NEUROCHEMICAL STUDIES OF THE AGING BASAL GANGLIA

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It is our central hypothesis that changes in the functional properties of dopamine (DA) neurons in the basal ganglia of the CNS contribute to age-related declines in motoric function in aged animals and humans. Prior studies from our laboratory and others support the hypothesis that age-related declines in motoric function are not associated with a robust decline in DA neurons. Rather, functional properties of DA regulation and release are affected in DA-containing areas. A striking finding from our recent studies is that somatodendritic release of DA, evoked by d-amphetamine and measured with in vivo microdialysis, is greatly decreased in the substantia nigra of aged monkeys. Using MRI guided stereotaxic surgery, this Project will use recently developed methods that allow for repeated in vivo microdialysis measures in anesthetized monkeys. This method has been combined with postmortem Western blot immunoassays and HPLC-EC methods for studies of the putamen, caudate nucleus, GPe and SN of young adult (5-9 year old), adult (13-16 year old) and late middleage/aged (20-25 year old) rhesus monkeys. This project will perform functional studies of neurochemical changes to the monkey basal ganglia during aging in conjunction with the behavioral, histological and immunohistochemical studies of Project by Gash and anatomical and functional MRIimaging studies in Project by Zhang. In addition, recent results from our laboratory support that glial cell linederived neurotrophic factor (GDNF) may be capable of restoring function to aged DA neurons. Our second series of neurochemical studies will be performed in late middle-aged/aged monkeys that have received chronic intranigral infusions of vehicle or GDNF, in an attempt to restore or enhance the function of aged DA neurons. These studies address the role of DA in decreased motor behavior in aging and the neurochemical properties of aged dopaminergic neurons in nonhuman primates.