Prevention of Hippocampal Neurodegeneration due to Age and Apnea

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DESCRIPTION (provided by applicant): The tragedy of growing old is not the burden of accumulated years or the imminence of death, but rather the host of senescent changes that so often degrade and enfeeble even the most gallant and competent. Of all the various manifestations of senescence, as Hazlitt pointed out in the nineteenth century, "The worst old age is that of the mind." In this regard, deficits in cognition, memory and learning, and mood are among the most debilitating as well as ubiquitous sequelae of the aging process. In this regard, and of particular importance to the Veterans Health Administration is the fact that the population of Veterans is aging faster than the general population, but also that the effects of apnea and its related cognitive deficits are increasing not only at a rapid rate, but faster than that present in groups of elderly individuals who are not Veterans. The hypothesis underlying the proposed research is that the effects of hypoxia/apnea on neurocognitive and mood disorders are of critical importance, especially in elderly Veterans. We also hypothesize that the effects of hypoxia/apnea in old age are exacerbated by an age-dependent reduction in GABAergic control in the hippocampus, which results in enhanced excitotoxic processes and neurodegeneration. Importantly, we also propose that the application of the GABA agonist, zopiclone, will provide neuroprotection from the effects of age and apnea, particularly with respect to hippocampal memory and learning functions. In order to determine the veracity of our hypotheses, we propose to generate basic data relating to the electrophysiological, morphological and functional changes that underlie the neurocognitive deficits and mood disorders that arise as a result of hypoxia/apnea in old age. Accordingly, an intracellular and extracellular electrophysiological examination of synaptic activity of the hippocampus will be combined with pharmacological and morphological studies in aged and adult (control) guinea pigs. The effects of the administration of a putative neuroprotective agent, zopiclone, on electrophysiological, morphological and behavioral processes in adult and aged guinea pigs, will also be determined. Specifically, the preceding experiments will be complemented by functional studies of memory and learning that will be correlated with light and electron microscopic and immunocytochemical analyses. These data will establish a foundation of knowledge that will provide critical insights into the consequences of a decrease in oxygen on the functioning of hippocampal and other neurons that occur in old age. In addition, the data to be obtained will determine targets for the development of therapeutic agents that are capable of eliminating and/or reducing the pathological consequences of hypoxia/apnea in the elderly and especially in populations of elderly Veterans with OSA.