| In the adult brain neural stem cells (NSC) reside in specialized regions where they self-renew and give rise to mature neurons through neurogenesis. These cells then incorporate into the local circuitry and participate in memory and learning. What discriminates these neurogenic regions from the rest of the non-neurogenic brain is the composition of their local environment, or niche, as it contains a rich combination of growth factors and cell populations that interact to sustain the NSC. A combination of extrinsic and cell autonomous cues guide NSCs through the different steps of neurogenesis, and growth factors play an important role as guidance cues. Determining the identity and function of these factors is crucial to understanding ways in which the endogenous NSC population may be recruited for repair and regeneration. A key cell within the niche for the expression of growth factors is the astrocyte. One growth factor in particular, the astrocyte-derived vascular endothelial growth factors (VEGF), has strong mitotic properties that stimulate proliferation and neurogenesis in the adult brain when its levels are elevated by exogenous administration or experimentally induced to increase endogenous expression. In the naive brain, VEGF is found at high concentrations in neurogenic regions, but little is known about its functions, interactions, and whether it is involved in basal neurogenesis or the agerelated decline in neurogenesis. In this thesis, I focus on VEGF and introduce the following hypothesis: Astrocyte-derived VEGF regulates neurogenesis in the adult dentate gyrus. In support of this hypothesis, my first aim and chapter determine that VEGF promotes progenitor cell proliferation during basal neurogenesis in the adult dentate gyrus by activating its main receptor, Flk-1. My second aim and chapter determine, for the first time in vivo, that VEGF mediates the mitogenic effects of a second astrocyte-derived growth factor, fibroblast growth factors 2 (FGF2), in the adult hippocampus by activating Flk-1. Finally, my third aim and chapter determine that changes in the expression levels of astrocyte-derived VEGF and the neuronal-derived receptor Flk-1 with aging are region-specific in the adult brain. The decline in VEGF levels in the aged dentate gyrus corresponds to the age-related attenuation in neurogenesis, indicating a possible link with diminished cognitive function with age. The results of these aims contribute novel information about the contribution of VEGF to basal neurogenesis, its interaction with FGF2 to promote neurogenesis, and how the attenuated levels of VEGF may contribute to the age-related decline in neurogenesis. |
