Interrupted supply of oxygen is the main cause of neuron injury in cerebral stroke and transient cerebral ischemia. The long-range goal of this project is a comprehensive study of the acute effects of hypoxia on central nervous tissue of mammals. Hypoxic failure of cerebral function takes place in a succession of ell defined stages. First synaptic transmission is depressed, then cells lose membrane potential, release much of their potassium and take up sodium, chloride, calcium and water. Timely reoxygenation is still followed by recovery of neuron function, but if the depolarized state continues too long, injury becomes irreversible. In the past this laboratory has contributed to the understanding of each of these hypoxic changes. The goal for the present application is the biophysical mechanism of the hypoxic depolarization. Several hypotheses are proposed to explain the increased permeability of the neuronal membranes that result in the profound depolarization and transmembrane ion exchanges. The validity of these proposals will be tested with a variety techniques, including: Recording of ion changes in interstitial space of cerebral tissue slices; whole-cell recordings from neurons in brain tissue slices; single-channel recording from cell-attached patches; imaging of the intrinsic optical changes of cerebral tissue during hypoxia; confocal fluorescence microscopic imaging of intracellular calcium activity of cells in tissue slices. Besides neurons, the role of glial cells will also be studied.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS018670-14
Application #
2609571
Study Section
Neurology A Study Section (NEUA)
Program Officer
Jacobs, Tom P
Project Start
1982-07-01
Project End
1999-11-30
Budget Start
1997-12-01
Budget End
1998-11-30
Support Year
14
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Duke University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
071723621
City
Durham
State
NC
Country
United States
Zip Code
27705
Fayuk, Dmitriy; Aitken, Peter G; Somjen, George G et al. (2002) Two different mechanisms underlie reversible, intrinsic optical signals in rat hippocampal slices. J Neurophysiol 87:1924-37
Muller, M (2000) Effects of chloride transport inhibition and chloride substitution on neuron function and on hypoxic spreading-depression-like depolarization in rat hippocampal slices. Neuroscience 97:33-45
Borgdorff, A J; Somjen, G G; Wadman, W J (2000) Two mechanisms that raise free intracellular calcium in rat hippocampal neurons during hypoosmotic and low NaCl treatment. J Neurophysiol 83:81-9
Somjen, G G; Muller, M (2000) Potassium-induced enhancement of persistent inward current in hippocampal neurons in isolation and in tissue slices. Brain Res 885:102-10
Somjen, G G (2000) Enhancement of persistent sodium current by internal fluorescence in isolated hippocampal neurons. Brain Res 885:94-101
Bahar, S; Fayuk, D; Somjen, G G et al. (2000) Mitochondrial and intrinsic optical signals imaged during hypoxia and spreading depression in rat hippocampal slices. J Neurophysiol 84:311-24
Kager, H; Wadman, W J; Somjen, G G (2000) Simulated seizures and spreading depression in a neuron model incorporating interstitial space and ion concentrations. J Neurophysiol 84:495-512
Muller, M; Somjen, G G (2000) Na(+) and K(+) concentrations, extra- and intracellular voltages, and the effect of TTX in hypoxic rat hippocampal slices. J Neurophysiol 83:735-45
Muller, M; Somjen, G G (2000) Na(+) dependence and the role of glutamate receptors and Na(+) channels in ion fluxes during hypoxia of rat hippocampal slices. J Neurophysiol 84:1869-80
Balestrino, M; Young, J; Aitken, P (1999) Block of (Na+,K+)ATPase with ouabain induces spreading depression-like depolarization in hippocampal slices. Brain Res 838:37-44

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