Probably no other part of the CNS has been so thoroughly investigated as the cerebellum, yet large gaps still exist in our understanding of the basic relationships among structure, function and neurotransmission in this brain region and very little is known concerning the regulation of gene expression in cerebellar cortical neurons. This multidisciplinary program project proposal is designed to fill some of these gaps by using molecular, cellular and systems approaches to: 1) study neurodegeneration associated with SV40 T antigen expression in Purkinje precursors; 2) examine genes whose expression are important for granule cell development; 3) study the neural regulation of cerebellar blood flow; and 4) analyze the anatomy, chemistry and physiology of cerebellar afferent systems. This proposal also serves to bring together a group of investigators with diverse backgrounds and expertise who are committed to obtaining basic information that will enhance our knowledge of the structural organization, molecular biology, development, neurochemistry, pharmacology and physiology of the normal cerebellum and to providing new data regarding the molecular mechanisms involved with the development of cerebellar ataxia. Project 1: Will utilize transgenic mice to examine the molecular basis of Purkinje cell degeneration in a novel model of cerebellar ataxia. Project 2: Will examine the molecular events governing granule neuron development and the role this cell plays in the establishment of cerebellar cytoarchitecture. This will be achieved by using a novel gene, MN20, to examine transcriptional regulatory mechanisms operating during granule cell development. In addition transgenic mouse models in which granule neuron populations are deleted will be used to analyze the role of these cells in cerebellar development. Project 3: Will utilize ultrastructural tract tracing- immunocytochemical, microdialysis, receptor localization and in situ hybridization procedures to define the excitatory amino acid transmitters and receptors associated with cerebellar climbing and mossy fiber systems. Project 4: Will utilize the parallel fiber system of the cerebellar cortex to elucidate the mechanisms mediating the changes in cerebellar blood flow elicited by neural activation. Project 5: Will utilize voltage sensitive dyes and optical monitoring procedures to examine the spatial aspects of information processing in the cerebellar cortex and the interactions between climbing fiber and mossy fiber systems.
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