The brain can be considered the most vulnerable of the body's organs to hypoxic disruption of function. The long-term objective of this research project is to define the cellular mechanisms by which decreased oxygen tension changes intrinsic cell function and alters communication of information in the nervous system. The rat brain hippocampal slice model will be used primarily in determining the effects that several forms of oxidative energetic stress, like those seen during anoxia and ischemia, have on neurons of the central nervous system.This model was chosen because of its well-defined and organized structure which allows recording of transynaptic potentials in vitro, and because substantial work has previously been performed in this laboratory developing methods to investigate the causes of hypoxic neuronal dysfunction. Specifically, it is the aim of this proposed research: 1) to determine if pre-synaptic activity affects the rate at which post- synaptic transmission fails during hypoxia; and 2) to determine if changes in intracellular pH, or 3) ATP are directly related to hypoxia-induced synaptic transmission failure and neuronal dysfunction. Standard extracellular and intracellular electrophysiological methods that allow evaluation of both field synaptic activity and membrane potential will be combined with recently developed optical monitoring techniques using absorption and fluorescence dyes for quantitative evaluation of intracellular pH. Characterization of the neuronal cellular responses to hypoxia in different central nervous system regions is an important first step in determining the overall mechanism by which tissue hypoxia is detected and by which organismal compensatory responses are initiated and controlled. Consequently, promising results obtained in this study will be extended to medullary slices containing neurons of the RVLM and nucleus ambiguous and, eventually, to respiratory and vasomotor neurons in vivo.
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