Diseases of the basal ganglia account for many neurologic and neuropsychiatric disorders, such as Parkinson's and Huntington's Diseases. Progress in understanding the functional organization and pathophysiology of the basal ganglia has been rapid. Much of this work has been integrated into a working model of basal ganglia circuitry that can account for both normal and abnormal behavior. The present proposal represents a multi-disciplinary effort, including neuroanatomical, electrophysiological, neuropharmacological, neurosurgical, and behavioral approaches to further our understanding of the structural and functional organization of the basal ganglia within the framework of this model. According to the model there exists a family of 'basal ganglia- thalamocortical circuits' that are organized in a parallel fashion, largely secreted one from another, both structurally and functionally. In the primate, """"""""motor"""""""" """"""""Oculomotor"""""""", """"""""associative and """"""""limbic"""""""" circuits have been described which take origin from specific cortical areas. Within each circuit, there appears to exist even further parallel features, e.g., the striatum, the major input structure of the basal ganglia, influences the internal pallidum, the major output structure, via parallel """"""""direct"""""""" and indirect"""""""" pathways. Project 1 address the role of recently discovered dopamine and muscarinic acetylcholine receptor gene families with the primate basal ganglia. Using subtype-specific antibodies to the receptors, the molecular pharmacology and anatomy of identified striatal circuits will be delineated. These studies will help identify the best targets for new drugs aimed at the subtypes for better treatment of movement disorders. Project 2 addressed the basis model at the level of brainstem interactions with the basal ganglia-thalamocortical circuitry. This project will help to elucidate the influence of the midbrain tegmentum on movement and basal ganglia-thalamocortical circuits at the level of the internal pallidum (GPi) on parkinsonian signs in monkeys with experimental parkinsonism. Correlation of behavioral changes with lesion sites as determined electrophysiologically and by MRI will help to optimize the outcome and reduce surgical complications. Data from this study will also help to elucidate the pathophysiology of these disorders and will lead to improved surgical treatment strategies. Project 4 explores the issue of segregated functions of the associative/oculomotor and motor circuits as regards the phenomenon of adaption to prism-induced and tendon-induced target displacements. This adaptation involves two additive components - a visual and a proprioceptive shift, both of which appear to depend on the integrity of separate basal ganglia circuits. Together these studies will extend out understanding of basal ganglia function, help to elucidate the pathophysiologic basis of basal ganglia disorders and lead to new innovative therapies for these disorders.
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