In animal models of Parkinson's disease and in some Parkinsonian patients, neural and paraneural transplants of dopamine- rich tissue into the striatum have been shown to mediate functional recovery. Little is understood, however, of the mechanisms underlying the improvement of functional parameters. As an alternative to the traditional view that graft dopamine secretion accounts for the behavioral and neurochemical improvement, the trophic factor hypothesis of functional recovery following transplantation proposes that recovery occurs through graft-induced, trophic factor-mediated, modulation of injured host neural systems. The goal of the proposed research is to test aspects of this hypothesis by determining if neurotrophic factor production by tissue grafts or host mesostriatal system is a predictor of functional recovery in a rat model of Parkinson's disease. The studies will focus on the analysis of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), transforming growth factor-a TGFa), and glial cell line-derived neurotrophic factor (GDNF). These neurotrophic molecules have been shown to support dopaminergic neurons in vitro and in vivo, and are present within the mesostriatal system in vivo. Moreover, preliminary work from the applicant's laboratory indicates that mRNAs for BDNF and its receptor trkB are present within mesencephalic grafts subsequent to striatal implantation in normal rat. The first specific aim of these studies will examine neurotrophic factor expression in the 6-hydroxydopamine (6-OHDA)-lesioned rat subsequent to intrastriatal implantation of fetal mesencephalic grafts. The second two specific aims will directly test the hypothesis that trophic factors produced by the transplant ameliorate functional deficits by (a) implanting fetal midbrain tissue derived from recently developed """"""""knockout"""""""" mice lacking a functional BDNF or NT-3 gene, or (b) by infusing trophic factors, into denervated rat striatum. In situ hybridization of cRNA probes will be used in all experiments to evaluate levels, regional distribution, and cellular localization of neurotrophic factor mRNAs in appropriate donor transplant tissue and in host striatum and ventral mesencephalon. Trophic factor expression will be correlated with amelioration of functional deficits as well as with neurochemical measures of dopamine metabolism. Overall, the proposed experiments should add significantly to our understanding of the properties of the mesostriatal system in 6-OHDA-lesioned rats. In particular, these studies will provide insight into processes underlying plasticity and regeneration associated with functional recovery following neural grafting and trophic factor administration. (From the Abstract)
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