DESCRIPTION (provided by applicant): The adult mammalian hippocampus contains precursor cells that differentiate into neurons during adulthood. This phenomenon is referred to as adult neurogenesis. The proposed studies address whether neurons that form in the adult hippocampus, a brain region involved in learning and memory, affect behavior. Predictions of four hypotheses will be tested. The learning hypothesis posits that adult hippocampal neurogenesis plays a role in the acquisition of hippocampus-dependent behavior. Thus, according to the learning hypothesis, factors that increase neurogenesis should improve learning. The forgetting hypothesis posits that new hippocampal neurons contribute to forgetting and that factors that increase neurogenesis will interfere with the long-term retention of hippocampus-dependent behavior. The self-repair hypothesis holds that newly formed neurons repair damaged hippocampal circuitry and predicts that factors that increase neurogenesis will improve recovery of function after hippocampal injury. The injury process hypothesis, in contrast, posits that new neurons that form in response to hippocampal injury interfere with the functioning of the remaining intact hippocampal tissue. Thus, the injury hypothesis predicts that factors that increase hippocampal neurogenesis will exacerbate the behavioral impairments caused by hippocampus damage. The methods used to test these hypotheses will involve studying learning and memory using rats as experimental subjects. Hippocampal neurogenesis will be controlled using the selective serotonin reuptake inhibitor, fluoxetine, and exercise (wheel running). Neurogenesis will be quantified using immunohistochemical methods including BrdU-, NeuN-, GFAP-, and doublecortin-labeling, confocal laser microscopy, and unbiased stereology methods. The proposed studies will provide important new information about the function of adult hippocampal neurogenesis and assess whether factors that increase the rate of neurogenesis enhance, or disrupt, recovery of hippocampal function after brain damage.