Neural circuit formation in aging brain: Hippocampus is another region of the brain that produces new neurons in adult animal. Neural stem cells reside in the subgranular zone of dentate gyrus of the hippocampus and produce new granule neurons that project their axons to the CA3 region. In collaboration with Dr. Cheng (UC Davis), we are investigating how newborn neurons are incorporated into existing neural circuits of the hippocampus. Moreover, aging is known to slow down the rate of neurogenesis, but it is not known whether aging has any effects on integration of new neurons into the circuits. Using Gli1-CreER and Tau-mGFP mice to genetically label the neural stem cells in the hippocampus, we are visualizing the axonal projections through the detection of membrane-bound GFP reporter expression. We have compared the labeled new neurons at various ages and analyzed the differentiation and maturation processes using serial immuno-elecronmicroscopy and three-dimensional reconstruction. Our preliminary results indicate that developmental integration of mossy fiber synaptic structures are compromised in aged hippocampus. Generation of novel circuitry reporter mice: Temporal and spatial control of marking cells of specific genetic lineages provides valuable insights into the gene function during development and maturation processes. We developed Gli1-FlpePR-CreER(T2), a dual Genetic Inducible Fate Mapping (GIFM) system that allows us to control recombination events at two distinct time points with Tamoxifen and RU486. In addition, we are currently characterizing two universal reporter mouse lines that conditionally express fluorescent protein-tagged wheat germ agglutinin (tWGA:FP), which can be transferred across synapses during neural activities. Combinatorial use of our dual GIFM with the novel trans-synaptic reporter system enables us to trace the neural circuits that are formed between adult born granule neurons from Shh-responding neural stem cells with pyramidal neurons of CA3 and subsequently of CA1.
