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 神经对能量代谢和体重调节的认识 大脑和脊髓中的回路。肥胖是一种常见的、复杂的疾病 其后果正在成为日益严重的公共卫生问题 意义。能量调节失调的治疗进展 在这种情况下的新陈代谢将有助于理解 控制能量消耗的途径的功能组织和 阐明调节其作用的神经递质。建议数 研究将验证这样一种假设，即苍白球吻侧中缝中的神经元 (RPA)构成共同的交感运动前通路，对 交感神经调节的产热激活对两者的反应 代谢/能量平衡相关和体温调节刺激。未来的模式是 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石，以确定(A) 下丘脑神经元调节能量和温度的途径 蝙蝠产热的动态平衡效应变化和(B)主要 调节放电的神经递质及其受体亚型 RPA生热神经元，并通过它来控制活动 蝙蝠的脊髓交感节前神经元。 阐明其功能和药理作用的实验研究 纵向组织的能源利用调节核心路径 将涉及交感神经的电生理记录 BAT和来自延髓和脊髓中单个神经元的结合 通过微刺激和微注射技术改变神经元的活动 在脑干、下丘脑和脊髓的受限区域。第一 具体目的是确定RPA神经元在BAT SNA变化中的作用 由影响蝙蝠能量消耗的代谢刺激和 诱导蝙蝠产热的冷刺激。交感神经前运动神经元 将确定这些影响的中介以及它们对这些影响的反应 刺激因素将会被确定。第二个目标将本地化 强而强的GABA能抑制RPA神经元，并确定这是如何 抑制被调节以产生交感神经流出到蝙蝠的变化。 将使用解剖道追踪技术来识别传入 调节代谢和体温调节稳态的RPA途径 条件反射。确定这些输入对RPA神经元活动和 BAT交感神经流出将有助于理解它们在网络中的功能 控制蝙蝠能源利用。在第三个具体目标中，我们将测试 假设谷氨酸是调节两者的主要神经递质 RPA神经元的兴奋及其对蝙蝠交感神经的影响 脊髓中的节前神经元。了解神经递质 决定蝙蝠交感神经流出的通路中的药理学将是一个 为制定改变该模型中的能量平衡的策略奠定基础 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.