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

7.项目总结： 该提案描述了培训李晔博士以实现他在中国成为一名独立调查员的目标的五年计划。 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讲授科学和职业发展研讨会和课程。申请人有 十多年在分子代谢和系统神经科学方面的工作经验。在他获得博士学位期间， 叶诗文的师从是肥胖和糖尿病领域公认的领导者布鲁斯·斯皮格尔曼博士。他的前任 代谢研究的发现发表在许多有影响力的期刊上，随后被引用了近4000篇 在他的同龄人随后的作品中。在拟议的培训期间，Karl Deisseroth博士是 神经科学将指导申请者的科学和职业发展。戴瑟罗斯博士已经训练了无数 现在在学术机构担任教职的杰出科学家。此外，还有一个咨询委员会，该委员会有 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Brad Lowell博士)将提供 应聘者提供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新陈代谢的神经机制。 要求。肥胖症的流行给公共卫生系统带来了巨大的负担，因为它导致 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 不平衡，即能源消耗长期超过支出。有两种类型的喂料，一种是驱动的 一种是新陈代谢的需要，另一种是可口食物的享乐性。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 生长激素释放素。后者主要由奖赏系统控制，包括中脑边缘通路和多巴胺。 发信号。初步研究表明，这些系统汇聚在下丘脑外侧区。解剖学研究 在黄体生成素中分离这两个系统的电路、细胞和分子碱基是理解中枢控制的关键。 然而，肥胖期间的能量平衡及其功能障碍，区分了大脑中混合的神经丛 该地区一直很困难。 在他早期的博士后工作中，这位候选人开发了一系列基于清晰度和光遗传学的技术 具有足够的吞吐量来绘制全脑连接图，以及能够在 单细胞水平以区分混合的神经元群体。使用这些工具，应聘者成功地 解剖了两个在解剖上相互交织但在功能上不同的合奏，它们代表了内侧的相反的价态 前额叶皮质。这些系统神经科学的最新进展为我们提供了一个独特的机会来剖析和 区分由享乐性喂养和代谢喂养招募的黄体生成素组合。这项提议的中心假设是 享乐主义和新陈代谢饮食在黄体生成素中招募不同的群体。具体地说，这两个组合在数量上是不同的 在：(1)它们从上游大脑区域接收的输入，(2)不同类型进食时的神经元活动，以及(3) 对喂食行为的因果影响。此外，这些群体对长期高脂肪饮食的适应是 出现吞噬过度。一般的方法将是使用系统神经科学工具来监控和操纵 行为动物(Aim1和AIM2)的神经元活动。分子和结构的适应性将用 核糖体分析和高通量成像方法(Aim3)。总之，这项提案研究将阐明神经 HFD诱导的吞噬过度的潜在机制；同时，为应聘者提供必要的培训 启动一项独立的研究计划，专注于能量动态平衡的中央调节。 戴瑟罗斯实验室和斯坦福医学院的研究社区为培训提供了理想的环境 未来的独立调查人员。该项目还将汇集咨询委员会的主要实验室， 优势互补。这些突出的资源将最大限度地发挥申请者的潜力 成功过渡到一名独立的调查员。

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.