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

控制肥胖症享乐喂养的回路的全脑功能图谱

• 批准号: 9369999
• 负责人: Li Ye
• 金额: $ 5.67万
• 依托单位: STANFORD UNIVERSITY
• 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 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9369999
• 关键词: Address; Adult; Advisory Committees; Anatomy; Animals; Area; Behavior; Behavioral; Brain; Brain region; Calories; Cardiovascular Diseases; Cells; Chronic; Communities; Complement; Consummatory Behavior; Consumption; Development; Development Plans; Diabetes Mellitus; Diet; Doctor of Philosophy; Dopamine; Eating; Endocrine; Energy Intake; Epidemic; Expenditure; Faculty; Feeding behaviors; Fiber; Five-Year Plans; Food; Functional disorder; Future; Gene Expression; Goals; Health system; High Fat Diet; Homeostasis; Hormonal; Human; Hyperphagia; Hypothalamic structure; Image; Imaging Techniques; Immediate-Early Genes; Institution; Insulin; Journals; Laboratories; Lateral; Learning; Leptin; Maps; Measures; Medial; Mentors; Metabolic; Metabolic Diseases; Metabolism; Modeling; Molecular; Monitor; Neurobiology; Neurodegenerative Disorders; Neurons; Neurosciences; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Palate; Pathway interactions; Peripheral; Photometry; Physiology; Play; Population; Positioning Attribute; Prefrontal Cortex; Prevalence; Property; Public Health; Publishing; Recruitment Activity; Regulation; Research; Research Personnel; Research Project Grants; Resources; Rewards; Rodent; Role; Scientist; Series; Signal Transduction; Structure; System; Techniques; Technology; Testing; Therapeutic; Time; Training; Vocational Guidance; Work; base; career development; cellular imaging; energy balance; experience; feeding; food consumption; ghrelin; hedonic; hindbrain; imaging approach; imaging study; in vivo; insight; medical schools; motivated behavior; neural circuit; neuromechanism; novel; obesity treatment; optogenetics; peer; post-doctoral training; programs; relating to nervous system; ribosome profiling; therapeutic target; tool

7. Project Summary: The proposal describes a five-year plan for training Dr. Li Ye to achieve his goal to become an independent investigator in the central regulation of metabolism. The training and career development plan includes a compelling research project, training in laboratory techniques and didactic scientific and career development seminars and courses. The applicant has more than a decade of experiences working in both molecular metabolism and systems neurosciences. During his Ph.D., Dr. Ye was trained with Dr. Bruce Spiegelman, a well-recognized leader in the field of obesity and diabetes. His previous findings in metabolic research have been published in many high-impact journals and have been then cited near 4,000 times in the subsequent works of his peers. During the proposed training, Dr. Karl Deisseroth, a leading expert in neurosciences will mentor the applicant’s scientific and career development. Dr. Deisseroth has trained numerous prominent scientists who now hold faculty positions in academic institutions. In addition, an advisory committee with highly regarded expertise in hypothalamic and feeding research (Dr. Luis de Lecea and Dr. Brad Lowell) will provide the applicant scientific advice and career guidance. The overall goal of the project is to study neural mechanisms responsible for coordinating food intake and metabolic demands. The obesity epidemic is putting an enormous burden on the public health systems, by contributing to the increased prevalence of type 2 diabetes, cardiovascular and neurodegenerative diseases. Obesity is a result of energy imbalance, in which energy consumption chronically exceeds the expenditure. There are two types of feeding, one driven by metabolic need and the other by the hedonic aspect of palatable food. The former is mainly regulated by the hypothalamic and hindbrain structures that are responsive to peripheral hormonal signals such as leptin, insulin, and ghrelin. The latter is predominantly controlled by the reward systems including the mesolimbic pathway and dopamine signaling. Preliminary studies suggested these systems converge in the lateral hypothalamus area (LH). Dissecting the circuit, cellular and molecular bases separating these two systems in the LH is key to understanding the central control of energy balance and its dysfunction during obesity, however, differentiating intermingled neural ensembles within a brain region has been difficult. In his early postdoctoral work, the candidate has developed a series of CLARITY and optogenetics-based technologies with sufficient throughput to map brain-wide connectivity as well as with the ability to retain molecular information at the single cell level to distinguish intermingled neuronal populations. Using these tools, the candidate has successfully dissected two anatomically intermingled but functionally distinct ensembles representing opposite valences in the medial prefrontal cortex. These recent advances in systems neuroscience provide us a unique opportunity to dissect and differentiate the LH ensembles recruited by hedonic vs. metabolic feeding. The central hypothesis of this proposal is that hedonic and metabolic feeding recruit distinct ensembles in the LH. Specifically, these two ensembles quantitatively differ in: (1) the inputs they receive from upstream brain regions, (2) neuronal activity during different types of feeding, and (3) causal impact on feeding behaviors. Moreover, the adaptation of these ensembles to chronic high-fat diet is key to the development of hyperphagia. The general approach will be to use systems neuroscience tools to monitor and manipulate neuronal activity in behaving animals (Aim1 and Aim2). The molecular and structural adaption will be measured using ribosome-profiling and high-throughput imaging approaches (Aim3). Together, the proposal study will elucidate neural mechanisms underlying the HFD-induced hyperphagia; in the meantime, provide the candidate with the essential training to start an independent research program focusing on the central regulation of energy homeostasis. The Deisseroth laboratory and Stanford School of Medicine research community provide an ideal setting for training future independent investigators. This project will also bring together leading laboratories of the advisory committee that complement each other’s expertise. These outstanding resources will maximize the potential for the applicant to successfully transition to an independent investigator.

