The cerebellar noradrenergic system is important for plasticity related to motor learning. As animals age, there is a decline in Beta-adrenergic receptor (BetaAR) function that is associated with a decline in learning of specific motor learning tasks. We have demonstrated that nutritional sources of antioxidants can reverse age-induced cognitive deficits in rats and reverse declines in cerebellar BAR function and motor learning. We propose to further these studies by examining the effects of nutritional sources of antioxidants on hippocampal plasticity (LTP). We have observed that in aged rats, there is a reactive oxygen species mediated increase in bcl-2 in Purkinje neurons. We will test the hypothesis that this increase in bcl-2 and an abnormal nuclear localization of bc1-2 underlies an imbalance of cellular homeostasis and is part of a key molecular mechanism underlying the age-related decline in cerebellar BetaAR function and motor learning. A second line of inquiry in this proposal will be to study a line of rats that is resistant to normobaric hyperoxia. These rats do not show the normal age-related declines in cerebellar BetaAR function and motor learning, and thus are an interesting model of aging. It is hypothesized that leukocyte function associated antigen (LFA-1) is deficient in these rats, and that this is the mechanism of resistance to hyperoxia. We will test the hypothesis that this is the mechanism underlying the resistance to aging by examining immune function in the brains of these rats. In addition, LFA-1 knockout mice will be studied to further test the hypothesis that LFA-1 is a critical contributor to the resistance to aging-related declines in cerebellar BetaAR function and motor learning. We have been examining the signal transduction system of the BetaAR in aged rats. Our results have focused our investigation on protein kinase A (PKA) subunit expression and localization. Important regulators of PKA are A-kinase anchoring proteins (AKAP). AKAP have been shown to localize PKA to specific subcellular domains. We plan to investigate alterations in PKA subunit expression as well as alterations in AKAP with the hypothesis that changes in the subcellular localization of PKA will resemble an apparent loss of PKA activity, as we have observed. Understanding the molecular mechanisms that underlie the age-related loss of cerebellar BetaAR function is critical for designing appropriate pharmacological interventions to improve cerebellar plasticity in aged animals. In very simplified terms, our overall hypothesis is that aging results in an increase in inflammatory processes that, in turn, results in an increase in oxidative stress that results in a disruption of cellular homeostasis and a decline in cognition.
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