Thalamocortical afferents are the sole source of sensory input to the mammalian neocortex. Their role during cortical development is equally important. Recent work has established that thalamocortical afferents are required during development for the differentiation of the architectural, connectional and functional features that distinguish and define the functionally specialized """"""""areas"""""""" in the adult neocortex. The four specific aims of this proposal are designed to test hypotheses on mechanisms postulated to control the development of area-specific thalamocortical connections. This work will be done principally in rats, an excellent model for studies of cortical development and plasticity. It will combine a variety of anatomical and cellular methods, using in vivo and in vitro experimental approaches, as well as time-lapse imaging of cultured tissue. The major experimental goals are: (1) to assess the specificity in the targeting of thalamocortical axons and their invasion of the cortical plate. (2) to investigate a role for putative position-dependent molecular cues hypothesized to control specificity in thalamocortical axon targeting. (3) to determine whether maturation-dependent changes in membrane- associate molecules on the surfaces of cortical plate neurons and/or their secretion of a diffusible chemoattractant promotes the invasion of the cortical plate by waiting thalamocortical axons. (4) to analyze the degree of dispersion of neuroepithelial cells and their progeny during the development of the neocortical preplate as a means to evaluate hypothesized mechanisms of establishing position-dependent information in the subplate. The long term objectives of this work are to elucidate critical early events in the development of the mammalian cerebral cortex, with a focus on the neocortex. It is expected that the information gathered will provide insights not only into normal developmental mechanisms employed in the cortex, but that it will contribute to our understanding of the basis of the many congenital cortical abnormalities that afflict humans, as well as later striking neurodegenerative diseases.
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