Proliferating cells that produce both neurons and glia have been demonstrated in the adult dentate gyrus of many mammals including mice, rats, monkeys, and humans. The identity of some or all of these proliferating cells as "stem" cells is the subject of considerable attention and is of significance to numerous disciplines in both basic and clinical science. The goal of this application is to define quantitatively the proliferating population in the dentate gyrus of adult mice and the dynamics of their proliferation and survival. This information will clarify and advance understanding of the characteristics of stem vs. progenitor cells within the adult. In addition, this project will begin to address the genetic control of adult proliferation by building upon an important set of experiments that have identified two phenotypic differences in adult neurogenesis in the dentate gyrus of the mouse which indicate, that both the number of proliferating cells (stem or progenitor) and the survival potential of the cells produced are under genetic control. The project has 4 Specific Aims, all focused on understanding the in vivo regulation of stem/progenitor cell behavior in the adult murine dentate gyrus. The first 3 Specific Aims will define: 1) the role of cell cycle kinetics in strain differences, 2) the dynamics and proportional contributions of proliferation and survival to maintaining the size of the intrahilar proliferative population, and 3) the extent of cell death in the proliferating and post-proliferative populations. In order to exploit the known genetic differences Specific Aims 1 through 3 will all be carried out on both C57BLJ6 and BALB/c mice. In the fourth Specific Aim, data from the first 3 Specific Aims will be incorporated into a cell biologically relevant, quantitatively based mathematical model and computer simulation that describes the composition and behaviors of complex proliferative populations. This model will be used to determine whether these specific phenotypes are completely accounted for by the cell biologically relevant parameters of cell proliferation and cell death. In addition, it will provide a basis for both hypothesis formulation for future experiments on the proliferative population in the adult dentate gyrus and rigorous testing of data interpretations from such experiments.