Understanding how the thermogenic response is orchestrated in the central nervous system

了解中枢神经系统如何协调产热反应

• 批准号: 9891665
• 负责人: Marc Schneeberger
• 金额: $ 9.15万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-15 至 2021-12-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891665
• 关键词: Address; Affect; American; Anatomy; Area; Automobile Driving; Back; Behavioral Mechanisms; Body Temperature; Brain; Brain Stem; Brown Fat; Calcium; Cell Nucleus; Cells; Clinical; Data; Development; Disease; Eating; Energy Metabolism; Environment; Epidemic; Exposure to; Future; Goals; Health; Heart; Heterogeneity; Homeostasis; Human; Hypothalamic structure; Image; Laboratories; Lead; Lung; Mammals; Mediating; Mentors; Metabolic; Metabolic dysfunction; Metabolism; Methods; Molecular; Molecular Profiling; Motor Activity; Neuraxis; Neurons; Neurosciences; Obesity; Outcome; Pattern; Peripheral; Peripheral Nervous System; Pharmacology; Phase; Physiologic Thermoregulation; Population; Process; Regulation; Research; Research Personnel; Respiratory physiology; Role; Shivering; Skin; Sympathetic Nervous System; System; Technology; Temperature; Testing; Thermogenesis; Tissues; Training; Validation; Vasodilation; Viral; Work; base; career; cell type; dorsal raphe nucleus; effective therapy; experimental study; feeding; heart function; improved; in vivo calcium imaging; interdisciplinary approach; mad itch virus; molecular marker; molecular phenotype; nerve supply; neural circuit; novel; novel therapeutics; obesity treatment; optogenetics; relating to nervous system; response

Thermogenesis is the principal mechanism through which mammals dissipate energy. Pioneering work dating back to the 1930s demonstrated that neurons within the hypothalamus are sensitive to ambient and local deviations in temperature, and that in turn, these neurons could outcome a potent change in body temperature. A basic goal of neuroscience has been to identify the neural substrates underlying thermoregulation. Significant progress has been made on understanding how hypothalamic cell types regulate thermogenesis and thermogenesis related processes such as shivering; however, what populations outside of the hypothalamus regulate temperature and how they accomplish this feat is incompletely understood. Mentored work will focus on establishing the dorsal raphe nucleus (DRN) as a critical regulator of thermogenesis. In particular, we plan to delineate the neural circuits embedded within the DRN that regulate energy expenditure through changes in thermogenesis. Preliminary data using whole-brain activity mapping, demonstrate activation of GABAergic DRN neurons in heat environment. Furthermore, through a combination of chemogenetic approaches, we proof that activation of these neurons directly regulate thermogenesis through autonomic and/or behavioral mechanisms. Together, through a combination of functional, molecular, and anatomic approaches, we will dissect whether the DRN bidirectionally controls thermogenesis and its specific upstream and downstream neurocircuitry in thermal regulation. Previous identified roles in feeding regulation for this region together with these results opens a new horizon in obesity treatment. On the independent phase, I plan to identify the molecular identity of neurons in premotor areas of the CNS responsible for a thermogenic response. My overarching hypothesis is that one subset of premotor neurons in the CNS drives a coordinated response to control thermogenesis through sympathetic nervous system mediated outflow to specific peripheral tissues. Furthermore, after corroborating that direct modulation of these neurons modulates body temperature, the proposed research will focus on defining if there is neuronal molecular heterogeneity in these premotor areas regarding the sympathetic nervous system mediated coordinated thermogenic response. I will take an interdisciplinary approach, using a combination of novel, state-of-the-art molecular technologies, such as optogenetics, neuronal tracing, calcium imaging and molecular phenotyping, together with metabolic assessments. This work will ultimately identify how the CNS orchestrates a thermogenic response. The proposed work will set the grounds for my own laboratory on central nervous system (CNS) mediated regulation of thermogenesis. Altogether, this work seeks to better understand thermogenesis regulation and establish the framework of my career as an independent investigator. Additionally, future molecular profiling studies of these neurons will allow us to perform cell-type specific targeted pharmacology mimicking the metabolic outcomes of cold exposure to ultimately treat obesity. !

产热是哺乳动物消耗能量的主要机制。创业约会 早在20世纪30年代，他就证明了下丘脑内的神经元对周围环境和局部环境敏感。 温度的偏差，反过来，这些神经元可以导致体温的强烈变化。 神经科学的一个基本目标是确定温度调节的神经基质。 对下丘脑细胞类型如何调节产热的研究取得了重大进展 和产热相关的过程，如颤抖;然而， 下丘脑调节体温，以及它们如何完成这一壮举还不完全清楚。 指导工作将集中在建立中缝背核（DRN）作为一个关键的调节器， 产热作用特别是，我们计划描绘嵌入DRN的神经回路， 通过产热作用的变化消耗能量。使用全脑活动绘图的初步数据， 证明GABA能DRN神经元在热环境中的活化。此外，通过结合 化学发生的方法，我们证明，这些神经元的激活直接调节产热 通过自主和/或行为机制。一起，通过功能，分子， 和解剖学方法，我们将解剖DRN是否双向控制产热及其 特定的上游和下游神经回路的热调节。先前确定的喂养作用 对该区域的调控以及这些结果为肥胖症治疗开辟了新的视野。上 在独立阶段，我计划确定中枢神经系统运动前区神经元的分子身份 负责产热反应。我的假设是前运动神经元的一个子集 中枢神经系统中的神经元驱动协调反应，通过交感神经系统控制产热， 神经系统介导的流出到特定的外周组织。此外，在证实， 这些神经元的直接调制调节体温，拟议的研究将集中在定义 如果交感神经系统的这些运动前区存在神经元分子异质性 介导的协调产热反应。我将采取跨学科的方法，结合使用 新的，最先进的分子技术，如光遗传学，神经元示踪，钙成像和 分子表型分析以及代谢评估。这项工作将最终确定中枢神经系统如何 协调了产热反应这项拟议中的工作将为我在中环的实验室奠定基础。 神经系统（CNS）介导的产热调节。总而言之，这项工作旨在更好地理解 产热调节和建立我的职业生涯作为一个独立的调查框架。 此外，未来对这些神经元的分子分析研究将使我们能够进行细胞类型特异性的研究。 靶向药理学模拟冷暴露的代谢结果，以最终治疗肥胖。 !