HYPEROXIA AND RESISTANT RATS--MODELS OF CEREBELLAR AGING

Aging produces deficits in cerebellar noradrenergic function and associated motor learning. Because the elderly are more susceptible to falls, it is desirable that motor systems remain highly functional with age. Declines in motor learning are associated with declines in cerebellar beta-adrenergic signal transduction. Therefore it is important to understand the mechanisms that produce this noradrenergic deficit. A key issue in research of aging is whether oxidative stress is major factor in age-related deficits. Initial studies suggest yes. A unique approach to this critical issue is to use rats that have been bred for the trait of resistance to normobaric hyperoxia. In young control rats, exposure to hyperoxia induce deficits in cerebellar beta- adrenergic function similar to deficits seen in aged rats. The hyperoxia resistant rats, however, do not show this deficit. More interesting, cerebellar beta-adrenergic function in aged hyperoxia resistant rats is not deficient. This is in stark contrast to age- matched controls. Thus, normobaric hyperoxia is a model of aging that can induce oxidative damage in the cerebellar beta-adrenergic signal transduction cascade and hyperoxia resistant rats provide a unique opportunity to study the role of oxidative stress in aging. Three important questions addressed here are 1) Does hyperoxia affect certain proteins in the beta-adrenergic signal transduction cascade? 2) Are hyperoxia resistant rat resistant to in vitro oxidative stress? 3) Will aged hyperoxia resistant rats retain high levels of motor learning? The first experiment uses a model of aging (i.e., hyperoxia) that allows in vitro intracellular study of the effects of oxidative stres on the cerebellar beta-adrenergic signal transduction cascade. The second experiment tests if hyperoxia resistant rats ar immune to hydroxyl and/or superoxide radical-induced damage. Cerebellar tissue from control and hyperoxia resistant rats will be incubated in hydrogen peroxide to generate hydroxyl radicals or in dihydroxyfumarate to generate superoxide. Intracellular assessment of cerevellar beta- adrenergic function will be made and dose response curves for oxidants will be compared between groups. Exposure to hyperoxia and oxzidants has been demonstrated to generate damage similar to age-related damage. Finally, in young rats cerebellar beta-adrenergic function is positively correlated with motor learning. The third experiment investigates if aged hyperoxia resistant rats have a high level of motor learning that correlates with a functional cerebellar beta- adrenergic system. In sum, these experiments are initial steps in understanding of both the effects of oxidative stress and whether oxidative stress is a major playeer in age-related deficits.