Neurogenesis occurs throughout life in the dentate gyrus of the hippocampus where adult neural stem cells proliferate and give rise to functionally integrated neurons. We are interested in understanding cellular and molecular mechanisms that regulate adult neural stem cells and their development in the mature central nervous system. Stem cells, especially human stem cells, also provide unique tools to model diseases of the nervous system. Our laboratory is using integrated approaches to study stem cells both in cell culture and in animal models using technologies in molecular biology, cell biology, biochemistry, virology, histology, in vivo multiphoton confocal imaging, electrophysiology, mouse genetics and animal behaviors.

(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 markers or neuronal markers. We are currently using these lines to investigate mechanisms that control the reprogramming of multipotent adult neural stem cells into pluoripotent cells as well as differentiation of neural stem cells into different neuronal subtypes.

(2). Intrinsic mechanisms regulating adult neural stem cells and their development in the adult brain: Adult neurogenesis recapitulates the neuronal developmental process in a mature central nervous system environment, including neuronal morphogenesis, migration, formation, maturation and maintenance of both GABAergic and glutamatergic synapses. We are currently focusing on several genes that have been implicated in specific human disorders to examine their roles in different phases of adult neurogenesis, including MeCP2 (Rett Syndrome), NF1 (neurofibromatosis type 1) and DISC1 (Schizophrenia). In addition, we are generating animal models to examine the potential contribution of specific defects in adult neurogenesis to these brain disorders with behavior tests.

(3). Extrinsic mechanisms regulating self-renewal and development of neural stem cells in the adult brain: We are particularly interested in activity-dependent extrinsic mechanisms originated from different local niche cells, including signaling from neurotransmitters and growth factors, and epigenetic regulation involving changes in histone and DNA methylation.

(4). Understanding mechanisms of neurological diseases using pluripotent human stem cells: By introducing human diseases mutants into relevant cell types derived from human embryonic stem cells, we aim to establish models to understand disease mechanisms. In parallel, we are deriving induced pluripotent stem cells (iPSCs) from fibroblasts of human patients to establish models of defined neurological diseases. We are particularly interested in degenerative neurological diseases (ALS, Parkinson’s Disease) and psychiatric disorders (Schizophrenia).