Influence of nutritional status on the neurochemical bases of habit

PROJECT SUMMARY / ABSTRACT … ……………………….. Early success with weight loss is too often followed by weight regain. One factor contributing to weight regain is the re-emergence of old eating habits after exposure to familiar food cues. Striatal dopamine drives habits, but the inhibitory neurotransmitter GABA can regulate dopamine and affect habit as well. Initial evidence suggests

that factors related to nutritional status, for example body mass (BMI) and diet composition, may be associated with this neurochemistry. To facilitate improving long term dietary adherence and weight management, it is critical to determine what influence one’s weight and diet might have on dopaminergic and GABAergic function

and thus susceptibility to habit-driven eating. The long-term goal of the candidate, Dr. Darcey, is to establish an independent research career identifying and developing nutritional approaches which impact neurochemistry to affect the strength of habit-driven vs. goal-directed behavior. The overall objective for this K99/R00 application

is to determine how BMI and diet composition influence the neurochemistry of habit-driven eating behavior. In the K99 phase, to isolate the relationship between body weight and habit neurochemistry, Dr. Darcey will lead a cross-sectional inpatient study under standardized dietary conditions to determine the relationship between

striatal GABAergic tone, dopamine D2 receptor availability, and adiposity in adults across a wide range in BMI (n=50). In the R00 phase, to isolate the causal role of diet on habit neurochemistry, Dr. Darcey will lead a randomized cross-over outpatient, controlled feeding study to determine the effect of dietary fat versus

carbohydrate restriction on GABAergic tone, DA function, and habit-driven behavior in only adults with obesity (n=72). This proposal also includes training designed to aid Dr. Darcey’s transition from a mentored postdoctoral fellowship to an independent tenure-track assistant professorship at a research-intensive institution studying the

interaction between diet and the neurochemistry of behavioral control using multi-modal neuroimaging. Dr. Darcey will continue to expand her existing knowledge base and skills in PET and fMRI neuroimaging and data analysis. Through this award she will gain new skills in rigorous clinical trial design and Magnetic Resonance

Spectroscopy (MRS), a noninvasive neuroimaging technique to probe neurochemistry. Dr. Darcey’s mentoring team includes leading experts in diet/metabolism and body weight regulation (Dr. Kevin Hall), dopamine receptor PET imaging and alcohol/substance use disorders (Dr. Gene-Jack Wang), and GABA MRS in psychiatric

disease (Dr. Graeme Mason). The NIDDK Intramural Research Program provides an ideal environment to accomplish this proposal, from the participant recruitment resources, inpatient use of the Metabolic Research Unit and precisely prepared study meals in the Metabolic Kitchen, to dopamine D2 receptor PET imaging and

the MRS Core. Successful completion of the proposed studies and career development activities will position Dr. Darcey for success in attaining a faculty position, establishing her independent research program, and competing for future NIH support for research to advance the neuroscientific understanding of dietary adherence.