HYPEROXIA AND RESISTANT RATS--MODELS OF CEREBELLAR AGING

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date9/30/979/29/99

Funding

  • National Institute on Aging
  • National Institute on Aging

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