The cerebral cortex, the organ of human intellect, is the site of many mental and neurological dysfunctions, the causes of which can be traced to genetic and acquired developmental abnormalities in early prenatal life. A fundamental question in understanding this phase of corticogenesis is how, after their last cell division in the proliferative ventricular zone, postmitotic neurons achieve their laminar and radial positions in the cortical plate, differentiate into specific phenotypes, generate a repertoire of neurotransmitters and receptors, and establish functional synaptic circuits. Previous findings from research in this program Project include i) development of novel surface neuron-glia junctional proteins that are involved in neuronal migration, ii) demonstration of the role of voltage and ligand-gated Ca2+ channels in neuronal migration, iii) evidence of the role of the cytoskeleton in cell motility, iv) identification of specific proteoglycans that are involved in activity-dependent cortical differentiation, v) discovery of adrenergic receptors in the transient embryonic zones of the primate embryos, vi) demonstration of a cortical role for various neurotransmitter systems ina the regulation and generation of synaptic and neuronal activity in developing forebrain circuits. These findings have generated novel concepts regarding developmental mechanisms or opened new areas of research. The present proposal is based on the premise that these are causally interrelated and overlapping events that can be understood best in relationship to each other . With the support of this Program Project, a team of investigators with expertise in molecular biology, immunocytochemistry, laser microscopy, electron microscopy, neuroanatomy, receptor pharmacology, computer imaging, and electrophysiology have joined forces to explore five major themes: (1) Surface mediated mechanisms of neuronal migration; (2) Regulation of cell phenotype in the developing neocortex; (3) Transmitter regulation of cortical phenotype; (4) Neurotransmitter receptors as sites of morphogenetic activity in the transient embryonic zones of the developing primate cerebral cortex; (5) Development of network activity in thalamocortical circuits. Thr proposed experiments utilize some of the most advanced neurobiological approaches that can, at this time, be applied to the complex developmental problems involved in cortical ontogeny. Our experience is that a program project of this scope promotes communication between investigators with different backgrounds, fosters research collaboration, and enables comprehensive, multifaceted analyses that are either not possible or practical for individual investigators working alone.
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