Precursor cells in the ventricular zone migrate during embryonic development and establish a colony of perpetually reproducing progenitor cells in the subgranular zone that give rise to granule neurons and glia in the dentate gyrus. These progenitor cells are active throughout adulthood, and make the dentate gyrus one of the few brain regions to exhibit neurogenesis. The mammalian dentate gyrus is also a brain structure that is known to be involved in learning and memory processes. Recent evidence indicates that conditions that enhance neurogenesis in the adult brain can also be beneficial for both behavioral learning and electrophysiological models for learning and memory. The present project seeks to determine the fundamental mechanisms that act as permissive signals for this neurogenesis, and to also use the process of neurogenesis to further the understanding of learning and memory processes at the biological level. The proposed research has five specific aims: First, the investigators will test the hypothesis that neurogenesis and synaptic plasticity in the dentate gyrus of adult mice will be genetic background by comparing the rates of neurogenesis in different inbred and outbred strains of mice. Second, they will use mouse strains selected following the completion of Specific Aim 1 to test the hypothesis that increased neurogenesis will enhance the expression of the NR2B subunit of n-methyl-d-aspartate (NMDA) receptors in the dentate gyrus of adult mice. Third, they will test the hypothesis that voluntary exercise can prove to be beneficial in alleviating stress-induced reductions in hippocampal neurogenesis in adult mice. Fourth, the investigators will test the hypothesis that the bone morphogenic protein (BMP) and Wnt signaling pathways that established during early hippocampal development will be conserved during neurogenesis in the adult brain. Finally, they will test the hypothesis that behavioral conditions that increase or decrease neurogenesis (running and stress, respectively) will provide sufficient contrast to identify novel genes involved in neurogenesis. Identification of the mechanisms for neurogenesis will form the basis for the development of targeted neuronal replacement therapies to combat neurodegenerative pathologies.
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