Influence of nutritional status on the neurochemical bases of habit

项目概要/摘要..... 减肥的早期成功往往伴随着体重的反弹。导致体重反弹的一个因素是 在接触到熟悉的食物线索后，旧的饮食习惯重新出现。纹状体多巴胺驱动习惯，但 抑制性神经递质GABA可以调节多巴胺，也可以影响习惯。初步证据显示 与营养状况相关的因素，例如体重（BMI）和饮食组成，可能与 这种神经化学。为了促进改善长期饮食依从性和体重管理， 关键是确定一个人的体重和饮食可能对多巴胺能和GABA能功能的影响 从而导致对习惯性饮食的易感性。候选人达西博士的长期目标是建立一个 独立的研究生涯，确定和开发影响神经化学的营养方法， 影响习惯驱动与目标导向行为的强度。此K99/R 00应用程序的总体目标 是为了确定BMI和饮食成分如何影响习惯驱动的饮食行为的神经化学。在 在K99阶段，为了分离体重和习惯神经化学之间的关系，Darcey博士将领导一个 标准化饮食条件下的横断面住院研究，以确定 广泛BMI范围内成年人纹状体GABA能张力、多巴胺D2受体可用性和肥胖 （n=50）。在R 00阶段，为了分离饮食对习惯神经化学的因果作用，达西博士将领导一个 随机交叉门诊、对照喂养研究，以确定膳食脂肪与 碳水化合物限制对肥胖成年人GABA能张力、DA功能和习惯驱动行为的影响 （n=72）。这项建议还包括旨在帮助达西博士从一个有指导的博士后过渡到一个有指导的博士后的培训。 在一个研究密集型机构获得一个独立的终身助理教授职位的研究金， 饮食和行为控制的神经化学之间的相互作用，使用多模态神经成像。博士 Darcey将继续扩展她在PET和fMRI神经成像和数据方面的现有知识基础和技能 分析.通过这个奖项，她将获得严格的临床试验设计和磁共振方面的新技能。 波谱（MRS），一种用于探测神经化学的非侵入性神经成像技术。达西医生的指导 团队包括饮食/代谢和体重调节（Kevin Hall博士），多巴胺受体 PET成像和酒精/物质使用障碍（Gene-Jack Wang博士），以及精神病患者的GABA MRS 格雷姆·梅森（Graeme Mason）NIDDK校内研究计划提供了一个理想的环境， 完成这一建议，从参与者招募资源，住院使用的代谢研究 在代谢厨房中精确准备的研究餐，多巴胺D2受体PET成像， 核心夫人成功完成拟议的研究和职业发展活动将使 博士达西成功地获得了教职，建立了她的独立研究计划， 争取国家卫生研究院未来对研究的支持，以促进对饮食依从性的神经科学理解。

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.