CENTRAL REGULATION OF SYMPATHETIC ACTIVITY TO BROWN FAT

描述：这项研究的长期目标是改善我们的 了解神经系统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的复杂的疾病 其后果正在成为一个公共卫生问题， 意义能量失调治疗的发展 在这种情况下的新陈代谢将有助于了解 控制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 这项研究将验证一个假设，即苍白中缝吻侧的神经元 (RPa)构成了一个共同的交感神经运动前通路所必需的 交感神经调节的产热反应的激活 代谢/能量平衡相关和体温调节刺激。该模型 研究了大鼠棕色脂肪组织（BAT）的交感神经调节。 这些数据将为进一步研究提供基础，以确定（a） 下丘脑神经元调节能量和热量的途径 内稳态影响BAT产热的变化，以及（B）主要的 神经递质及其受体亚型，调节神经递质的释放， RPa产热神经元，并通过它们反过来控制活动 脊髓交感节前神经元的BAT。 实验阐明的功能和药理学的 管理能源利用的核心途径 涉及交感神经的电生理记录 到BAT以及来自延髓和脊髓中的单个神经元的组合 通过微刺激和微注射技术来改变神经元的活动 在脑干、下丘脑和脊髓的特定区域。第一 具体的目标将建立RPa神经元在BAT SNA变化中的作用 由影响BAT中能量消耗的代谢刺激引起， 冷刺激诱导BAT产热。交感运动前神经元 将确定介导这些影响的因素，并确定它们对这些影响的反应。 将确定刺激。第二个目标将本地化的来源， 强烈的，紧张性GABA能抑制RPa神经元，并确定如何这 调节抑制以产生到BAT的交感神经流出的变化。 解剖束追踪技术将用于识别传入 调节代谢和体温调节稳态的RPa途径 反射确定这些输入对RPa神经元活动的影响， BAT交感神经流出有助于了解它们在网络中的功能 控制最佳可得技术的能源利用。在第三个具体目标中，我们将测试 假设谷氨酸是介导这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 确定BAT交感神经流出的途径内的药理学将是一个 制定改变该模型中能量平衡的战略的基础 组织.

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.