Granule cell neurogenesis and LTP

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Neurons are continually added at a low rate to the granule cell layer of the hippocampal dentate gyrus during adulthood in rats, mice [2,8,75] and primates [53], including humans [44]. Recent studies report that both enriched environments [75,4 1,138] and spatial learning [51] increase dentate granule cells, whereas age-related decreases in granule cell proliferation n parallel a decline in spatial learning [77,114]. These findings suggest that sustained granule cell neurogenesis is important for normal learning and memory. Our studies indicate that activation of granule cell axons (the mossy fibers) in the adult rat sufficient to induce mossy fiber LTP, a mechanism of synapticplasticity thought involved in learning [11,92] increases granule cell neurogenesis [41,139]. Thus both LTP and conditions that promote learning increase granule cells in adult animals. However, the mechanisms regulating neurogenesis are unknown. The collaborative studies proposed in this project will determine (1) if granule cell neurogenesis that follows LTP induction requires LTP induction, or if it is a process dependent on mossy fiber activation and/or granule cell depolarization, and (2) if increases in neurogenesis is the result of increase in the proliferation or differentiation of precursor or newly formed cells to granule cells, or increase in granule survival or differentiation. These studies will be conducted in vivo in adult rats with chronically implanted electrodes, and will employ bromodeoxyuridine (BrdU) incorporation, a measure of neurogenesis, in conjunction with fluorescent immunocytochemistry allowing co-labeling of precursor, glia, granule cells, immature neurons ,and apoptotic cells to distinguish among these possibilities. In Specific Aim 1, we will determine time at which neurogenesis is maximal following mossy fiber LTP induction using single doses of BrdU at daily intervals following LTP induction, and if neurogenesis following stimulation of results from an increase in granule cell proliferation, survival, differentiation, or in response to cell death using fluorescent markers for mitosis, cell phenotype, and markers for apoptosis. In Specific Aim 2, we will determine if LTP induction at perforant path-granule cell synapses increases neurogenesis, and if stimulation parameters that allow for selective potentiation of perforant path-dentate synapse, the mossy fiber-CA3 synapse, or both [136] differentially alter neurogenesis. In Specific Aim 3, we will determine if pharmacological treatments that block the induction of LTP similarly block neurogenesis. In Specific Aim 4, we will determine if exploration of novel environments, which associated with hippocampal place field formation and LTP induction [30,31] also increase granule cell proliferation, survival, or differentiation of mature cells to granule cells. The complimentary areas of expertise of the investigators will provide a mutually beneficial research program that will enhance both the understanding of mechanisms regulating neurogenesis, as well as enhance training of the diverse population of undergraduate, graduate and Ph.D. students at UTSA.