Neural basis of reward anticipation and its genetic determinants

Significance We characterize in humans a coordinated network of brain activity describing neurobehavioral correlates of reward anticipation. The network involves nodes in striatal and cortical brain regions, which are preferentially associated with distinct externalizing behaviors—hyperactivity and alcohol consumption—suggesting that the heterogeneity of reward-related behaviors might be accounted for by different association patterns of nodes and their connecting links. In a genome-wide association study of the striatal node with subsequent functional validation in Drosophila, we identify molecular genetic mechanisms involving vacuolar protein sorting-associated protein 4A (VPS4A) in dopamine regulation, reward anticipation, and hyperactivity. Our approach might facilitate the identification of causal neural mechanisms, important for the identification of previously unidentified targets and the establishment of neurobehaviorally informed end points for clinical trials. Dysfunctional reward processing is implicated in various mental disorders, including attention deficit hyperactivity disorder (ADHD) and addictions. Such impairments might involve different components of the reward process, including brain activity during reward anticipation. We examined brain nodes engaged by reward anticipation in 1,544 adolescents and identified a network containing a core striatal node and cortical nodes facilitating outcome prediction and response preparation. Distinct nodes and functional connections were preferentially associated with either adolescent hyperactivity or alcohol consumption, thus conveying specificity of reward processing to clinically relevant behavior. We observed associations between the striatal node, hyperactivity, and the vacuolar protein sorting-associated protein 4A (VPS4A) gene in humans, and the causal role of Vps4 for hyperactivity was validated in Drosophila. Our data provide a neurobehavioral model explaining the heterogeneity of reward-related behaviors and generate a hypothesis accounting for their enduring nature.

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