Obesity and related metabolic disorders have become a significant public health problem, and overconsumption of highly palatable calorically dense food is a contributing factor. This proposal investigates the neural circuitry that integrate the rewarding value of food with input from gut-derived satiation and satiety signals, and will address the physiological relevance of these circuits for the control of food intake. We propose that brain mediation of satiety signaling involves a decrease in the rewarding value of food, and that conversely, cues predicting highly rewarding food can dampen satiety signaling within the brain. The experiments proposed here will examine two of the circuits that we believe to be involved in these interactions: 1) the glucagon-like peptide 1 (GLP-1) projection from the hindbrain nucleus of the solitary tract (NTS) to the forebrain nucleus accumbens core (NAcC), an area known to plays an important role in food reward; and 2) the Orexin-A (OrxA) projection from the lateral hypothalamus (LH) to the NTS, an area critical for the detection of and response to satiation and satiety signals. Recent data from our laboratory suggests that GLP-1 action in NAcC reduces food intake and may contribute to nutrient-induced satiety. We will apply detailed analysis of the meal pattern effects of intra-NAcC GLP-1 agonist and antagonist treatment, and examine whether NAcC- projecting GLP-1 neurons are activated by meal-related gastrointestinal signals in order to determine whether the GLP-1 projection to NAcC mediates meal-induced satiation or satiety in rats. Next, we will evaluate whether GLP-1 action in NAcC reduces food palatability or rats' motivation to obtain food. We hypothesize that the OrxA projection to NTS functions in the opposite manner. These neurons are activated by cues that predict highly rewarding food, and we have new evidence that hindbrain OrxA treatment can increase food intake by impairing satiation. Here we will investigate the role of endogenous OrxA action in the hindbrain in nutrient- induced satiation and satiety, food-motivated operant behavior, and the behavioral response to cues that predict the availability of highly palatable food. We believe that improved understanding of how reward and satiation/satiety interact within the brain will ultimately lead to new candidates for treatment of obesity and overeating that more effectively target the specific dysfunctional behaviors involved in these disorders.