Neuronal birth, migration, and differentiation continue in restricted regions of the postnatal mammalian brain. An understanding of neural stem cells and the mechanisms of migration and maturation of their progeny will lead to new neuroregenerative therapies. The subventricular zone (SVZ) contains the largest pool of neural stem cells in the adult brain. These cells are astrocytes, which constantly generate transient-amplifying cells (C cells) for the formation of new neurons that migrate to the olfactory bulb (OB). The proposed experiments aim to answer the following questions (1) How do astrocytes from germinal and non-germinal brain regions differ in structure and in their ability to function as neural stem cells? Grafting, cell culture, and molecular markers will be used to characterize different populations of postnatal astrocytes. Preliminary studies show that cultured SVZ astrocytes maintain the capacity to form neurons after transplantation. (2) Are SVZ neural stem cells multipotent in vivo? Can they generate oligodendrocytes and neurons? Preliminary evidence suggests that SVZ astrocytes also produce oligodendrocytes. In vivo and in vitro clonal analyses will determine if individual SVZ astrocytes generate both cell classes. The migratory pathways of young oligodendrocytes will also be determined. (3) How is the survival of neuroblasts and new neurons in the OB regulated in adult mice? The role of the neurotrophin, BDNF, in the survival of migrating neuroblasts and young OB neurons will be investigated. The cells in the SVZ and OB that express BDNF and its receptor, TrkB, will be identified. A novel method to selectively mutate TrkB in a subpopulation of newly formed neurons will be used to study the function of TrkB signaling in vivo. (4) What is the cellular composition, organization, and identity of the neural stem cells in the SVZ of the juvenile and adult human brain? Preliminary data indicate that human SVZ astrocytes also function as neural stem cells. Their location and properties will be extensively studied. Together these studies will help explain how new neurons and glia are produced, migrate, and survive in the postnatal brain. This work will also help elucidate the function of the SVZ, a germinal region that produces many brain cells during juvenile and adult life.
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