PROJECT SUMMARY: 40% of U.S. adults are obese. Obesity produces type II diabetes, which increases the risk for cardiovascular disease, many cancers, and Alzheimer's. The NIH strategic plan for obesity research provides “a blueprint (to) encourage the research community to examine the epidemic of obesity from diverse perspectives…in order to develop and evaluate new prevention and treatment strategies”. Further, the NIDDK Cognitive and Clinical Neuroscience of Obesity Program was formed to promote studies of “non-homeostatic brain-behavior mechanisms (to prevent) obesity”. This proposal directly addresses these needs by using novel approaches to understand differences in neural function and behavior in preclinical obesity models. In people, exposure to cues associated with food (food cues), like the smell of brownies or a blinking donuts sign, increases food craving and the amount of food consumed. Obese people report stronger craving and eat larger portions in response to food cues. Further, increases in activity of the nucleus accumbens (NAc) triggered by food cues predict future weight gain inability to lose weight. Thus in people, enhanced neurobehavioral responses to food cues contribute to obesity. But, the mechanism underlying this enhanced neurobehavioral reactivity is unknown. Our long-term goal is to understand the neurobehavioral mechanisms that underlie enhanced cue-triggered `cravings' that contribute to obesity. AMPA type glutamate receptors (AMPAR) provide the main source of excitation to the NAc, and NAc activity is required for cue-triggered motivation in non-obese rats. My lab has found that that cue-triggered food-seeking is stronger in obesity-susceptible males and females prior to obesity and that consumption of a sugary, fatty `junk-food' diet enhances excitatory transmission within the NAc. Our objectives here are to determine the role of NAc glutamatergic plasticity in cue-triggered food-seeking after junk- food exposure, and the degree to which junk-food-induced glutamate plasticity occurs in specific circuits and NAc cell types. These studies address significant gaps in our current understanding of diet-induced plasticity that drives obesity. Our studies will provide key insights into the neural basis of cue-triggered motivation and help delineate behavioral processes and specific circuits involved in both sexes, and as a function of obesity- susceptibility. Eating is often initiated by food cues and eating in response to food cues contributes to human obesity. Thus, this work inform treatment by providing a better understanding of the neurobiological underpinnings of cue-triggered motivation in relevant preclinical models.