Project Summary The incentive value of drug-associated cues drives several facets of addiction, including escalation of drug use and the propensity to relapse even after long periods of abstinence. Cues with high incentive value can drive reward-seeking behaviors that are disconnected from an individual’s goals and the value of expected outcomes (i.e. rewards or punishments). This may lead to perseverative or compulsive drug use despite adverse consequences. A critical barrier to progress in neuromodulation-based treatments for addiction is lack of knowledge regarding the circuits engaged in cue-driven reward-seeking behavior, and how these circuits are distinct from those involved in goal-directed behavior, which relies on accurate mental representations of expected outcomes and their value. This proposal focuses on the role of the ventral pallidum (VP), a region of the basal forebrain that is critical for both relapse to drug use and positive affect. Our objective is to identify the VP neural populations that encode the incentive value of cues, and the neural circuit mechanisms by which cues drive motivated behavior. Our central hypothesis is that neurons that represent the incentive value of cues are distinct from those that represent the expected value of future outcomes, and that these neurons can be defined based on output pathway. We predict that the activity of GABAergic VP neurons projecting to the ventral tegmental area (VTA) encodes cue-driven reward-seeking and that activity in this population is critical for cue-driven motivated behavior. We will test our hypothesis by pursuing the following aims. In Aim 1 we will examine encoding of the incentive value of cues and expected value of outcomes by individual neurons in VP. Our hypothesis is that separate neurons in VP encode incentive value and expected value. We will use in vivo single unit electrophysiology to measure activity patterns in individual VP neurons during presentations of reward-related cues and determine whether activity in these neurons predicts cue- elicited reward-seeking behavior and/or the current expected value of a predicted outcome. In Aim 2 we will identify the VP output pathway(s) that encode the incentive value of cues. Our hypothesis is that VP neurons that encode incentive value are GABAergic and project to the VTA. We will use fiber photometry to measure calcium signals in VP GABA neurons projecting to the VTA or thalamus during presentations of reward cues and determine whether activity in these populations predicts cue-elicited reward-seeking behavior and/or expected value. In Aim 3 we will test the functional role of activity in these VP output pathways in behavioral responses to cues. Successful completion of this research will characterize the brain mechanisms of incentive value representations and define the downstream circuit targets for the invigoration of motivated behavior by VP incentive value signals. Advancements in our understanding of these ...