It has been suggested that age related decline in motor skills may be due at least in part to loss of dopaminergic neurons in the nigrostriatal system. The long term objective of this project is to use functional Magnetic Resonance Imaging (fMRI) to map patterns of neuronal activation in the nigrostriatal system of female rhesus monkeys in response to specific well defined dopaminergic stimuli, and to examine the age related changes in these responses. Once these age related changes have been characterized, the ability of neurotrophic factors to arrest and/or reverse them will be examined. If age related changes in nigrostriatal activity can be identified in this monkey model, the non-invasive nature of the fMRI measurement will be easily applicable to studies in humans.
The specific aims of the project are to test the following hypotheses: 1) Dopamine and dopamine receptor agonist induced nigrostriatal activation in the rhesus monkey is correlated in an age dependent manner with motor performance and dopaminergic status. FMIR will be used to measure the spatial and temporal patterns of neural activation in the nigrostriatal system of Adult Female Rhesus monkeys (5-24 years) in response to the dopamine precursor levodopa, the D1 + D2 agonist apomorphine, and the D2 agonist quinpirole. 2) Tropic factors directly administered to the nigrostriatal system of older rhesus monkeys will cause changes in the spatial and temporal patterns of neural activation consistent with improved nigrostriatal function. FMRI will be used to compare spatial and temporal patterns of dopaminergic activation in elderly female rhesus given trophic factor with the activation in age-matched animals given vehicle alone. 3) Specific age related changes in cerebral anatomy of the rhesus monkey correlate with age related decline in motor skill. MRI data obtained for coregistration of functional changes with anatomy, and for planning of stereotaxic surgery will be used to generate an 'average' brain for animals in three age groups (Young Adults (5-9 years); Middle Age Adults (14-17 years); Late Middle Age Adults (20-24 years)). The 'average' brains will be compared statistically, with particular emphasis being placed on identifying changes in nigrostriatal anatomy.
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