Obesity is characterized by excess fat accumulation that predisposes patients to chronic disease and death. Thought to result from dysregulated energy balance, obesity develops in part from aberrant feeding. This complex behavior is governed by homeostatic and reward centers in the hypothalamus and mesolimbic dopamine system (MDS), respectively. In the MDS, the ventral tegmental area (VTA) releases dopamine in frontal regions to regulate responses to rewarding stimuli, yet the mechanisms that govern this process are not fully understood. Brain-derived neurotrophic factor (BDNF) is a critical regulator of hedonic feeding behavior and its depletion from neurons produces altered dopaminergic transmission in the MDS. Although the molecular mechanisms underlying BDNF's effects on feeding remain unclear, the transcription factor, Nurr1, has been identified as a candidate mediator of these phenomena. Previous work has shown that the transcription factor, Nurr1, is reduced in the VTA of BDNF mutant mice. The relationship between MDS BDNF and Nurr1 will be further investigated by examining feeding behavior and Nurr1 levels in mice that over- express BDNF specifically in dopaminergic neurons. Viral delivery of Nurr1 to the VTA of BDNF mutant mice will allow for testing whether Nurr1 deficiency contributes to decreased dopamine secretion and aberrant hedonic feeding behavior in mice with central BDNF depletion. Finally, the functional effects of up-regulated Nurr1 signaling by infusion of its downstream mediator GDNF into the VTA of mice will be tested. This research will utilize genetic, molecular, electrophysiological and behavioral techniques to investigate Nurr1 and its downstream targets as potential mediators of BDNF-dependent mesolimbic function and hedonic feeding. These studies will enhance understanding of hedonic feeding, a component behavior in the etiology of obesity, and thus provide a foundation for the development of therapies to prevent and combat this chronic, debilitating disorder.

Public Health Relevance

Obesity increases risk of chronic disease including type-II diabetes mellitus, cardiovascular disease, cancers, and depression. Despite its continually rising prevalence and the resulting burden on the American health care system, estimates of adult obesity in the US now surpass 30%. While the etiology of this state of excessive fat accumulation is clearly multi-factorial, with arguably significant contributions of lifestyle changs and availability of high-fat and high-sugar foods, inheritable biological factors also appear to play a critical. Much evidence has linked the human protein, brain-derived neurotrophic factor, to feeding behavior and obesity. Here we propose that gaining understanding of the mechanisms that underlie this association is a promising new avenue for the development of novel and effective prevention and treatment therapies or obesity.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZDK1-GRB-R (J1))
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Mcbryde, Kevin D
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Tufts University
Schools of Medicine
United States
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