Intermediate Progenitor Cells in Adult Hippocampal Neurogenesis

描述(由申请人提供)：本项目修订将我们对成年期的海马神经发生的分析扩展到出生后的小鼠，成年期是父母资助的重点。家长项目的总体目标是更好地了解成年海马神经发生、其机制和调节。成人神经发生对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的情况。这个修订项目的目标是深入了解海马体，特别是齿状回的出生后发育。齿状回的发育不仅为成年神经发生奠定了基础，而且还利用了独特的发育机制，这些机制可能对疾病发病机制中的扰动敏感。事实上，出生后海马体发育的异常与抑郁症、精神分裂症、癫痫和成瘾的病理生理学有关。这个项目将特别关注转录因子，特别是Tbr2，在出生后海马体发育中的作用。该项目的初步研究表明，Tbr2对齿状回的发育是必不可少的：条件性失活会导致齿状回严重发育不良，并伴有细胞迁移和分化缺陷。为了进一步研究影响的机制，我们将追求以下两个具体目标：(1)首先，我们将利用一组细胞类型特异性标记物分析和比较不同类型的祖细胞和神经元在正常和Tbr2条件性零出生后海马区的迁移。(2)第二，我们将利用多光子时间推移成像技术，直接观察和表征不同类型祖细胞在正常和Tbr2条件性缺失性出生后海马区的迁移。这些研究完成后，我们将明确细胞在出生后齿状回的迁移机制，以及转录因子Tbr2对它们的调控。这些见解将为了解涉及海马体发育异常的疾病提供更详细的科学依据。该项目通过加快这一研究领域的进展速度，并通过增加努力和为研究技术员创造一个新的工作岗位，为科学家提供留住和就业机会，从而实现了恢复法的目标。 公共卫生相关性：出生后和成人海马齿状回(DG)的神经发生异常与几种神经精神疾病的病理生理学有关，包括抑郁症、精神分裂症、癫痫和成瘾。这一修订项目扩展了我们在DG中对成年神经发生的分析，以进一步研究出生后齿状回发育的基本机制。特别是，将在缺乏转录因子Tbr2的靶向基因突变小鼠中研究细胞迁移、分化和海马体形态发生的缺陷。这些研究不仅将提高我们对疾病机制的理解，还将加强神经再生作为一种潜在的治疗方法。

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.