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

项目概述：《方案》描述了一项为期五年的计划，将李晔博士培训为 实现他的目标，成为新陈代谢中央调节的独立调查者。培训 计划包括引人注目的研究项目、实验室技术培训、教学科学和职业生涯 发展课程。应聘者有十多年在新陈代谢和代谢方面的工作经验 系统神经科学。叶博士之前在新陈代谢研究中的发现发表在许多高水平的期刊上。 影响期刊，随后被他的同行引用了近6000次。在拟议的培训期间，卡尔博士 神经科学领域的顶尖专家Deisseroth和Hollie Cline博士将指导申请者的科学和 职业发展。在下丘脑研究方面有专长的委员会(Luis de Lecea博士和Brad博士 Lowell)将提供进一步的科学和职业指导。 该项目的目标是研究协调食物摄入量和代谢需求的神经机制。肥胖 是能源不平衡的结果，即能源消耗大于支出。食物的摄入量可以 受新陈代谢需求或美味食物的享乐主义价值的驱动。前者主要由 对荷尔蒙信号有反应的下丘脑结构。后者主要由 中级边缘奖励系统。初步研究表明，这些系统汇聚在下丘脑的外侧。 面积(Lh)。解剖分离这两个系统的电路、细胞和分子碱基是关键 了解肥胖期间能量平衡的中枢控制及其功能障碍，然而，区分 混杂在一起的神经集合一直很困难。候选人已经发展出一系列的清晰度和 基于光遗传学的技术，具有足够的吞吐量来绘制全脑连接图，并具有 保留分子信息以区分混合的神经元群体。候选人有 成功地解剖了两个解剖学上相互交织但功能截然不同的合奏，代表着相反的 前额叶皮质的价态。因此，这些系统为我们提供了一个剖析黄体生成素的独特机会。 由享乐主义与新陈代谢喂养招募的合奏。中心假设是享乐性和新陈代谢 喂食新成员不同的黄体生成素。具体地说，这些集合在数量上的不同在于：(1)它们的输入 从上游地区接收，(2)不同类型喂食期间的活动，(3)对喂食的因果影响。 这些群体对饮食的适应是发展过度吞噬的关键。方法是使用 监测和操纵动物神经活动的神经科学工具(目标1和2)。电路改编将是 使用核糖体图谱和成像方法进行测量(Aim3)。总而言之，这项研究将阐明神经 HFD诱导的吞噬过度的潜在机制，并为应试者提供开始 专注于能量动态平衡的中央调节的独立研究计划。

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.