Brain-wide functional mapping of circuits controlling hedonic feeding in obesity

控制肥胖享乐喂养的回路的全脑功能图谱

• 批准号: 10434601
• 负责人: Li Ye
• 金额: $ 7.52万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10434601
• 关键词: Anatomy; Animals; Area; Brain; Calories; Consumption; Development; Diet; Eating; Expenditure; Five-Year Plans; Food; Functional disorder; Future; Goals; Holly; Homeostasis; Human; Hyperphagia; Hypothalamic structure; Journals; Laboratories; Lateral; Maps; Measures; Mentors; Metabolic; Metabolism; Molecular; Monitor; Neurons; Neurosciences; Obesity; Obesity Epidemic; Palate; Population; Prefrontal Cortex; Publishing; Regulation; Research; Research Personnel; Research Project Grants; Rewards; Series; System; Techniques; Technology; Therapeutic; Time; Training; Vocational Guidance; base; career development; course development; energy balance; experience; feeding; hedonic; hormonal signals; imaging approach; neural circuit; neuromechanism; novel; optogenetics; peer; programs; recruit; relating to nervous system; ribosome profiling; tool

Project Summary: The proposal describes a five-year plan with a one-year extension for training Dr. Li Ye to achieve his goal to become an independent investigator in the central regulation of metabolism. The training plan includes a compelling research project, training in laboratory techniques, didactic scientific and career development courses. The applicant has more than a decade of experiences working in both metabolism and systems neurosciences. Dr. Ye’s previous findings in metabolic research have been published in many high- impact journals and have been then cited near 6,000 times by his peers. During the proposed training, Dr. Karl Deisseroth and Dr. Hollies Cline, leading experts in neurosciences will mentor the applicant’s scientific and career development. A committee with expertise in hypothalamic research (Dr. Luis de Lecea and Dr. Brad Lowell) will provide further scientific and career guidance. The goal of the project is to study neural mechanisms coordinating food intake and metabolic demands. Obesity is a result of energy imbalance, in which energy consumption exceeds the expenditure. Food intake can be driven by metabolic need or the hedonic value of palatable food. The former is mainly regulated by the hypothalamic structures that are responsive to hormonal signals. The latter is largely controlled by the mesolimbic reward systems. Preliminary studies suggested these systems converge in the lateral hypothalamus area (LH). Dissecting the circuit, cellular and molecular bases separating these two systems is key to understanding the central control of energy balance and its dysfunction during obesity, however, differentiating intermingled neural ensembles has been difficult. The candidate has developed a series of CLARITY and optogenetics-based technologies with sufficient throughput to map brain-wide connectivity and with the ability to retain molecular information to distinguish intermingled neuronal populations. The candidate has successfully dissected two anatomically intermingled but functionally distinct ensembles representing opposite valences in the prefrontal cortex. Thus, these systems provide us a unique opportunity to dissect the LH ensembles recruited by hedonic vs. metabolic feeding. The central hypothesis is that hedonic and metabolic feeding recruit distinct LH ensembles. Specifically, these ensembles quantitatively differ in: (1) the inputs they receive from upstream regions, (2) activity during different types of feeding, and (3) causal impact on feeding. The adaptation of these ensembles to diet is key to the development of hyperphagia. The approach is to use neuroscience tools to monitor and manipulate neural activity in animals (Aim 1&2). The circuit adaption will be measured using ribosome-profiling and imaging approaches (Aim3). Together, this study will elucidate neural mechanisms underlying the HFD-induced hyperphagia and provide the candidate with the training to start an independent research program focusing on the central regulation of energy homeostasis.

项目概要：该项目提出了一个五年计划，其中延长一年，用于培养李烨博士， 实现他的目标，成为一个独立的研究人员在中央调节代谢。培训 计划包括一个引人注目的研究项目，实验室技术培训，教学科学和职业生涯 发展课程。申请人有十多年的工作经验，在代谢和 系统神经科学叶博士以前在代谢研究方面的发现已发表在许多高- 影响力的期刊，并被同行引用近6,000次。在培训期间，卡尔博士 Deisseroth和Hollies Cline博士，神经科学领域的顶尖专家将指导申请人的科学和 职业发展。下丘脑研究专家委员会（Luis de Lecea博士和布拉德博士 洛厄尔）将提供进一步的科学和职业指导。 该项目的目标是研究协调食物摄入和代谢需求的神经机制。肥胖 是能量不平衡的结果，其中能量消耗超过支出。食物摄入量可以 由新陈代谢需要或美味食物的享乐价值驱动。前者主要由 下丘脑结构对激素信号有反应。后者在很大程度上由 中脑边缘奖励系统初步研究表明，这些系统集中在外侧下丘脑 面积（LH）。解剖电路，细胞和分子基础分离这两个系统是关键， 了解肥胖期间能量平衡的中枢控制及其功能障碍，然而， 混合的神经系统是很困难的候选人已经制定了一系列的能力， 基于光遗传学的技术，具有足够的吞吐量来绘制全脑连接， 来保留分子信息以区分混合的神经元群体。这位候选人有 成功解剖了两个解剖学上混合但功能上不同的集合体， 前额叶皮层的效价因此，这些系统为我们提供了一个独特的机会， 由享乐与代谢喂养招募的群体。核心假设是享乐和新陈代谢 喂养募集不同的LH系综。具体而言，这些集合在数量上不同：（1）它们的输入 从上游地区接收，（2）在不同类型的喂养活动，（3）对喂养的因果关系的影响。 这些集合体对饮食的适应是暴食症发展的关键。方法是使用 神经科学工具来监测和操纵动物的神经活动（目标1和2）。电路适配将是 使用核糖体分析和成像方法（Aim 3）测量。总之，这项研究将阐明神经 HFD诱导的食欲过盛的潜在机制，并为候选人提供训练， 专注于能量稳态的中央调节的独立研究计划。

项目成果

Pathways to clinical CLARITY: volumetric analysis of irregular, soft, and heterogeneous tissues in development and disease.

• DOI: 10.1038/s41598-017-05614-4
• 发表时间: 2017-07-19
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Hsueh B;Burns VM;Pauerstein P;Holzem K;Ye L;Engberg K;Wang AC;Gu X;Chakravarthy H;Arda HE;Charville G;Vogel H;Efimov IR;Kim S;Deisseroth K
• 通讯作者: Deisseroth K