This is a competing renewal for a longitudinal project dedicated to the study of the neurogenetic processes of the primate brain. The proposed research is focused on the macaque monkey brain and designed to provide information about timing, sequences and developmental mechanisms that ultimately may determine the wiring diagram of the human central nervous system. Although empirical data on cellular events in fetal, neonatal and adolescent primates are important in their own right, we are continuously exploring broad conceptual issues concerning determinants of cell phenotype, control of cell number, capacity for compensatory plasticity and recovery of function, the validity of the radial unit hypothesis and the postulate of a cortical protomap. In the next cycle of this grant, emphasis will be on (1) determining the duration of the cell mitotic cycle and the kinetics of proliferation during critical developmental stages in various structures of the primate brain using a combination of bromodeoxyuridine immunocytochemistry and 3H-thymidine autoradiography; (2) determinants of cell lineages and the emergence of phenotypic individuality of neuronal cell classes in developing primate brain using recombinant retroviral vectors inserted in the genome of dividing ventricular cells; (3) expression of developmentally regulated molecules (protooncogenes, homeoboxes, proteoglycans), biochemical differentiation of neurons and emergence of synaptic connectivity (neurotransmitters, neuromodulators and receptors) using immunocytochemistry, in vitro binding of various ligands and in situ hybridization; (4) crossregional transplantation of 3H-thymidine prelabeled tissue slabs in age-matched primate fetuses; and (5) correlation of critical developmental periods as defined in experiments on developing monkeys with the corresponding stages in human based on structural and molecular criteria applied to the postmortem fetal brain. Altogether, the proposed experiments should advance our understanding of the development of the human brain and the pathogenesis of abnormalities caused by genetic and environmental factors.
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