This multidisciplinary program project is designed to gain a better understanding of the neural circuitry of the neostriatum and other regions where dopamine neuronal systems appear to be important and to ascertain how transmitter synthesis, release and postsynaptic responses are regulated. Particular emphasis will be placed on the development and plasticity of transplanted central nervous or neuroendocrine tissues to the brain after lesions have been produced with specific neurotoxins. Special attention will be directed to the biochemical and electrophysiological events which accompany DA pathway activation and the biochemical, electrophysiological and behavioral consequences of the interactions. The plasticity of the ventral mesencephalic dopamine systems will be investigated with particular regard to their responses to acute and chronic neural activity, pharmacologic perturbation and the ability of transplanted fetal nervous or chromaffin cell donor tissue to develop and inervate host nervous tissue in situ. The central paradigm of this project is the study of lesions of the dopamine containing neurons of the rat nigro-striated pathway by the selective neurotoxin 6-hydroxydopamine (6--OHDA) and the subsequent treatment of such lesioned animals by transplantation of cells derived from rat fetuses. The focus is to better define the immunologic relationship between the host and fetal allogeneic neural tissue transplanted into the brain of inbred rats. Specifically we will determine the effect of bacterial toxin (superantigen) stimulation of peripheral T cells on graft function and survival, investigate properties of T cells which initiate graft rejection using adoptive transfer protocols, and determine if the immunological relationship between the host and the fetal allograft is altered by treating the grafted animals with glial cell line- derived neurotrophic factor. We will also investigate host immunization by graft antigens by limiting dilution analysis in vitro using deep cervical LN cells which are believed to receive lymphatic-like drainage from the brain and by determining if a second neural allograft will be accepted or reject ed when it is transplanted into a host which has previously received an allograft of identical donor origin. Finally we will investigate the question of trophic vs. transmitter effects of grafts in lesioned animals by employing co-transplantation of chromafin cells plus Schwann cells in syngeneic and allogeneic combinations. These studies will provide important information regarding the potential for using allogeneic tissue grafts in the treatment of Parkinson's disease and for the design of more effective treatment protocols.
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