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
基本信息
- 批准号:10507835
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AddressAffectAmericanAnatomyAreaAutomobile DrivingBackBehavioral MechanismsBody TemperatureBrainBrain StemBrown FatCalciumCell NucleusCellsClinicalDataDevelopmentDiseaseEatingEnergy MetabolismEnvironmentEpidemicExposure toFutureGoalsHealthHeartHeterogeneityHomeostasisHumanHypothalamic structureImageLaboratoriesLeadLungMammalsMediatingMentorsMetabolicMetabolic dysfunctionMetabolismMethodsMolecularMolecular ProfilingMotor ActivityNeuraxisNeuronsNeurosciencesObesityOutcomePatternPeripheralPeripheral Nervous SystemPharmacologyPhasePhysiologic ThermoregulationPopulationProcessRegulationResearchResearch PersonnelRoleShiveringSkinSympathetic Nervous SystemSystemTechnologyTemperatureTestingThermogenesisTissuesTrainingValidationVasodilationViralWorkbasecareercell typedorsal raphe nucleuseffective therapyefficacious treatmentexperimental studyfeedingheart functionimprovedin vivo calcium imaginginterdisciplinary approachmad itch virusmolecular markermolecular phenotypenerve supplyneural circuitnovelnovel therapeuticsobesity treatmentoptogeneticspulmonary functionrelating to nervous systemresponse
项目摘要
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.
!
产热作用是哺乳动物耗散能量的主要机制。开创性作品交友
早在20世纪30年代就表明,下丘脑内的神经元对周围环境和局部环境都很敏感
温度的偏差,反过来,这些神经元可能会导致体温的显着变化。
神经科学的一个基本目标是确定体温调节的神经基础。
在了解下丘脑细胞类型如何调节产热方面取得了重大进展
以及与产热相关的过程,如颤抖;然而,在
下丘脑调节温度,以及它们是如何完成这一壮举的,目前还不完全清楚。
指导工作将集中于建立中缝背核(DRN)作为一种关键的调节
生热作用。特别是,我们计划描绘嵌入DRN的神经电路,这些神经电路调节
通过生热作用的变化来消耗能量。使用全脑活动图的初步数据,
显示热环境中GABA能DRN神经元的激活。此外,通过组合
在化学发生途径中,我们证明了这些神经元的激活直接调节产热。
通过自主和/或行为机制。通过功能、分子、
和解剖学方法,我们将剖析DRN是否双向控制生热作用及其
体温调节中特定的上游和下游神经回路。以前确定的喂食角色
对该区域的监管以及这些结果开辟了肥胖症治疗的新天地。论
独立阶段,我计划确定中枢神经系统运动前区域神经元的分子身份
负责生热反应的。我最重要的假设是运动前期的一个子集
中枢神经系统中的神经元通过交感神经驱动协调反应来控制产热
神经系统介导的外流到特定的外周组织。此外,在证实了这一点之后,
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
交感神经系统的这些运动前区是否存在神经元分子异质性
介导的协调生热反应。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
分子表型和代谢评估。这项工作最终将确定CNS是如何
协调了一种生热反应。拟议的工作将为我在中环建立自己的实验室奠定基础
神经系统(CNS)参与产热的调节。总之,这项工作试图更好地理解
并为我作为一名独立调查员的职业生涯奠定了基础。
此外,未来对这些神经元的分子图谱研究将使我们能够进行细胞类型特异性
模拟寒冷暴露的代谢结果,最终治疗肥胖症的靶向药物。
好了!
项目成果
期刊论文数量(0)
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Marc Schneeberger其他文献
Marc Schneeberger的其他文献
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{{ truncateString('Marc Schneeberger', 18)}}的其他基金
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:
10647872 - 财政年份:2022
- 资助金额:
$ 24.9万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 24.9万 - 项目类别:
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:
10066350 - 财政年份:2019
- 资助金额:
$ 24.9万 - 项目类别:
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:
10201028 - 财政年份:2019
- 资助金额:
$ 24.9万 - 项目类别:
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