Fetal cell transplantation strategies have targeted the striatum to reestablish dopaminergic (DA) function within the basal ganglia.. Our preliminary data indicate that the DA reinnervation of other targets within the system produce significant behavioral changes, when established as single targets, and may be necessary in combination to maximize functional recovery in Parkinson's disease (PD). To test this hypothesis, we will first determine the effects of dopamine reinnervation of substantia nigra, in addition to the striatum, in a MPTP primate model of PD. In addition, the subthalamic nucleus is a major component of the indirect pathways and motor circuitry of the basal ganglia. Our preliminary studies of dopamine reinnervation of the STN as a single target have shown significant behavioral recoveries in models of PD. We will therefore explore the contribution of DA reinnervation of the STN in behavioral and functional recovery of MPTP-induced parkinsonism. We will transplant DA cells to subthalamic nucleus alone or in combination with placement in striatum and substantia nigra. The evaluation of functional effects in all of our experiments will be determined by PET and MRI studies, including 11C-CFT, dopamine D2 receptors with 11C-raclopride, pharmacological MRI studies of amphetamine and apomorphine stimulated changes in striatal blood volume. Studies of neurochemical include N-acetyl aspartate (NAA), creatine (Cr) and choline (Cho). Behavioral Actigraph movement activity and video analysis completes the functional analysis. The functional data will be analyzed and intercorrelated. This project will determine how DA neural replacement in all of the regions denervated in PD will improve and fully restore the dysfunctional circuitry responsible for PD.
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