REGULATION OF ADULT HIPPOCAMPAL NEUROGENESIS BY HYPOXIA INDUCIBLE FACTOR 1-ALPHA (HIF1-α)
Lauren Carrica, Lee Anna Cunningham, Lu Li.
University of New Mexico, Albuquerque, NM.
Adult hippocampal neurogenesis from neural stem and progenitor cells (NSPCs) is a unique form of adult brain plasticity linked to learning and memory. Previous studies by our lab have demonstrated constitutive expression of stabilized HIF1-α within NSPCs of the hippocampal subgranular zone (SGZ) of adult mice. Here, we investigated the hypothesis that HIF1-α performs a vital role in neurogenesis and performance on a neurogenesis-dependent learning task. We utilized a tamoxifen-inducible Cre-loxP approach to selectively delete exon 1 of the Hif1α gene within NSPCs from nestin-CreERT2/R26R-YFP/ Hif1α fl/fl triple transgenic mice. The inactivation of HIF1-α within NSPCs resulted in a 70% reduction in the number of YFP+ dentate granule cells (DGCs) compared to control nestin-CreERT2/R26R-YFP/ Hif1α wt/wt mice (p < 0.05, n = 5 mice/group) by 45 days following tamoxifen administration. To determine whether the impaired neurogenesis following Hif1α gene deletion is associated with impaired performance on a neurogenesis-dependent learning task, we tested mice on an A-B context discrimination fear conditioning learning paradigm. This task requires the formation of associations between distinct environmental contexts and an aversive stimulus. Our preliminary experiments demonstrated a significant impairment of learning in nestin-CreERT2/R26R-YFP/ Hif1α fl/fl compared to nestin-CreERT2/R26R-YFP/ Hif1α wt/wt mice at 45 days post tamoxifen exposure (p < 0.025 at days 4 and 5 of training, n = 3 to 7 per group). Currently, we are conducting fate map analysis of YFP+ cells to determine the stage of neurogenesis that is most vulnerable to Hif1α gene deletion.