Summary Overweight/obesity affects more than 70% of US adults creating an enormous health and economic burden, yet effective non-invasive treatments are limited, underscoring the importance of identifying new pharmacotherapies that promote and sustain reductions in food intake and body weight. Amylin receptor agonists reduce food intake and body weight in both humans and animal models, providing a platform for the development of new amylin-based pharmacotherapies to treat obesity. Our work identifies amylin signaling in the mesolimbic reward system as a key substrate in the control of feeding and food reward-motivated behaviors. In a series of complementary manuscripts, we showed that ventral tegmental area (VTA) amylin receptors are essential for the control of palatable food intake via downstream suppression of dopaminergic signaling to the nucleus accumbens (NAc). While these combined studies highlight the VTA as a neural substrate for amylin's control of food reward, the behavioral and physiological mechanisms, neurochemical phenotype(s), and additional amylin modulated circuitry within the CNS that control food reward remain unknown. As the neural control of body weight involves the contribution of many nuclei, clearly the most effective of future amylin-based anti-obesity pharmacotherapies will be those that act in multiple CNS sites to modulate motivated feeding. To this end, we will investigate the hypothesis that amylin signaling within the lateral dorsal tegmental nucleus (LDTg) and the dorsal vagal complex (DVC) of the brainstem modulate food reward by influencing VTA neural activity. Preliminary studies also provide compelling rationale to explore endogenous amylin signaling in the NAc in control of behaviors directed at food reward. Using innovative approaches, we will investigate the following aims. Aim I: Investigate the endogenous contribution and underlying neuroanatomical circuitry of LDTg and DVC amylin receptor expressing neurons in the control of food reward. Aim II: Examine the neural activity of VTA dopaminergic and GABAergic neurons that are downstream of DVC or LDTg amylin receptor activation. Aim III: Investigate the contribution of amylin receptor signaling on D1 and D2 receptor expressing neurons in the NAc in the control of food intake and modulation of food impulsivity.