Ramon y Cajal once said that """"""""nothing maybe regenerated"""""""" in the adult brain. Indeed, mature neurons lose the ability to divide and generate new cells. However, pools of neural stem cells in the subventricular zone (SVZ) surrounding the ventricles and the subgranular zone (SGZ) ofthe hippocampus are retained well into adulthood, and new cells can be generated from these pools. Characterization ofthese adult-born neurons, or neurogenesis, has revealed that they are highly evolutionarily conserved thoughout many species including primates, rodents, and birds. The cells in the SVZ migrate to the olfactory bulb while new neurons from the SGZ migrate to the dentate gyrus ofthe hippocampus. While the migratory patterns ofthese cells are well-defined, their paths can be altered in response to brain trauma. Neurogenesis may help alleviate cognitive deficits following brain injury or neurodegenerative disease. While the functional roles of the hippocampus and the olfactory bulb have been studied extensively utilizing brain lesions in animal models, the specific role of the subpopulations of adult newborn neurons is unclear. Interestingly, neurogenesis is not a static property. Factors that decrease neurogenesis in animal models can cause deficits in some cognitive tasks, while factors that increase neurogenesis can improve behavioral performance. Most of these manipulations yield promising but mostly con^elative data. Previous attempts to ablate adult neurogenesis to ascertain its function using anti-mitotic agents, irradiation, or transgneic models are limited by incomplete ablation, additional ablation of gliogenesis, or other off-target and possibly behavior-altering effects. In this study, we propose to create a new transgenic mouse with the ability to inducibly ablate adult neurogenesis, while sparing gliogenesis. We will then characterize any possible cognitive deficits in learning, memory, and olfactory tasks. We will also explore the potential of a neurogenesis-targeted therapy in alleviating cognitive deficits following a hippocampal lesion. Public Health Relevance - Understanding the role of neurogenesis in the adult brain is critical for the analysis of any neurogenesis-targeted therapies following cell loss in brain trauma or neurodegeneration. This project directly investigates the role of neurogenesis using unique transgenic mouse models.
