Among adult mammals, brain neurogenesis is highly restricted, both spatially and phylogenetically, and has not previously been found in primates. In contrast, neurogenesis is widespread and robust in the adult songbird forebrain, which continues to generate neurons from mitotic ventricular zone (VZ) precursor cells. We previously established a preparation by which neurogenesis could be studied in cultures of the adult avian forebrain. The percentage of neurons generated in these cultures varied as an inverse function of the serum level, indicating that serum might harbor or induce factors which are anti-mitotic for VZ precursors. On this basis, we proposed that the lack of neuronal production by non-neurogenic adult brain might result not from an absence of suitable precursor cells, but rather from their tonic inhibition by serum-born or locally-derived agents. Consistent with this idea, recent reports have demonstrated that neuronal precursor cells are present in cultures derIved from adult rodent brain. Since brain neurogenesis in mammalian embryogeny is VZ-based, just as it is in the adult songbird, we hypothesized that the adult human VZ might continue to harbor neuroepithelial stem cells; these cells may remain neurogenic in selected groups such as the songbirds, yet become vestigial in mammals. We further postulated that the adult human forebrain might also harbor such cells, which although non-neurogenic in vivo, retain the capacity for neurogenesis in vitro, once removed from local tissue influences. In preliminary studies, we indeed obtained evidence of newly produced neurons in cultures of adult human temporal lobe. We now propose to further study this phenomenon, by examining the mitotic capability, lineage potential of, and regulatory constraints upon, these precursor cells of the adult mammalian forebrain. Although the emphasis of this proposal is upon adult human forebrain, these experiments will include study of both rat and human brain cells: Rat tissue will be used as a more accessible alternative to human brain for experiments requiring many matched samples run in parallel, such as comparisons of the effects of defined growth factors upon VZ cell proliferation and differentiation. In this proposal, we will ask, and hope to answer, the following questions: 1. Can mitotic precursor cells with neuronal potential be identified in explant cultures of the adult human forebrain ventricular zone? 2. At what regulatory level is neurogenesis suppressed in the adult mammalian brain in vivo? What humoral signals are operative in the temporal and spatial restriction of adult neurogenesis? 3. Can typically quiescent glial phenotypes, particularly oligodendrocytes, also be generated anew from resident precursor cells in the adult human brain? 4. Are individual adult human forebrain ventricular zone precursor cells multipotential? Does the cell type generated by the ventricular zone stem cell depend upon its ambient environment? The establishment of adult human neurogenesis in vitro may permit us to induce this process in vivo, whether from endogenous or introduced progenitors. In pursuing this work, we hope to develop an operational rationale by which induced neurogenesis may become a viable option in the repair of structurally-damaged brain.
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