| Summary: | Controlling neurogenesis constitutive to the hippocampal dentate gyrus of adult mammals could improve strategies geared toward replacing neurons lost in the diseased or injured human CNS. This thesis resolves and expands upon conflicting reports about estradiol's influence over neurogenesis (progenitor proliferation and daughter cell differentiation and survival) in the adult rodent dentate gyrus. Chapter 2 showed that reproductive status regulates neurogenesis in the dentate gyri of adult laboratory-reared female meadow voles. Specifically, reproductively inactive (low estradiol) females had more dividing cells than reproductively active (high estradiol) females or females exposed to estradiol for 48 h. However, females exposed to estradiol for 4 h had more dividing cells than reproductively inactive females, suggesting that estradiol dynamically regulates cell proliferation. Because the ratio of new cells surviving 5 weeks versus 2 h was higher in the dentate gyri of reproductively active versus inactive females, estradiol appeared to enhance the survival of young cells. Chapters 3 and 4 confirmed that estradiol dynamically regulates dentate cell proliferation robustly across rodent species. Cell proliferation in the dentate gyri of female rats (Chapter 3) and meadow voles (Chapter 4) increased 4 h after but decreased 48 h after estradiol- versus vehicle-treatment. In part, estradiol suppressed proliferation by stimulating adrenal activity because adrenalectomy eliminated the suppression in adult female rats. Consistent with the effects reported in other species, NMDAr activation decreased and NMDAr inactivation increased proliferation in the dentate gyri of adult female voles but estradiol did not stimulate NMDArs to influence cell proliferation. Chapter 5 showed that estradiol potently enhances young granule neuron survival and that enhanced survival is related to improved hippocampus-dependent memory (but not learning). Specifically, estradiol doubled the number of 16-day old neurons in the dentate gyri of adult male meadow voles when administered over Days 6-10 after the neurons are born. Estradiol treated voles (Days 6-10), exhibited similar hormone-free performance Morris water maze training trials but outperformed vehicle-treated voles on a probe trial. Chapter 6 discusses how estradiol-induced changes in components of neurogenesis may influence normal hippocampus function and discusses how the findings of this thesis may relate to neuronal replacement strategies.
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