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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL025830-13
Application #
3780172
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Case Western Reserve University
Department
Type
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Prabhakar, Nanduri R; Semenza, Gregg L (2012) Adaptive and maladaptive cardiorespiratory responses to continuous and intermittent hypoxia mediated by hypoxia-inducible factors 1 and 2. Physiol Rev 92:967-1003
Kline, David D (2010) Chronic intermittent hypoxia affects integration of sensory input by neurons in the nucleus tractus solitarii. Respir Physiol Neurobiol 174:29-36
Peng, Y-J; Nanduri, J; Yuan, G et al. (2009) NADPH oxidase is required for the sensory plasticity of the carotid body by chronic intermittent hypoxia. J Neurosci 29:4903-10
Kline, David D; Hendricks, Gabriel; Hermann, Gerlinda et al. (2009) Dopamine inhibits N-type channels in visceral afferents to reduce synaptic transmitter release under normoxic and chronic intermittent hypoxic conditions. J Neurophysiol 101:2270-8
Prabhakar, Nanduri R; Kumar, Ganesh K; Nanduri, Jayasri (2009) Intermittent hypoxia-mediated plasticity of acute O2 sensing requires altered red-ox regulation by HIF-1 and HIF-2. Ann N Y Acad Sci 1177:162-8
Braga, Valdir A; Prabhakar, Nanduri R (2009) Refinement of telemetry for measuring blood pressure in conscious rats. J Am Assoc Lab Anim Sci 48:268-71
Kline, David D (2008) Plasticity in glutamatergic NTS neurotransmission. Respir Physiol Neurobiol 164:105-11
Buniel, Maria; Glazebrook, Patricia A; Ramirez-Navarro, Angelina et al. (2008) Distribution of voltage-gated potassium and hyperpolarization-activated channels in sensory afferent fibers in the rat carotid body. J Comp Neurol 510:367-77
Pawar, Anita; Peng, Ying-Jie; Jacono, Frank J et al. (2008) Comparative analysis of neonatal and adult rat carotid body responses to chronic intermittent hypoxia. J Appl Physiol 104:1287-94
Hsieh, Yee-Hsee; Dick, Thomas E; Siegel, Ruth E (2008) Adaptation to hypobaric hypoxia involves GABA A receptors in the pons. Am J Physiol Regul Integr Comp Physiol 294:R549-57

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