Intrastriatal injections of excitotoxins such as quinolinic acid (QA) result in a selective loss of striatal neurons mimicking the selective vulnerability of neuronal populations seen in Huntington's disease. Using this as a model system, investigators have been able to prevent the loss of some of these neurons by administration of growth factors such as nerve growth factor (NGF). Information from several laboratories indicates that the method of NGF administration correlates with the specific type of neurons that are spared following intrastriatal injection of QA. Infusions of NGF consistently protects only cholinergic interneurons, whereas, the implantation of fibroblasts genetically modified to secrete NGF protects both cholinergic and some noncholinergic striatal neurons. These contrasting patterns of striatal neuron protection by NGF infusion and fibroblast transplants serve as the basis for this proposal. The PI hypothesizes that either a synergistic effect between factors secreted by the modified fibroblasts and NGF confer the added protection to neurons not normally spared by NGF infusion or that striatal-derived trophic factors resulting from the implantation procedure are synergistic with the NGF secreted from the implanted cells. To test these hypotheses, the PI will compare implanted NGF-secreting fibroblasts with implanted NGF-secreting oligodendrocytes and NGF infusions for their ability to prevent the degeneration of cholinergic and noncholinergic striatal neurons following QA lesions. Grafts of non NGF-secreting fibroblasts and sham grafts will be used as controls. Immunocytochemical reactions for the major neuronal cell types in the striatum will be carried and the number of each cell type will be obtained. Because there is such a different pattern of cell sparing depending on the manner in which the factors are made available to the striatal tissue, the patterns of functional recovery conferred by the different NGF-secreting implants will be compared to those detected with NGF infusion, following a bilateral infusion of QA. Analysis of treated animals will involve measures of both motor and cognitive function, employing the Morris water maze and a paw reaching task.
Aim 4 will attempt to determine the mechanisms of action by which NGF influences sparing of striatal neurons after excitotoxic injury. The hypothesis is that NGF can have a direct effect on only those cells capable of NGF uptake and retrograde transport. An indirect action would be necessitated in those cells lacking these capabilities. It is proposed that these studies will determine the breadth of protection afforded by trophic-factor secreting transplants and elucidate the mechanisms by which the protection can occur.
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