CENTRAL REGULATION OF SYMPATHETIC ACTIVITY TO BROWN FAT

棕色脂肪交感神经活动的中枢调节

• 批准号: 6696897
• 负责人: SHAUN F MORRISON
• 金额: $ 22.65万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-15 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696897
• 关键词: bioenergetics; biological signal transduction; brown fat; central nervous system; central neural pathway /tract; electrophysiology; glutamates; heat stimulus; hypothalamus; laboratory rat; lenticular nucleus; lipid metabolism; male; microinjections; neurons; neuropharmacology; neuroregulation; neurotransmitter receptor; neurotransmitters; sympathetic nervous system; thermogenesis

DESCRIPTION: The long-term objective of this research is to improve our understanding of the regulation of energy metabolism and body-weight by neural circuits in the brain and spinal cord. Obesity is a common, complex disorder with consequences that are becoming a public health problem of increasing significance. Development of treatments for the dysregulation of energy metabolism in this condition will be aided by an understanding of the functional organization of the pathways that control energy expenditure and an elucidation of the neurotransmitters mediating their effects. The proposed research will test the hypothesis that neurons in the rostral raphe pallidus (RPa) constitute a common sympathetic premotor pathway necessary for the activation of sympathetically-regulated thermogenesis in response to both metabolic/energy balance-related and thermoregulatory stimuli. The model to be studied is the sympathetic regulation of brown adipose tissue (BAT) in the rat. These data will provide the cornerstone for further studies to determine (a) the pathways by which hypothalamic neurons regulating energy and thermal homeostasis effect changes in BAT thermogenesis and (b) the principal neurotransmitters and their receptor subtypes that regulate the discharge of RPa thermogenic neurons and through which they, in turn, control the activity of spinal sympathetic preganglionic neurons for BAT. Experiments to elucidate the function and pharmacology of the longitudinally-organized core pathway for the regulation of energy utilization in BAT will involve electrophysiological recordings from the sympathetic nerves to BAT and from single neurons in the medulla and spinal cord in combination with microstimulation and microinjection techniques to alter neuronal activity in restricted regions of the brainstem, hypothalamus and spinal cord. The first specific aim will establish the role of RPa neurons in the changes in BAT SNA evoked by metabolic stimuli that influence energy expenditure in BAT and by cold stimuli that induce BAT thermogenesis. The sympathetic premotor neurons that mediate these effects will be identified and their responses to these stimuli will be determined. The second aim will localize the source of the strong, tonic GABAergic inhibition of RPa neurons and determine how this inhibition is modulated to produce changes in the sympathetic outflow to BAT. Anatomical tract tracing techniques will be used to identify the afferent pathways to RPa that mediate metabolic and thermoregulatory homeostatic reflexes. Determining the effects of these inputs on RPa neuronal activity and BAT sympathetic outflow will help to understand their function in the network controlling BAT energy utilization. In the third specific aim, we will test the hypothesis that glutamate is the principal neurotransmitter in mediating both the excitation of RPa neurons and their effects on BAT sympathetic preganglionic neurons in the spinal cord. Understanding the neurotransmitter pharmacology within pathways determining BAT sympathetic outflow will be a foundation for development of strategies to alter energy balance in this model tissue.

描述：这项研究的长期目标是提高我们的 了解神经元对能量代谢和体重的调节 大脑和脊髓中的回路。肥胖是一种常见且复杂的疾病 其后果正在成为日益严重的公共卫生问题 意义。能量失调治疗方法的开发 在这种情况下的新陈代谢将有助于理解 控制能量消耗和能量消耗的途径的功能组织 阐明介导其作用的神经递质。拟议的 研究将验证中缝苍白嘴端神经元的假设 (RPa) 构成了一个共同的交感神经运动前通路，这是 激活交感调节的生热作用以响应两者 代谢/能量平衡相关和体温调节刺激。模型应为 研究的是大鼠棕色脂肪组织（BAT）的交感神经调节。 这些数据将为进一步研究提供基石，以确定 (a) 下丘脑神经元调节能量和热的途径 BAT 产热过程中稳态效应的变化以及 (b) 主要 调节放电的神经递质及其受体亚型 RPa 产热神经元并通过它们反过来控制活动 BAT 的脊髓交感神经节前神经元。 阐明其功能和药理学的实验 纵向组织的能源利用调控核心路径 BAT 中将涉及交感神经的电生理记录 BAT 以及髓质和脊髓中单个神经元的组合 通过微刺激和显微注射技术来改变神经元活动 在脑干、下丘脑和脊髓的限制区域。第一个 具体目标是确定 RPa 神经元在 BAT SNA 变化中的作用 由影响 BAT 能量消耗的代谢刺激引起 诱导 BAT 生热作用的冷刺激。交感运动前神经元 将确定介导这些影响的因素及其对这些影响的反应 刺激将被确定。第二个目标是本地化信息源 对 RPa 神经元的强效 GABA 能抑制，并确定其如何 抑制作用被调节以产生 BAT 交感神经流出的变化。 解剖束追踪技术将用于识别传入神经 介导代谢和体温调节稳态的 RPa 通路 反射。确定这些输入对 RPa 神经元活动的影响和 BAT交感流出将有助于理解它们在网络中的功能 控制 BAT 能源利用。在第三个具体目标中，我们将测试 假设谷氨酸是介导两者的主要神经递质 RPa神经元的兴奋及其对BAT交感神经的影响 脊髓中的节前神经元。了解神经递质 决定 BAT 交感神经流出途径内的药理学将是 制定改变该模型中能量平衡的策略的基础 组织。