The principal aim of research into the neurobiology of transplantation has been to develop strategies that would permit the reconstitution of functional capacity in a portion of the nervous system that is damaged. Both fetal mesencephalic grafts and autografts of the adrenal medulla are used experimentally and clinically to address this problem. However, the use of fetal cells has raised ethical questions and the survival of adrenal chromaffin cells is moderate unless neuronotrophic support is provided. Surprisingly, it now is well documented that the host can respond to transplantation, even with poor graft survival, by a sprouting response presumably from spared elements of dopaminergic pathway. Evidence suggests that this host sprouting response may play a very important role in functional recovery in animal models of Parkinson's disease. This proposal will test the hypothesis that a host sprouting response is important for restoring striatal dopamine levels and may be the single most important event in ameliorating functional deficits that result from dopamine depletion in the striatum. This hypothesis will be tested in a selective unilateral 6-OHDA lesioned rat model in which the dopamine neurons of the ventral tegmental area (VTA) are spared but the dopamine neurons of the substantia nigra pars compacta are lesioned. This model more closely resembles the neurodegeneration observed in idiopathic parkinsonism and provides the potential for sprouting from the spared axons of the VTA neurons in response to grafting. The focus of this proposal will be to determine the origin of the sprouting axons, to investigate the mechanisms that initiate the sprouting response, to determine if this response will restore neostriatal dopamine to levels sufficient for functional recovery, and to assess the effects of chronic L-dopa therapy on the host sprouting response. Immunohistochemical, neurochemical, neuroanatomical mapping, receptor autoradiography and behavioral experiments will be employed to address the hypothesis. Long term, we remain convinced that once the basic underlying mechanisms of neural grafting and the host responses are determined, that eventual clinical application will proceed with greater success. In the process, a significant amount of basic neurobiology will be researched with the expected promise of a better understanding of normal and pathological neurology.
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