Hypothalamic-Striatal Control of Motivation for Obesogenic Food

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PROJECT ABSTRACT Obesity is an alarming chronic health crisis that currently affects 39.8% of the adult population (2015-2016) in the United States. Obese individuals present a challenging public health problem because they are at increased risk for several life-threatening and costly co-morbidities including diabetes, metabolic syndrome, cardiovascular disease, and cancer. Because the financial and health burdens of obesity are so pernicious, a more mechanistic appreciation of the feeding behavior(s) that contribute to obesity is critical to understanding the etiology of this disease and for identifying druggable targets. One feeding behavior that contributes to obesity is overconsumption of highly palatable food. Highly palatable food, including high-fat food, is an important driver of obesity and has demonstrated reinforcement value in rodents. Reinforcement is mediated in part by the nucleus accumbens shell (NAcSh), a key neuroanatomical substrate that regulates hedonic feeding. Another substrate governing food intake is the paraventricular nucleus of the hypothalamus (PVN). The PVN regulates food intake at the level of physiological energy requirements, and facilitates homeostatic feeding behavior. PVN neurons project to the NAcSh (PVN→NAcSh) and orchestrate social reward, but their role in motivation for high-fat food remains unknown. Preliminary data indicate that the neurotransmitter Glutamate (Glu) plays an integral role in PVN→NAcSh transmission. Pharmacogenetic stimulation of PVN→NAcSh neurons results in robust and sustained presynaptic Glu release in the NAcSh. Additionally, administration of Glu agonists directly to the NAcSh decrease feeding, while administration of Glu antagonists evoke an immediate and sustained increase in consumption behavior. Despite considerable evidence of Glu involvement in consumption behavior, the role of Glu in motivation for high fat food has not been explored. We propose that Glu signaling within PVN→NAcSh neurons is a critical neuromodulator of motivation for high-fat food. The objectives of this proposal are to (1) establish the neuroanatomical basis for Glu signaling in PVN→NAcSh and (2) manipulate presynaptic Glu release in PVN→NAcSh to test specific hypotheses concerning the role of Glu in the regulation of motivation for high-fat food. Completion of these objectives will provide the applicant with training in new concepts and methodologies, including the neurobiology of obesity, the design and interpretation of behavioral experiments, principles and methods of neuropharmacology, and the application of genetic technology. The outcomes of these studies will have a sustained, powerful impact on our field by identifying a key regulatory role for Glu transmission in PVN→NAcSh mediated motivation for highfat food, which will critically advance efforts to improve treatment outcomes in obesity and metabolic dysregulation.