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: 9660386
• 负责人: Li Ye
• 金额: $ 9.09万
• 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 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9660386
• 关键词: Brain; wide; functional; mapping; circuits

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。项目摘要： 该提案描述了培训李叶博士的五年计划，以实现他的目标，以成为独立研究员 代谢的中心调节。培训和职业发展计划包括一个引人入胜的研究项目， 实验室技术以及教学科学和职业发展半手赛和课程的培训。申请人有 在分子代谢和系统神经科学方面的经验十多年。在他的博士学位期间 Ye博士接受了Bruce Spiegelman博士的培训，Bruce Spiegelman博士是肥胖和糖尿病领域的公认领导者。他的前任 代谢研究的发现已在许多高影响期刊上发表，然后被引用了近4,000 在他的同龄人的随后作品中。在拟议的培训期间，Karl Deisseroth博士 神经科学将指导申请人的科学和职业发展。 Deisseroth博士已经训练了无数次 现在在学术机构中担任教师职位的著名科学家。此外，由 在下丘脑和饲养研究方面的高度评价专业知识（Luis de Lecea博士和Brad Lowell博士）将提供 申请人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 需求。肥胖流行正在为公共卫生系统造成巨大的烧伤，这是通过贡献的 2型糖尿病，心血管和神经退行性疾病的患病率增加。肥胖是能量的结果 失衡，其中能源消耗长期超过了支出。喂食有两种类型，一个驱动器 通过代谢需求，而另一种是可口食品的享乐主义方面。前者主要由 响应于周围的马信号（例如瘦素，胰岛素和）的下丘脑和后脑结构 ghrelin。后者主要由奖励系统控制，包括中边途径和多巴胺 信号。初步研究表明，这些系统在下丘脑面积（LH）侧汇合。解剖 在LH中将这两个系统分开的电路，细胞和分子碱基是理解中心控制的关键 能量平衡及其在肥胖期间的功能障碍，但是，大脑内的神经合奏区分了 地区很困难。 候选人在早期的博士后工作中开发了一系列基于光遗传学的技术 具有足够的吞吐量，以绘制范围范围的连通性以及保留分子信息的能力 单细胞水平以区分神经元群体。使用这些工具，候选人已成功 解剖了两个解剖学上的但功能上不同的集合，代表介质中相反的价值 前额叶皮层。这些系统神经科学的最新进展为我们提供了独特的剖析和 区分Hedonic vs.代谢喂养招募的LH合奏。该提议的核心假设是 Hedonic和代谢喂养在LH中招募了不同的合奏。具体而言，这两个集合在定量上不同 在：（1）它们从上游大脑区域收到的输入，（2）在不同类型的进食过程中的神经元活动，以及（3） 因果对喂养行为的影响。此外，这些合奏对慢性高脂饮食的适应是 脾气发育。一般方法是使用系统神经科学工具来监视和操纵 行为动物中的神经元活性（AIM1和AIM2）。分子和结构适应将使用 核糖体促进和高通量成像方法（AIM3）。建议研究将阐明神经元 HFD诱导的心晶状体的基础机制；同时，为候选人提供基本培训 启动一个独立的研究计划，重点是对能量稳态的中心法规。 Deisseroth实验室和斯坦福大学医学研究所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领先实验室， 补充彼此的专业知识。这些杰出的资源将最大化申请人的潜力 成功地过渡到独立研究者。