Dissociating Invigoration and Reinforcement by GABAergic Ventral Pallidum Projections to the Ventral Tegmental Area During Cue-Elicited Reward-Seeking

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PROJECT SUMMARY Sensory cues associated with reward allow us to predict future outcomes and modify behavior accordingly. However, reward-predictive cues acquire motivating and reinforcing properties which enable them to capture attention and powerfully bias behavior in favor of reward pursuit. Drug-predictive cues, for example, can trigger potent cravings and sustain compulsive drug seeking. The impact of such cues contributes to chronic risk of relapse in addiction, a significant challenge to long-term patient outcomes. The ventral pallidum (VP) is a basal forebrain nucleus critical for the expression of cue-elicited behavior, including preclinical models of cue-induced relapse. Recent work suggests VP projections to the ventral tegmental area (VTA) are specifically necessary for cue-induced reinstatement of drug seeking, yet the underlying neurobiological and psychological mechanisms by which this pathway (VP→VTA) mediates cue-elicited reward seeking are unknown. Previous work has not attempted to dissociate this pathway’s contributions to the invigorating and reinforcing properties of cues. Clarifying these mechanisms is necessary to improve circuit-based models of motivated behavior and generate translationally relevant models of motivational disorders including addiction. Thus, the broad objective of the proposed work is to elucidate mechanisms by which reward-predictive cues dynamically regulate activity of VP→VTA and mediate reward-seeking behavior. The overall goal of this proposal is to 1) characterize value encoding of VP-VTA projections during cue-elicited reward-seeking and 2) characterize the impact of modulations of VP→VTA activity on cue-elicited reward- seeking. Since GABAergic VP neurons generally promote appetitive reward seeking, I aim to target GABAergic VP neurons projecting to the VTA (VPGABA→VTA). Given preliminary data from my lab suggesting a role of VP→VTA in reinforcement and parallel work identifying VP neurons that encode reward-prediction error (RPE) signals canonically associated with reinforcement learning models, I hypothesize that VPGABA→VTA encode RPE and promote the reinforcing value of reward and associated cues. To test this hypothesis, I will use in-vivo fiber photometry to record from (Aim 1) and optogenetics to manipulate (Aim 2) this pathway during cue-elicited behavior. Experiments proposed under these Aims will advance our understanding of the neural mechanisms by which cues motivate and reinforce naturalistic reward-seeking. These results will resolve inconsistencies in prior literature and serve as a foundation for future work investigating VP and VTA roles in acquisition, escalation, and relapse of compulsive behavior. In addition, I will gain substantial training in the design and execution of behavioral neuroscience experiments, technical expertise with versatile methods to manipulate (optogenetics) and record (fiber photometry) neuronal subpopulations in freely behaving animals, and advanced quantitative skills for relating neuronal activity to behavior and decision-making variables. Collectively, activities performed under this award will prepare me for a successful career as an independent researcher.