Central Regulation of Sympathetic Activity to Brown Fat

肥胖和糖尿病是异常普遍的能量稳态机制的破坏， 严重影响患者的健康和生活质量， 对我们国家的医疗保健系统的财政负担。这项研究的长期目标是了解 大脑影响能量消耗的中枢神经回路，能量消耗是能量的关键组成部分。 体内平衡和体重调节。治疗这种能量平衡失调将是 通过了解中枢神经系统内的功能组织和神经递质， 代谢信号激活的途径。拟议中的研究计划是 结果从最初的资金期，直接测试一系列的具体假设代表在我们的模型 代谢信号在下丘脑内起作用，影响中枢神经回路， 棕色脂肪组织（BAT）产热和心率通过改变特定人群的活动， 脑干交感运动前神经元这些研究将首次提供一个独特的机会 以确定下丘脑神经元调节的通路中的每个突触整合位点， 交感神经介导的能量消耗 建议的研究，以阐明组织，功能和药理学的纵向- 有组织的，核心途径的代谢调节交感神经激活BAT产热和 心率将结合联合收割机数据从解剖跟踪和免疫细胞化学实验与那些从 研究检查将物质显微注射到特定脑中对交感神经流出的影响 区域，以指导随后的电生理记录，从单个神经元的网站在 下丘脑、脑桥和延髓苍白中缝。这三个具体目标将侧重于相关的 解剖连接，诱发的生理反应和功能识别的行为 下丘脑背内侧核、中脑导水管周围灰质腹内侧核和中脑内侧核的神经元 视前下丘脑，分别测试明确定义的假设，他们的功能作用， RPa神经元的激活，导致增加的能量消耗和心率诱发期间， 对瘦素或黑皮质素激动剂给药的反应。了解其中的药理学 在发烧期间驱动交感神经反应的通路可以为开发策略提供基础 以改变交感神经介导的能量消耗，从而支持能量储存库的减少。

Obesity and diabetes are unusually prevalent disruptions of energy homeostatic mechanisms which have significant consequences for the health and quality of life of afflicted individuals and impose an enormous financial burden on our nation's health care system. The long-term objective of this research is to understand the central neural circuits through which the brain influences energy expenditure, a key component of energy homeostasis and body weight regulation. Treating such dysregulatiohs of energy homeostasis would be aided by an understanding of the functional organization and neurotransmitters within the central neural pathways that are activated by metabolic signals. The proposed research plan is a logical extension of the results from the initial funding period to directly test a series of specific hypotheses represented in our model of the central neural circuits through which metabolic signals, acting within the hypothalamus, influence brown adipose tissue (BAT) thermogenesis and heart rate by changing the activity of specific populations of brainstem sympathetic premotor neurons. These studies will provide, for the first time, the unique opportunity to define each of the synaptic integration sites in the pathways by which hypothalamic neurons regulate sympathetically-mediated energy expenditure. The proposed studies to elucidate the organization, function and pharmacology of the longitudinally- organized, core pathway for the metabolically-regulated sympathetic activation of BAT thermogenesis and heart rate will combine data from anatomical tracing and immunocytochemical experiments with those from studies examining the effects on sympathetic outflows from microinjection of substances into specific brain regions to guide subsequent electrophysiological recordings from single neurons at sites in the hypothalamus, pons and medullary raphe pallidus. The three specific aims will focus on the relevant anatomical connections, the evoked physiological responses and the behavior of functionally-identified neurons in (1) the dorsomedial hypothalamus, (2) the ventromedial periaqueductal gray and (3) the medial preoptic hypothalamus, respectively, to test clearly defined hypotheses on their functional roles in the activation of RPa neurons that leads to increased energy expenditure and heart rate evoked during the response to leptin or melanocortin agonist administration. Understanding the pharmacology within this pathway driving the sympathetic responses during fever could provide a foundation for developing strategies to alter sympathetically-mediated energy expenditure in support of a reduction in energy storage depots.