七、项目概要： 该提案描述了培训李野博士的五年计划，以实现他成为独立研究者的目标 新陈代谢的中心调节。培训和职业发展计划包括一个引人注目的研究项目， 申请人接受过实验室技术培训以及教学科学和职业发展研讨会和课程。 在攻读博士学位期间，他在分子代谢和系统神经科学领域拥有十多年的工作经验。 叶博士曾师从布鲁斯·斯皮格曼博士（Bruce Spiegelman），布鲁斯·斯皮格曼博士是肥胖和糖尿病领域公认的领导者。 代谢研究的发现已发表在许多高影响力期刊上，并被引用近 4,000 次 在提议的培训期间，领先专家 Karl Deisseroth 博士多次在他的同行的后续工作中提出了这一点。 神经科学将指导申请人的科学和职业发展。Deisseroth 博士培训了许多人。 目前在学术机构担任教职的杰出科学家此外，还设有一个顾问委员会。 下丘脑和喂养研究方面备受推崇的专业知识（Luis de Lecea 博士和 Brad Lowell 博士）将提供 申请人的科学建议和职业指导。 该项目的总体目标是研究负责协调食物摄入和代谢的神经机制 肥胖症的流行给公共卫生系统带来了巨大的负担。 2 型糖尿病、心血管疾病和神经退行性疾病的患病率增加是能量消耗的结果。 不平衡，能量消耗长期超过支出。有两种类型的喂养，一种是驱动性的。 一个是由代谢需要决定的，另一个是由可口食物的享乐方面决定的。 下丘脑和后脑结构对外周激素信号（如瘦素、胰岛素和 后者主要由奖赏系统控制，包括中脑边缘通路和多巴胺。 初步研究表明这些系统集中在下丘脑外侧区域（LH）。 区分 LH 中这两个系统的电路、细胞和分子基础是理解 LH 中央控制的关键 然而，肥胖期间的能量平衡及其功能障碍，可以区分大脑内混合的神经系统 地区一直很困难。 在其早期博士后工作中，该候选人开发了一系列基于 CLARITY 和光遗传学的技术 具有足够的吞吐量来绘制全脑连接图，并能够保留分子信息 使用这些工具，候选人已经成功地在单细胞水平上区分混合的神经群体。 解剖了两个解剖学上混合但功能上不同的整体，代表内侧相反的价态 系统神经科学的这些最新进展为我们提供了解剖和研究前额皮质的独特机会。 区分享乐性喂养和代谢性喂养招募的 LH 整体 该提案的中心假设是： 享乐和代谢喂养在 LH 中招募不同的整体，具体而言，这两个整体在数量上有所不同。 在：（1）它们从上游大脑区域接收的输入，（2）不同类型进食期间的神经活动，以及（3） 此外，这些群体对长期高脂肪饮食的适应是关键。 一般方法是使用系统神经科学工具来监测和操纵。 行为动物的神经活动（Aim1 和 Aim2）将使用测量。 核糖体分析和高通量成像方法（目标3）一起，该提案研究将阐明神经网络。 HFD 引起的食欲亢进的机制；同时，为候选人提供必要的培训 启动一项独立研究计划，重点关注能量稳态的中央调节。 Deisseroth 实验室和斯坦福大学医学院研究社区为培训提供了理想的环境 该项目还将汇集咨询委员会的主要实验室。 这些优秀的资源将最大限度地发挥申请人的潜力。 成功转型为独立调查员。