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: 10197899
• 负责人: Li Ye
• 金额: $ 15.04万
• 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/10197899
• 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; Doctor of Philosophy; Dopamine; Eating; Endocrine; Energy Intake; Expenditure; Faculty; Feeding behaviors; Fiber; Five-Year Plans; Food; Functional disorder; Future; Gene Expression; Goals; Health system; High Fat Diet; Homeostasis; 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; Molecular Structure; Monitor; Neurobiology; Neurodegenerative Disorders; Neurons; Neurosciences; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Overweight; Palate; Pathway interactions; Peripheral; Photometry; Physiology; Play; Population; Positioning Attribute; Prefrontal Cortex; Prevalence; Property; Public Health; Publishing; 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; diet-induced obesity; energy balance; experience; feeding; food consumption; ghrelin; hedonic; hindbrain; hormonal signals; imaging approach; imaging study; in vivo; insight; medical schools; motivated behavior; neural circuit; neuromechanism; novel; obesity treatment; optogenetics; peer; post-doctoral training; programs; recruit; 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.

7.项目概要： 该提案描述了一个五年计划，培训李叶博士，以实现他的目标，成为一名独立的研究者， 新陈代谢的中枢调节培训和职业发展计划包括一个引人注目的研究项目， 实验室技术培训以及教学科学和职业发展研讨会和课程。申请人已经 在分子代谢和系统神经科学领域有十多年的工作经验。在他的博士学位， 博士Ye接受了布鲁斯斯皮格曼博士的培训，他是肥胖和糖尿病领域公认的领导者。他以前 代谢研究的发现已经发表在许多高影响力的期刊上，并被引用了近4000次。 在他的同行随后的作品中。在拟议的培训期间，卡尔·戴瑟罗斯博士，一位在 神经科学将指导申请人的科学和职业发展。戴瑟罗斯博士训练了许多 现在在学术机构担任教职的杰出科学家。此外，一个咨询委员会， 在下丘脑和喂养研究方面备受推崇的专业知识（Luis de Lecea博士和布拉德洛厄尔博士）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 要求。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、心血管和神经退行性疾病的发病率增加。肥胖是能量的结果 不平衡，能源消耗长期超过支出。有两种喂养方式，一种是驱动型 一个是新陈代谢的需要，另一个是美味食物的享乐方面。前者主要由 下丘脑和后脑结构对外周激素信号如瘦素、胰岛素和 胃饥饿素后者主要由包括中脑边缘通路和多巴胺在内的奖赏系统控制 发信号。初步研究表明，这些系统会聚在外侧下丘脑区（LH）。解剖 在LH中分离这两个系统的电路，细胞和分子基础是理解中枢控制的关键。 然而，在肥胖症期间，能量平衡及其功能障碍， 区域是困难的。 在他早期的博士后工作中，该候选人开发了一系列基于生物学和光遗传学的技术 具有足够的吞吐量来绘制全脑连接，以及能够保留分子信息， 在单个细胞水平上区分混合的神经元群体。利用这些工具，候选人成功地 解剖两个解剖学上混合，但功能不同的合奏代表相反的价在内侧 前额皮质系统神经科学的这些最新进展为我们提供了一个独特的机会， 区分由享乐与代谢喂养募集的LH系综。这一提议的核心假设是， 享乐和代谢性摄食在LH中募集不同的集合。具体而言，这两个集合在数量上不同 在：（1）他们从上游大脑区域接收的输入，（2）在不同类型的喂养过程中的神经元活动，以及（3） 对摄食行为的因果影响。此外，这些组合对慢性高脂饮食的适应是 食欲过盛的发展。一般的方法将是使用系统神经科学工具来监测和操纵 行为动物的神经元活动（Aim 1和Aim 2）。分子和结构适应性将使用 核糖体分析和高通量成像方法（Aim 3）。总之，这项提案研究将阐明神经 HFD诱导的摄食过多的潜在机制;同时，为候选人提供必要的培训 开始一项独立的研究计划，专注于能量稳态的中枢调节。 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 未来的独立调查员该项目还将汇集咨询委员会的主要实验室， 互相补充对方的专业知识。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。