We have identified the cerebellar noradrenergic system as being critical in motor learning processes. Plasticity in the motor system is important for the elderly because many individuals must adapt to new environments and new ways of moving around in old environments; in addition, rehabilitation from strokes which affect the motor system require relearning of basic motor skills. Aged animals and humans demonstrate a decline in plasticity of motor learning. Thus, understanding this decline in plasticity in aged animals will be of significant importance. We have been examining motor learning in aged rats and have demonstrated that the decline in learning is associated with a loss of cerebellar noradrenergic function. We seek to understand the biological mechanism underlying the age-associated decline in cerebellar beta-noradrenergic receptor function and associated motor behavior. We will examine the signal transduction mechanisms of the beta- adrenergic receptor using electrophysiological techniques. We can stimulate the transduction cascade at various points to determine if the deficit in beta-adrenergic responsiveness is up or downstream from the point of stimulation. The free radical theory of aging postulates that oxidative stress is a major etiological factor for the decline in physiological functions that eventually lead to death of the organism. Oxidation stress has also been implicated to play a major role in Alzheimer's disease and Parkinson's disease. Thus, a second goal of this project is to examine the role of oxidative stress and reactive oxygen species (ROS) in a specific neurobiological model system of aging; the cerebellar noradrenergic system and its role in motor learning. The response of the cerebellar noradrenergic system, in terms of electrophysiology and motor learning behavior, to oxidative stress will be studied in aged rats and in young rats exposed to normobaric hyperoxia. We will examine the induction of the proteins that ameliorate oxidative stress (catalase, CuZn SOD, Mn SOD, glutathione peroxidase). An important aspect of this research will be in examining the effect of N-tert-butyl-alpha- phenylnitrone (PBN) and antioxidant drugs on age-related cerebellar noradrenergic function and motor learning. Our initial findings have demonstrated that PBN will improve beta-adrenergic receptor function in aged rats. Thus, we will extend this finding to other drugs and to behavioral studies.
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