Date of Award

Spring 2009

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program/Concentration

Biomedical Sciences

Committee Director

Gyorgy Lonart

Committee Member

Richard A. Britten

Committee Member

Laura K. Hanson

Committee Member

Larry D. Sanford

Abstract

Space radiation represents a significant risk to the CNS (central nervous system) during space missions. Most harmful are the HZE (high mass, highly charged (Z), high energy) particles, e.g. 56Fe, which possess high ionizing ability, dense energy deposition pattern, and high penetrance.

Accumulating evidence suggests that radiation has significant impact on cognitive functions. In ground-base experiments, HZE radiation induces pronounced deficits in hippocampus dependent learning and memory in rodents. However, the mechanisms underlying these impairments are mostly unknown.

Exposure to HZE radiation elevates the level of oxidation, resulting in cell loss, tissue damage and functional deficits through direct ionization and generation of reactive oxygen species (ROS). When hippocampal slices were exposed to ROS, neuronal excitability was reduced. My preliminary results showed enhanced radio-vulnerability of the hippocampus and reduction in basal and depolarization-evoked [3H]-norepinephrine release after HZE exposure. These results raised the possibility that HZE radiation deteriorates cognitive function through radiation-induced impairments in hippocampal chemical neurotransmission, the hypothesis of this dissertation.

In Aim 1 I have focused on the effects of HZE radiation on release of major neurotransmitter systems in the hippocampus. I have further extended my research on the levels of receptors of these systems in Aim 2. In Aim 3, I have studied the level of oxidation in membranes of my samples.

My research reveals that HZE radiation significantly reduces hyperosmotic sucrose evoked [3H]-glutamate and [14C]-GABA release both three and six months post irradiation. The same radiation regimen also significantly enhances oxidative stress as indicated by increased levels of lipid peroxidation in the hippocampus, suggesting that increased levels of lipid peroxidation may play a role in reduction of neurotransmitter release. HZE radiation also significantly reduces levels of neurotransmitter receptors critical to synaptic plasticity; glutamatergic NMDA (N-methyl D-aspartate) receptors and β1 adrenergic receptors, three months post irradiation. By six months post irradiation, the levels of these receptors are returned to normal, implying that partial repair may take place.

My findings demonstrate that a single dose of HZE radiation alters the neurochemical environment in the hippocampus, which may underlie radiation-induced cognitive dysfunction.

Comments

Dissertation submitted to the Faculty of Eastern Virginia Medical School and Old Dominion University in Partial Fulfillment of the Requirement for the Degree of Doctor of Philosophy in Biomedical Sciences.

DOI

10.25777/ehwj-f815

ISBN

9781109217544

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