Intermediate Progenitor Cells in Adult Hippocampal Neurogenesis

描述（由申请人提供）：本项目修订将我们对小鼠海马神经发生的分析从成年期（父母资助的重点）扩展到出生后年龄。本项目的总体目标是进一步了解成人海马神经发生及其机制和调控。成人神经发生对于设计神经替代治疗策略具有重要意义，可用于治疗神经退行性疾病和其他神经元丧失疾病。本修订项目的目的是深入了解出生后海马，特别是齿状回的发育。齿状回的发育不仅为成人神经发生奠定了基础，而且具有独特的发育机制，可能对疾病发病机制中的扰动很敏感。事实上，产后海马发育异常与抑郁症、精神分裂症、癫痫和成瘾的病理生理有关。本项目将特别关注转录因子，特别是Tbr2在出生后海马发育中的作用。本项目的初步研究表明，Tbr2对齿状回的发育至关重要：条状Tbr2失活导致齿状回严重发育不全，细胞迁移和分化缺陷。为了进一步研究受影响的机制，我们将追求以下两个具体目标：(1)首先，我们将使用一组细胞类型特异性标记分析和比较正常和Tbr2条件空出生后海马中不同祖细胞类型和神经元的迁移。(2)其次，我们将利用多光子延时成像直接观察和表征正常和Tbr2条件空出生后海马中不同祖细胞类型的迁移。在完成这些研究后，我们将明确出生后齿状回细胞迁移的机制以及转录因子Tbr2对其的调节。这些见解将为理解涉及海马异常发育的疾病提供更详细的科学基础。该项目通过加快该研究领域的进展速度，并通过增加努力以及为研究技术人员创造新的工作岗位，为科学家提供保留和就业，实现了《复苏法案》的目标。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.