Stem cells have the extraordinary potential to produce many different cell types. The hippocampus is one of two regions in the adult mammalian brain where neural stem cells continue to generate new cells throughout life. The current model of adult hippocampal neurogenesis suggests that radial astrocyte stem cells residing in the subgranular zone of the hippocampal dentate gyrus produce intermediate progenitor cells that divide many times before differentiation. Of these adult-born cells, the largest proportion differentiate into granule neurons. The functional significance of these adult-born neurons is controversial, partially because the extent to which they persist in the dentate gyrus is unknown. To evaluate the persistence of adult-born cells throughout life, an inducible bitransgenic mouse system capable of specific indelible labeling of the adult-born lineage was created. Using this system, the life-long persistence of adult-born cells in the hippocampal dentate gyrus was established. Adult-born cells comprised as much as 6% of the dentate granule cell layer under the relatively impoverished conditions of standard laboratory housing. Furthermore, both stem cells and neurons within the linage increased in number over time. When analyses were divided between the blades of the dentate, the relationship between stem cells and neurons was found to vary by blade. The stem cell-neuron relationship was linear in the lower blade of the dentate. In the upper blade, relatively few stem cells produced a large range in the number of neurons. The adult-born lineage was next assessed after environmental interventions known to alter neurogenesis. Environmental enrichment potently increases neurogenesis, while focal x-irradiation and social isolation are known to decrease it. After exposure to X-irradiation, neurogenesis was abolished but accumulation of stem cells still occurred. Social isolation decreased neurogenesis and increased the number of stem cells present in the lineage. Enrichment increased neuronal production within the adult-born lineage. Adult-born cells comprised over 20% of the dentate after exposure to an enriched environment. New models of adult hippocampal neurogenesis are presented to reconcile these results with the previous model. Additionally, evaluation of the volume of the dentate granule cell layer showed that it was not directly changed by the addition of adult born cells; nor could cell death fully account for adult-born cell addition. Thus, it is likely that the density of cells in dentate gyrus increases to accommodate the accumulating population of adult-born cells. The results suggest that factors known to regulate neurogenesis affect not just the population of neurons, but also the population of stem cells. Furthermore, the relationship between stem cells and the neurons they produce is under control of the either the anatomic or environmental niche of the stem cell. In the hippocampus, fate specification may represent a novel form of cellular plasticity for adapting to environmental changes. In general, these results inform a greater understanding of adult hippocampal neurogenesis and neural stem cells in the adult brain. In the future, the therapeutic power of these stem cells may be harnessed to help treat psychiatric and neurological disease.
|School Location:||United States -- New York|
|Source:||DAI-B 71/03, Dissertation Abstracts International|
|Subjects:||Neurosciences, Cellular biology|
|Keywords:||Cell fate, Dentate gyrus, Hippocampus, Neural stem cells|
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