Central Autonomic Control, Aging and Oxidative Stress

这次更新专门的神经科学研究计划(SNRP)是基于 霍华德大学和医学院，在保证长期支持发展的目标方面 才华横溢的少数民族神经学家。在SNRP-1期间，我们开发了广泛的研究基础设施，建立了 多个跨部门和跨机构的研究协作，并在 跨学科研究。这些成就对于我们能够吸引三个新的 该计划(SNRP-2)续订的项目负责人。在SNRP的第一阶段，我们专注于神经元 调节呼吸和与参与行为状态的系统相耦合的呼吸道功能的网络 控制力。目前的四个相互关联的项目试图更好地了解环境变化、老龄化和 遗传因素导致网络中动态的结构和功能变化，从而影响呼吸和 心血管功能和认知能力。项目1将使用超微结构、分子生物学和生理学 确定慢性间歇性低氧诱导的呼吸道高反应性的中枢机制的方法。在……里面 在雪貂模型中，它将检验反复短期缺氧(氧化应激)会增强 中枢兴奋性神经传入通过下行调节对气道相关迷走神经节前神经元(AVPN)的影响 GABA能和单胺能(5-羟色胺和去甲肾上腺素)抑制影响，导致过度兴奋 这些动静脉管的状态和呼吸道多动。项目2将使用超微结构、心电图仪、 超声心动图和生理学方法确定调节心肺功能的特定神经机制 整合。猫模型将被用来研究右室功能的副交感神经调节。 也就是说，它将研究室间隔(IVS)神经节的外部神经控制，其神经元 为支配右心室的迷走神经节后终末提供主要来源。的功能 这些神经元可能会受到氧化应激的影响，这是病理条件的结果，而氧化应激又会增强 心血管功能障碍。项目3的总体目标是使用果蝇模型来理解 氧化损伤保护系统的机制基础以及它如何致力于维护 神经系统、认知力和神经肌肉能力随年龄的变化。项目4将利用一个成熟的 氧化应激模型、毒性G-淀粉样蛋白(AB)的双转基因表达及最新研究进展 神经体视学技术和定量受体放射自显影，以确定与年龄和性别相关的特征 杏仁核、海马体和额叶皮质去甲肾上腺素能通路的改变。这些研究将 测试与阿尔茨海默病相关的有毒蛋白与年龄相关的积累导致级联反应的假设 导致去甲肾上腺素能通路进行性退化的神经炎性反应 认知和情感神经功能。核心A将维护集中的财务记录保存，准备 财政和科学报告，促进共同资源的使用，并监测科学进步。核心B将 提供中央设施，促进解剖学、神经化学、分子、生理学和 药理学方法，并确保数据分析的统一标准。 本更新提案中的每个项目都直接来自我们在霍华德大学的实验室正在进行的工作。 整个计划将提供关于调节自主神经的中央网络的可塑性的新知识 功能、行为状态控制和认知。

This renewal of the Specialized Neuroscience Research Program (SNRP) is based on commitments made by Howard University and the College of Medicine, in guaranteeing long-term support toward the goal of developing talented minority neuroscientists. During SNRP-1 we have developed an extensive research infrastructure, established multiple inter-departmental and inter-institutional research collaborations, and accomplished significant goals in interdisciplinary research. These achievements were crucial to the process by which we were able to attract three new project leaders in the renewal of this program, (SNRP-2). In phase one of the SNRP, we focused on neuronal networks regulating breathing and the airway functions that are coupled to systems involved in behavioral state control. The current four interrelated projects seek to better understand how environmental changes, aging, and genetic factors lead to dynamic structural and functional alterations in the networks that affect respiratory and cardiovascular functions, and cognition. Project 1 will use ultrastructural, molecular biological, and physiological approaches to define central mechanisms involved in chronic intermittent hypoxia-induced airway hyper-reactivity. In the ferret model, it will test the hypothesis that repeated short-term oxygen deprivation (oxidative stress) enhances the central excitatory neural inputs upon airway-related vagal preganglionic neurons (AVPNs) through down regulation of GABAergic and monoaminergic (serotonergic and noradrenergic) inhibitory influences, leading to a hyperexcitable state of these AVPNs and to airway hyperactivity. Project 2 will use ultrastructural, electrocardiographic, echocardiographic, and physiological methods to define selected neural mechanisms mediating cardio-pulmonary integration. The cat model will be used to study the parasympathetic regulation of right ventricular functions . Namely, it will examine the extrinsic nervous control of the interventriculo-septal (IVS) ganglion, neurons of which provide the major source of vagal postganglionic terminals innervating the right ventricle of the heart. The function of these neurons can be affected by oxidative stress as a consequence of pathological conditions that in turn enhances cardiovascular dysfunctions. The overall goal of Project 3 is to use the Drosophila model to understand the mechanistic basis of an oxidative damage protection system and how it is devoted towards maintaining the integrity of the nervous system, cognition, and neuromuscular ability as a function of age. Project 4 will utilize a well established model of oxidative stress, the double transgenic expression of toxic g-amyloid (AB), in combination with state-of theart neurostereological techniques and quantitative receptor autoradiography, to characterize age- and gender-related alterations in noradrenergic pathways innervating the amygdala, hippocampus, and frontal cortex. These studies will test the hypothesis that the age-related accumulation of toxic proteins related to Alzheimer's disease cause a cascade of neuroinflammatory responses leading to progressive degeneration of noradrenergic pathways responsible for cognitive and affective neurological functions. Core A will maintain centralized financial record keeping, prepare financial and scientific reports, facilitate the use of common resources, and monitor scientific progress. Core B will provide central facilities, facilitate standardization of anatomical, neurochemical, molecular, physiological, and pharmacological methods, and assure uniform criteria for data analysis. Each project in this renewal proposal arises directly from on-going work in our laboratories at Howard University. The overall program will provide new knowledge on plasticity of central networks that regulate autonomic functions, behavioral state control, and cognition.