Modern dietary practices are out of control: despite knowing better, we consume too many calories, too much fat, and too much sugar. Herein we propose an idea that may explain our lack of success in combating obesity and that promises to transform our approach to this problem. This hypothesis arises from the recognized importance of midbrain dopamine signaling in complex aspects of food intake AND the seminal observation that insulin directly regulates dopamine signaling and reward. We propose that intact insulin signaling in midbrain areas such as striatum supports dopaminergic signaling and normal reward for food, which is adaptive when calories are scarce. In our modern, energy-dense food environment, reward drives poor dietary decisions. Reward-driven over-consumption of obesogenic foods quickly leads to neuronal insulin resistance and impaired dopamine signaling in striatum. In this stage the "hypodopaminergic reward deficiency syndrome" is established, in which decreased dopamine tone results in increased intake of obesogenic foods to achieve a normal level of reward in the setting of decreased dopamine tone. Our overarching hypothesis is that reward for food triggers midbrain insulin resistance, which sustains increased food intake, maladaptive feeding and behaviors, and as a consequence, obesity. Identification of the molecular mechanisms by which insulin fine-tunes control of feeding in the hypothalamus and reward centers in midbrain and identification of the mechanisms by which dysregulation of this system develops in obesity will yield tremendous insight. To achieve this goal, we will use a rodent model of diet-induced obesity in which dramatic changes in feeding behaviors occur. In this model a) for the first time we will quantify detailed pathological alterations in midbrain and hypothalamic insulin action and midbrain DA signaling over time, b) we will define the molecular mechanisms involved in these alterations in midbrain and hypothalamus using an array of cutting-edge tools, and c) as the model is refined and regulatory nodes identified, rescue the pathological alterations, proving the therapeutic potential of this work, and defining specific brain regions involved in obesity pathogenesis. We will initiate these studies in vivo, and will then model in vivo findings in ex vivo preparations, thereby distilling individual aspects of feeding regulation, a complex process involving cognition and reward. Finally, genetic tools in mouse models will illuminate the roles of insulin and dopamine signaling in the development of obesity in specific neuronal populations (e.g. dopamine neurons). Investigating this link between insulin and dopaminergic behavior will lay the foundation for understanding possible shared mechanisms of obesity and dopamine-related co- morbidities;cognitive dysfunction, bipolar disorder, schizophrenia, and attention-deficit disorder. PUBLIC HEALTH RELEVANCE: Obesity and other dopamine-related pathologies such as schizophrenia, bipolar disorder, and attention-deficit disorder are a tremendous public health burden. Dopamine signaling has been identified as a key element of feeding behavior and insulin has recently been demonstrated to regulate dopamine tone. This proposal will analyze how parallel changes in insulin and dopamine signaling, induced by high-fat feeding cement changes in feeding behavior that lead to obesity and related co-morbidities and thereby allow the development of new therapeutic interventions.