| The long-standing dogma that neuronal production is restricted to discreet periods of development has been overturned by recent evidence of neurogenesis in the adult mammalian brain. In the hippocampus, new neurons are added to the dentate gyrus throughout adulthood as neuronal precursors in the subgranular proliferative zone (SGZ) at the border of the dentate granule cell layer (GCL) and hilus continue to divide and give rise to new granule neurons. Neurogenesis in the adult dentate gyrus is upregulated by a number of factors, including environmental enrichment and exercise, a variety of brain insults, and multiple growth factors and hormones, whereas neuronal production declines with age and in response to stressful events.; This dissertation focuses on the ability of one growth factor, insulin-like growth factor-I (IGF-I), to influence neurogenesis in the adult and aging hippocampus. Given that IGF-I levels decline with age, approximately in parallel with the age-related decline in hippocampal neurogenesis, the first study tested the ability of IGF-I treatment to reverse the deficit in neurogenesis in old rats. The second study used a model of adult-onset IGF-I deficiency to test whether IGF-I depletion in normal, young adult rodents suppresses neurogenesis in the dentate gyrus.; 5-bromo-2′-deoxyuridine (BrdU), a thymidine analog that labels dividing cells, was used to identify newly generated cells in the adult hippocampus. Animals were perfused shortly after BrdU injection to assess proliferation of granule cell precursors. Other animals were perfused four weeks after BrdU injection to evaluate the survival and neuronal differentiation of newborn cells. Standard immunohistochemical detection of BrdU, along with multiple immunofluorescent labeling of BrdU in combination with cell-type specific markers, was performed on a series of sections through the rostrocaudal extent of the dentate gyrus and analyzed via standard or confocal microscopy.; Results indicate that IGF-I is an important mediator of neurogenesis in the adult dentate gyrus. Rather than influencing all phases of neurogenesis (proliferation, survival, differentiation) to an equal extent, IGF-I appears to selectively target individual neurogenic phases, and both the age of the animal and the endocrine or autocrine/paracrine source of IGF-I are important determinants for the neurogenic response to the factor. |
