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.

项目摘要：该提案描述了一项为期五年的计划，并延长了为期一年的培训Li Ye博士 实现他成为代谢中央法规的独立研究者的目标。培训 计划包括一个引人入胜的研究项目，实验室技术培训，教学科学和职业 发展课程。申请人在代谢和 系统神经科学。叶博士以前在代谢研究方面的发现已在许多高级研究中发表 影响期刊，然后被他的同龄人引用了近6,000次。在拟议的培训期间，卡尔博士 Deisseroth和Deisseroth和Hollies Cline博士，神经科学领域的主要专家将指导申请人的科学和 职业发展。一个具有下丘脑研究专业知识的委员会（Luis de Lecea博士和Brad博士 Lowell）将提供进一步的科学和职业指导。 该项目的目的是研究神经机制协调食物摄入和代谢需求。肥胖 是能源失衡的结果，其中能源消耗超过了支出。食物摄入可以是 由代谢需求或可口食品的享乐价值驱动。前者主要由 对激素信号有反应的下丘脑结构。后者主要由 中边奖励系统。初步研究表明，这些系统在下丘脑外侧汇聚 区域（LH）。剖析电路，分隔这两个系统的细胞和分子碱基是 但是，了解肥胖期间能量平衡及其功能障碍的中心控制 混合的神经合奏很困难。候选人已经开发了一系列清晰度， 基于光遗传学的技术，具有足够的吞吐量，可以绘制大脑范围的连通性和能力 保留分子信息以区分神经元间的人群。候选人有 成功地解剖了两个解剖学上的交织但功能上不同的集合，代表相反 前额叶皮层中的价。那就是这些系统为我们提供了一个独特的机会来剖析LH Hedonic vs.代谢喂养招募的合奏。中心假设是享乐和代谢 喂养招募不同的LH合奏。具体而言，这些集合在以下数字上不同：（1）输入它们 从上游区域接收，（2）在不同类型的进食期间的活动，以及（3）因果喂养的因果影响。 这些合奏对饮食的适应是脾气发展的关键。方法是使用 神经科学工具以监测和操纵动物的神经元活性（AIM 1和2）。电路适应将是 使用核糖体促进和成像方法测量（AIM3）。这项研究将共同​​阐明神经元 HFD诱导的心晶状体的基础机制，并为候选人提供培训以开始 独立研究计划，重点是对能量稳态的中心调节。

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