The central hypothesis of this grant is that age-related declines in motor function result from functional changes in the nigrostriatal dopaminergic system in animals and humans. To address this issue, our group has developed techniques to measure pharmacologically-evoked blood oxygen level-dependent (BOLD) changes in the basal ganglia of MRI-adapted, awake rhesus monkeys using functional magnetic resonance imaging (fMRI). In the studies proposed for this project, we will utilize fMRI to measure age-related changes in the BOLD response to various DA agonists. Specifically, we plan to compare the effects of apomorphine with the DA receptor-specific agonists SKF-81297 (D1 agonist) and LY17155 (quinpirole, a D2 agonist). We will then determine the relationship between pharmacologically evoked BOLD responses and underlying neural activity in specific regions of interest (ROD by using multiple single-unit electrophysiological recording. We will also utilize anatomical MRI to determine age-related changes in the volume of key basal ganglia structures. We will also measure iron accumulation in the globus pallidus and the substantia nigra. These anatomical measures will be conducted to test our hypothesis that age-related functional changes in these nuclei contribute more to behavioral deficits than do structural changes. We will assess the effects of GDNF on these functional and morphological measures in order to determine whether the potent DA neurotrophic factor possesses restorative properties in the basal ganglia. These studies will complement the behavioral, neurochemical and histopathological/biochemieal studies of Projects by Gash and Berhardt.
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