Pre-clinical studies of the neural mechanisms of motor function suggest that there may be regionally specific sites advantageous for intracerebral neural graft placement into the host. One site, the substantia nigra, ultimately might prove to be the most advantageous due tot he possible restoration of natural neural circuits. Clinical studies have begun which claim superiority of one placement site over another, particularly the putamen over the caudate, without any comparative studies in primates. This project will study the effectiveness of various graft placements in order to understand the site-dependency of functional improvements in parkinsonian behavior after grafting. Monkeys with stable MPTP-induced parkinsonism will be used exclusively in this project for functional studies. A battery of behavioral test will assess the extent and nature of functional changes. Spontaneous behavior will be used to assess the general status of the subject, and tests that examine cognitive and sensorimotor function will be used to determine the effectiveness of grafts on specific functional deficits. The specific experiments will compare placements in the caudate with placements into the putamen. Control comparisons will include cannula placement sham surgeries, cerebellar tissue grafts, and unilateral substantia nigra grafts into each structure. Since multiple small grafts might innervate the entire striatum better than a confined graft of equal volume, we will test this possibility. In addition, grafts into anatomically defined subregions of the striatum may result in selective improvements in specific behavior(s) or types of improvements measured by performance on different tasks or aspects of tasks that are dependent on striatal dopamine or the integrity of frontocaudate circuitry. Some preliminary studies have suggested simple vs complex behavior, or indeed motor vs cognitive behavior, may be affected differentially by the placements of grafts into subregions of the large and heterogenous caudate. If experiments using growth factors or co-grafts further support the possibility and demonstrate suitable methods, we will also examine whether grafts of fetal SN into the SN or bridge grafts from the SN to the striatum would produce some additional functional improvements particularly in behavior dependent on external afferent inputs impinging on the SN rather than tonic terminal increases in dopamine in the MPTP denervated striatum. The general methods, experimental design outlines and assessment measures are presented separately in detail in each of the Core sections. Transplantation methods as developed and standardized by the program will be utilized in these studies and maintained consistently to provide proper controls for the principal variable of interest -- distribution of grafts within the host. This project may provide data important for understanding how graft placement affects the various behavioral functions of the nigrostriatal dopamine system and more rational ways to ameliorate deficits in dopamine system function which may be of clinical relevance.
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