Central Autonomic Control, Aging and Oxidative Stress

描述（由申请人提供）： 专业神经科学研究计划（SNRP）的更新是基于霍华德大学和医学院做出的承诺，以保证对培养有才华的少数民族神经科学家的目标的长期支持。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合作，并在跨学科研究中实现了重要目标。这些成就对于我们能够吸引三位新的项目负责人更新该计划（SNRP-2）的过程至关重要。在SNRP的第一阶段，我们专注于调节呼吸和气道功能的神经元网络，这些神经元网络与参与行为状态控制的系统相耦合。目前的四个相互关联的项目旨在更好地了解环境变化，衰老和遗传因素如何导致影响呼吸和心血管功能以及认知的网络中的动态结构和功能改变。项目1将使用超微结构、分子生物学和生理学方法来确定慢性间歇性低氧诱导的气道高反应性的中枢机制。在雪貂模型中，将检验以下假设：反复短期缺氧（氧化应激）通过下调GABA能和单胺能（肾上腺素能和去甲肾上腺素能）抑制影响，增强对气道相关迷走神经节前神经元（AVPN）的中枢兴奋性神经输入，导致这些AVPN的过度兴奋状态和气道活动过度。项目2将使用超微结构，心电图，超声心动图和生理学方法来定义选定的神经机制介导的心肺整合。猫模型将用于研究右心室功能的副交感神经调节。也就是说，它将检查室间隔（IVS）神经节的外源性神经控制，其神经元提供了支配心脏右心室的迷走神经节后末梢的主要来源。这些神经元的功能可以受到氧化应激的影响，作为病理条件的结果，这反过来又增强了心血管功能障碍。项目3的总体目标是使用果蝇模型来了解氧化损伤保护系统的机制基础，以及它如何致力于维持神经系统，认知和神经肌肉能力的完整性作为年龄的函数。项目4将利用一个完善的氧化应激模型，即双转基因表达毒性？淀粉样蛋白（A？），结合最先进的神经体视学技术和定量受体放射自显影，以表征支配杏仁核、海马和额叶皮质的去甲肾上腺素能通路中与年龄和性别相关的改变。这些研究将检验以下假设：与阿尔茨海默病相关的毒性蛋白质的年龄相关积累引起神经炎症反应级联，导致负责认知和情感神经功能的去甲肾上腺素能通路进行性变性。核心A将保持集中的财务记录，编写财务和科学报告，促进共同资源的使用，并监测科学进展。核心B将提供中心设施，促进解剖学、神经化学、分子学、生理学和药理学方法的标准化，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霍华德大学实验室正在进行的工作。整个计划将提供有关调节自主功能，行为状态控制和认知的中央网络可塑性的新知识。

DESCRIPTION (provided by applicant): 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 ?-amyloid (A?), in combination with state-of-the-art 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.