The Physiology of Radial Units in Corticogenesis

University Of California, San Francisco, San Francisco CA

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Abstract

DESCRIPTION (provided by applicant): The mouse is the most widely used animal model in studies of cortical development. However, there are very important differences between mouse and human cerebral cortex both in the adult and during development. These important differences undercut the possible relevance of rodent studies for certain aspects of human cortical development, as well as for understanding human neurodevelopmental disorders. Recently, we described new types of neural stem cells found in the developing human brain in a region called the outer subventricular zone. In human brain, this fetal cortical region is very large, and because the cells divide multiple times before giving rise to nerve cells, they greatly increase neuronal output and are chiefly responsible for the huge number of nerve cells in the adult human neocortex. The finding of these novel neural stem and progenitor cells raises important new questions, such as how they contribute to the diversity of cell types found in the adult brain? How cells from this region migrate to reach the cortex? How they contribute to the columns of neurons that are a hallmark of cortical organization? These important questions have the potential to significantly alter our concepts of the development and organization of the human cortex, but they cannot be answered experimentally using human tissue. We propose to address these questions by taking advantage of the ferret, an animal that has a gyrencephalic cortex in the adult and similar neural stem and progenitor cells and similar progenitor zones as humans. We plan to use GFP-tagged retrovirus vectors to infect individual stem and progenitor cells in cortex both in vivo and in vitro. We will then monitor neuronal production and migration by long-term time-lapse imaging, and identify cell types by behavior, morphology, maker expression, and electrophysiological properties. We will determine the pattern of neurogenesis and the lineage of stem and progenitor cells and examine if there is an ontogenetic basis for circuit formation. This information will be necessary if we are to understand a host of developmental disorders of cortical function including autism, schizophrenia, epilepsy, and learning disabilities.