The underlying goal of this proposal is to investigate the morphological and molecular aspects of synaptic remodeling in the striatum using a rodent model system that mimics aspects of the multi-transmitter deficits found in Parkinson's disease. Degeneration of dopaminergic cells in the midbrain is the pathologic hallmark of Parkinson's disease, but there are well-established losses in other neurotransmitter systems involving the locus ceruleus and the raphe nucleus, as well as good evidence for pathological changes in the cortex. In this proposal, a dopaminergic deafferentation of the striatum will be combined with a lesion of the sensory-motor cortex, which our lab has previously demonstrated to be a model of reactive synaptogenesis; A golgi impregnation study will define the morphological restructuring of striatal neurons, and in situ hybridization studies will define the molecular sequence of events in neurite outgrowth, trophic promotion of synaptogenesis, and glial responses that are involved in this restructuring. In addition, the role of dopamine in the regulation of growth-associated mRNAs will be assessed by administering dopaminergic antagonists and agonists in lesioned gals and measuring RNA levels. These studies will help us better understand the response of striatal neurons and their remaining afferents when challenged with the loss of multiple afferent input, as is the case in many degenerative processes including Parkinson's disease.
