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: 10507835
• 负责人: Marc Schneeberger
• 金额: $ 24.9万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10507835
• 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; 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; efficacious treatment; 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; pulmonary function; 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. !

热发生是哺乳动物散发能量的主要机制。开创性的工作约会 回到1930年代，下丘脑内的神经元对环境和局部敏感 温度的偏差，而这些神经元又会导致体温的有效变化。 神经科学的一个基本目标是识别基于体温调节的神经底物。 在了解下丘脑细胞类型如何调节生热方面取得了重大进展 以及与热生成相关的过程，例如发抖；但是，什么人口 下丘脑调节温度及其如何完成这一壮举是不完全理解的。 指导的工作将集中于建立背侧raphe核（DRN）作为关键调节剂 热发生。特别是，我们计划描述调节的DRN中嵌入的神经回路 通过热发生的变化能量消耗。使用全脑活动映射的初步数据， 证明在热环境中激活GABA能DRN神经元。此外，通过组合 在化学发生方法中，我们证明了这些神经元的激活直接调节热生成 通过自主和/或行为机制。通过功能，分子的结合在一起 和解剖方法，我们将剖析DRN双向控制生热及其 热调节中的特定上游和下游神经通路。以前确定的饲料中的作用 该区域的调节以及这些结果为肥胖治疗开辟了新的视野。在 我计划识别中枢神经系统前运动前区域神经元的分子身份 负责热反应。我的总体假设是前一部分 中枢神经系统中的神经元通过交感神经来驱动控制热发生的协调反应 神经系统介导了特定的外围组织的流出。此外，在证实了 这些神经元的直接调节调节体温，拟议的研究将重点放在定义 如果这些前有关交感神经系统的神经元分子异质性 介导的协调热反应。我将采用跨学科的方法，结合 新颖的，最先进的分子技术，例如光遗传学，神经元跟踪，钙成像和 分子表型，以及代谢评估。这项工作最终将确定CNS如何 策划了热反应。拟议的工作将为我自己的中央实验室树立理由 神经系统（CNS）介导的热发生调节。总之，这项工作试图更好地理解 热生成调节并建立了我作为独立研究者职业的框架。 此外，这些神经元的未来分子分析研究将使我们能够执行细胞类型 有针对性的药理学模仿冷暴露的代谢结果，以最终治疗肥胖症。 呢