Epigenetic Regulation of Adult Hippocampal Neurogenesis

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Knowing the adult human brain has the innate ability to produce new neurons throughout life has propelled the study of adult neurogenesis to the forefront of scientific research. While numerous factors, such as aging and exercise, have been identified to regulate adult hippocampal neurogenesis, there is currently a gap in our knowledge with respect to the molecular mechanisms that cell-autonomously modulate hippocampal neural precursor development to contribute to hippocampal neurogenesis. Since epigenetics has emerged as a molecular interface that integrates extrinsic signals to determine intrinsic gene expressions, our long term goal is to understand how epigenetic mechanisms cell-autonomously regulate adult hippocampal neurogenesis. On the basis of our recent fruitful research regarding the role of a histone acetyltransferase, CBP (CREB binding protein) in regulating neural stem cell biology, we hypothesize that CBP regulates adult neural precursor development in vivo in a cell-autonomous and CREB binding-dependent manner, ultimately contributing to adult hippocampal neurogenesis and hippocampal-dependent memory. To test the hypothesis, we will pursue the following three aims. Aim 1: Determine the cell-autonomous effect of CBP in regulating adult neural precursor development in vivo. We will use inducible conditional CBP knock-out mouse lines to identify the stages of hippocampal neural precursor development that are regulated by CBP and its contribution to hippocampal neurogenesis and hippocampal-dependent memory. Aim 2: Determine the importance of CREB binding in CBPregulated adult neural precursor development in vivo. We will use CBPKIX mouse (lacking the ability to bind CREB) to assess the importance of CREB binding for CBP-mediated hippocampal neural precursor development in vivo and its contribution to hippocampal neurogenesis and hippocampal-dependent memory. Aim 3: Identify downstream targets of CBP upon Ser436 phosphorylation in adult hippocampal neural precursors. We will use CBPS436A mouse (lacking the atypical protein kinase C-mediated phosphorylation at Ser436) to identify the direct downstream targets of the aPKC-CBP pathway in adult hippocampal neural precursors, since our recent study shows that the aPKC-CBP pathway is essential to maintain homeostatic neurogenesis throughout adulthood. To do that, we will perform Laser Cap Microdissection to isolate hippocampal subgranular zone (SGZ) tissues, which contain enriched neural precursors, to conduct RNA-sequencing analysis and Chromatin immunoprecipitation assay (ChIP). The combination of both assays will allow us to identify the target genes that are directly regulated by CBP S436 phosphorylation. Elucidation of such epigenetic mechanisms will advance our understanding of the molecular basis of hippocampal plasticity including hippocampal neurogenesis and learning and memory.