Central Autonomic Control, Aging and Oxidative Stress

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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.