Dependent Regulation of Reward Learning and Addiction Vulnerability

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Project Summary Stressful life events lead to increased risk of addiction and other psychiatric disorders, while daily exercise may help reduce susceptibility to addiction and mitigate the influence of stress. Maladaptive attribution of incentive salience to environmental cues associated with rewards, such as addictive drugs or palatable foods, is thought drive cue-induced craving and relapse, one of the core symptoms of addictive disorders. Yet, how stress and exercise differentially regulate the reward learning processes that drive assignment of incentive value to environmental stimuli remains poorly understood. Thus, the goal of the current project is to determine the impact of stress and daily exercise on the mechanisms and rules governing cue-reward learning. Dopamine neurons in the ventral tegmental area (VTA) play a critical role in reward-based learning. These neurons acquire transient bursting responses to reward-predicting cues during repeated cue-reward pairing, thereby assigning incentive value to those cues. We have previously described Hebbian plasticity of NMDA receptor-mediated glutamatergic transmission onto dopamine neurons that may, in part, contribute to the acquisition of conditioned bursting responses. Using rats, this proposal will test the hypothesis that stress and daily exercise will exert opposing influences on NMDA plasticity and learning of drug/food-associated cues, thus enabling daily exercise to buffer the impact of stress. In Aim 1, we will ask how stress exposure regulates the magnitude, rate, and timing dependence of cue-reward learning. In Aim 2, we will determine the differential roles of corticotropin-releasing factor (CRF) and norepinephrine (NE), two major mediators of stress responses, in regulating cue-reward learning and NMDA plasticity. In these two aims, we will also investigate the influence of the psychostimulant amphetamine, which causes robust NE release in the brain and is a well- known risk factor for the development of concurrent non-drug addictions. In Aim 3, we will ask how daily running experience affects learning and plasticity in a manner that counteracts the effects of stress and amphetamine examined in the first two aims. Chemogenetic manipulations of the activity of noradrenergic neurons projecting to the VTA, together with measurement of NE levels in the VTA with microdialysis, will be performed to further probe the role of noradrenergic signaling. This project will allow determination of a plasticity mechanism that may contribute to the opposing effects of stress and exercise on addiction vulnerability and may lead to new preventive strategies for addiction in high-risk individuals.