This project revision extends our analysis of hippocampal neurogenesis from adulthood, the focus of the parent grant, into postnatal ages in mice. The overall goal of the parent project is to gain greater understanding of adult hippocampal neurogenesis, its mechanisms and regulation. Adult neurogenesis has important implications for designing strategies of neural replacement therapy, which could be used to treat neurodegenerative disorders and other conditions of neuronal loss. The goal of this revision project is to gain insights into postnatal development of the hippocampus, especially the dentate gyrus. Development of the dentate gyrus not only lays the foundation for adult neurogenesis, but also utilizes unique developmental mechanisms that may be sensitive to perturbation in disease pathogenesis. Indeed, abnormalities of postnatal hippocampal development have been implicated in the pathophysiology of depression, schizophrenia, epilepsy, and addiction. This project will particularly focus on the role of transcription factors, especially Tbr2, in postnatal hippocampal development. Preliminary studies for this project demonstrate that Tbr2 is essential for development of the dentate gyrus: conditional Tbr2 inactivation causes severe hypoplasia of the dentate gyrus, with defects of cell migration and differentiation. To further investigate the mechanisms affected, we will pursue the following 2 specific aims: (1) First, we will analyze and compare the migrations of different progenitor cell types and neurons in normal and Tbr2 conditional null postnatal hippocampus using a battery of cell type specific markers. (2) Second, we will use multiphoton time-lapse imaging to directly observe and characterize the migrations of different progenitor types in normal and Tbr2 conditional null postnatal hippocampus. Upon completion of these studies, we will have defined mechanisms of cell migration in the postnatal dentate gyrus and their regulation by transcription factor Tbr2. These insights will provide a more detailed scientific basis for understanding diseases involving abnormal hippocampal development. This project fulfills Recovery Act goals by accelerating the tempo of progress in this research area, and by providing for the retention and employment of scientists, through increased effort as well as creation of a new job position for a research technician.
Abnormalities of neurogenesis in the postnatal and adult dentate gyrus (DG) of the hippocampus have been implicated in the pathophysiology of several neuropsychiatric diseases, including depression, schizophrenia, epilepsy, and addiction. This revision project extends our analysis of adult neurogenesis in the DG, to further investigate basic mechanisms of dentate gyrus development in the postnatal period. In particular, defects of cell migration, differentiation, and hippocampal morphogenesis will be studied in targeted genetic mutant mice deficient in the transcription factor Tbr2. These studies will not only improve our understanding of disease mechanisms but also enhance approaches to neuroregeneration as a potential therapeutic approach.
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