Neurogenesis occurs throughout life in the dentate gyrus of the hippocampus where adult neural stem cells proliferate and give rise to functionally integrated granule neurons. We are interested in understanding cellular and molecular mechanisms that regulate de-differentiation and differentiation of adult neural stem cells, and migration, guidance and synaptic integration of their neuronal progeny in the mature central nervous system environment. Our laboratory is using an integrated approach to study rodent and human neural stem cells in cell culture and in animal models utilizing technologies in molecular biology, cell biology, biochemistry, virology, histology, multiphoton confocal imaging and electrophysiology.

(1). De-differentiation and differentiation of adult neural stem cells: We have derived adult neural stem cells from transgenic animals expressing EGFP under the control of specific promoters for pluripotent genes or neuronal genes.  We are currently investigating mechanisms that control the reprogramming of multipotent adult neural stem cells into pluoripotent cells as well as those control the differentiation of adult neural stem cells into different neuronal subtypes.

(2). Axonal/dendritic development guidance and neuronal migration of newborn neurons from adult neural stem cells: In collaboration with Dr. Guo-li Ming’s laboratory, we have developed several model systems to examine the navigation of newborn neurons in the adult brain. We are using growth cone turning assay to examine growth cone responses of labeled newborn neurons from adult transgenic mice to defined diffusible gradients of guidance cues. In parallel, we are examining migration, axonal/dendritic development and guidance of newborn neurons by manipulation of endogenous neural progenitors with engineered retrovirus in genetically modified mouse in vivo.

(3). Synaptic integration and plasticity by neuronal progeny of adult neural stem cells: We have developed retroviral vectors for both loss-of-function and gain-of-function analysis of individual newborn neurons in the adult brain in vivo.  We are currently examining the cellular and molecular mechanisms that regulate the functional integration and plasticity of newborn neurons using electrophysiology and multiphoton confocal imaging approaches.  We are particularly interested in activity-dependent extrinsic mechanisms. 

(4). Adult neurogenesis as a model for understanding human brain disorders: Adult neurogenesis recapitulates neuronal developmental process in a mature central nervous system environment.  Interestingly, the neuronal integration process for adult born neurons is significantly prolonged compared to those during fetal development. This offers a unique opportunity to examine in detail the sequential events involved in the formation, maturation and maintenance of both GABAergic and glutamatergic synapses in vivo. We are currently focusing on several genes that have been identified or implicated in specific human disorders to examine their roles in different phases of adult neurogenesis, such as MeCP2 (Rett Syndrome), NF1 (neurofibromatosis type 1) and DISC1 (Schizophrenia).  In addition, we are generating animal models to examine the potential contribution of defects in adult neurogenesis to these brain disorders with specific behavior tests.