682. Involvement of the brain reward system in the regulation and dysregulation of feeding: from genetic vulnerability to the implication of astrocytes

Abstract

Abstract Background Striatal circuits are classically associated with reward processing but are increasingly recognized as central regulators of eating behavior and energy balance. By integrating hedonic and motivational signals with metabolic inputs, the striatum contributes to both food-related reward and the maintenance of energy homeostasis, placing it at a critical interface between neural reward systems and peripheral metabolic control. Aims & Objectives The aim of this work is to provide direct experimental evidence for the role of striatal circuits in coordinating reward-related behaviors and metabolic regulation, and to identify the neuronal and glial mechanisms through which genetic and cellular perturbations influence these processes. Method We employed targeted, cell-type-specific manipulations within the striatum to dissect the contributions of distinct cellular populations. First, Ankk1 gene expression was selectively manipulated in dopamine D2 receptor–expressing striatal neurons to model the effects of the human ANKK1 Taq1A polymorphism. Second, we experimentally modulated the activity of striatal astrocytes in animals exposed to an obesogenic diet to assess their role in peripheral metabolism and cognitive flexibility. Results Selective manipulation of Ankk1 expression in D2 receptor–expressing neurons recapitulated key reward-related and metabolic phenotypes observed in human carriers of the ANKK1 Taq1A polymorphism, which has been associated with altered dopaminergic signaling and increased vulnerability to addictive and metabolic disorders. These findings demonstrate that genetic variation impacting striatal dopamine circuits exerts cell-type-specific effects that influence both behavior and systemic metabolism. In parallel, modulation of striatal astrocyte activity directly altered peripheral metabolic parameters and impaired cognitive flexibility in the context of an obesogenic diet, indicating that astrocytes actively participate in relaying metabolic information and shaping adaptive neural circuit responses. Discussion & Conclusions Together, these findings highlight the striatum as a major hub for body–brain communication, integrating neuronal and glial mechanisms to coordinate reward-driven behaviors with energy homeostasis.