Neural stem cells in the aging brain

衰老大脑中的神经干细胞

• 批准号: 8327695
• 负责人: GRIGORI N ENIKOLOPOV
• 金额: $ 41.05万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8327695
• 关键词: Ablation; Adult; Affect; Age; Age Factors; Age-associated memory impairment; Aging; Animals; Anterior Pituitary Gland; Antidepressive Agents; Applied Genetics; Astrocytes; Behavior; Bone Marrow; Brain; Brain Injuries; Cell Cycle; Cell Lineage; Cell Survival; Color; Computer Simulation; Electroconvulsive Shock; Exercise; Fluoxetine; Functional disorder; Gene Expression; Genetic; Genetic Recombination; Goals; Hair follicle structure; Hippocampus (Brain); Human; Image; Individual; Injury; Isotopes; Label; Length; Liver; Maps; Mass Spectrum Analysis; Measurement; Methods; Modality; Mus; Muscle; Natural regeneration; Neurons; Organ; Pancreas; Parahippocampal Gyrus; Pharmaceutical Preparations; Physiologic pulse; Physiological; Play; Positioning Attribute; Primates; Production; Property; Proteins; Reporter; Reporter Genes; Reporting; Retinal; S Phase; Scheme; Skeletal Muscle; Staging; Stem cells; Stimulus; Structure; Techniques; Testis; Tissues; Transgenes; Transgenic Mice; adult neurogenesis; age related; aging brain; base; brain repair; cell type; cellular targeting; cognitive function; dentate gyrus; depressive symptoms; dopaminergic neuron; juvenile animal; nerve stem cell; neurogenesis; new technology; novel strategies; relating to nervous system; repaired; research study; response; stem; stem cell differentiation; stem cell division; stem cell fate; tool

DESCRIPTION (provided by applicant): Increasing evidence indicates that production of new neurons in the adult brain is important for behavior, brain repair, and response to therapies. Aging is associated with a profound decline in production of new neurons and decreased neurogenesis may be related to the impaired functioning of the aging brain. This decrease may be due to several factors including changes in the division of stem and progenitor cells, survival of stem cells or their progeny and altered fate of the stem cell progeny. To understand the mechanism of age-related decline in adult neurogenesis it is necessary to identify the changes in the main parameters of the division/ differentiation cascade in the aging brain. We developed an experimental platform that combines reporter mouse lines, lineage tracing techniques, precise quantitation and computational modeling to determine changes in stem cells division and fate. We used this approach to determine the neurogenic targets of antidepressant treatments and of brain injury. Furthermore, we will combine genetic stem cell analysis with a new technology of unparalleled sensitivity and accuracy, Multi-Isotope Imaging Mass Spectroscopy (MIMS), for the quantitative analysis of stem cells turnover and fate in the aging brain. Since our reporter mouse lines mark stem and progenitor cells in several non-neuronal tissues, we are in a position to analyze the same individual animals for parallel changes in several stem cell compartments. The main goal of this proposal is to apply stringent quantitative methods to the problem of stem cell lineage and to determine the changes in the turnover rates and the lineages of stem cells in response to aging, antidepressant therapies and injury. In Aim 1 we will use reporter lines, single- and double-label pulse chase analysis, computational modeling and MIMS to determine age-related changes in the parameters of the division/differentiation cascade of neural stem and progenitor cells in the dentate gyrus of the hippocampus. In Aim 2 we will use multi-allelic reporter lines, Cre-based lineage tracing, and MIMS to determine age-related changes in the fate of stem cells. In Aim 3 we will apply genetic fate mapping and MIMS to determine the age-associated changes in the parameters of the division/differentiation cascade and in the fate of stem cells in response to antidepressant treatments of different modalities (fluoxetine, electroconvulsive shock and exercise) and to injury that induces depressive behavior (ablation of dopaminergic neurons). Finally, in Aim 4, we will use genetic fate mapping and MIMS to determine changes in the turnover and fate of stem/progenitor cells in a range of non-neuronal tissues that are marked by reporter gene expression in our multi-allelic reporter lines. Together, our results and genetic tools will provide a framework for studying division and differentiation of stem cells and tissue turnover as an integrated quantitative endeavor.

描述（由申请人提供）：越来越多的证据表明，成人大脑中新神经元的产生对于行为、大脑修复和治疗反应非常重要。衰老与新神经元产生的严重下降有关，神经发生的减少可能与衰老大脑功能受损有关。这种减少可能是由于多种因素造成的，包括干细胞和祖细胞分裂的变化、干细胞或其后代的存活以及干细胞后代命运的改变。为了了解成人神经发生与年龄相关的衰退机制，有必要确定衰老大脑中分裂/分化级联的主要参数的变化。我们开发了一个实验平台，结合了报告小鼠系、谱系追踪技术、精确定量和计算模型，以确定干细胞分裂和命运的变化。我们使用这种方法来确定抗抑郁治疗和脑损伤的神经源性目标。此外，我们将把遗传干细胞分析与具有无与伦比的灵敏度和准确性的新技术——多同位素成像质谱（MIMS）相结合，定量分析衰老大脑中干细胞的更新和命运。由于我们的报告小鼠系标记了几种非神经元组织中的干细胞和祖细胞，因此我们能够分析同一个体动物中几个干细胞区室的平行变化。该提案的主要目标是对干细胞谱系问题应用严格的定量方法，并确定干细胞的周转率和谱系因衰老、抗抑郁治疗和损伤而发生的变化。 在目标 1 中，我们将使用报告系、单标记和双标记脉冲追踪分析、计算模型和 MIMS 来确定神经干细胞和祖细胞齿状回中的分裂/分化级联参数的与年龄相关的变化。海马体。在目标 2 中，我们将使用多等位基因报告系、基于 Cre 的谱系追踪和 MIMS 来确定干细胞命运中与年龄相关的变化。在目标 3 中，我们将应用遗传命运图谱和 MIMS 来确定分裂/分化级联参数和干细胞命运中与年龄相关的变化，以响应不同方式的抗抑郁治疗（氟西汀、电休克和运动）以及诱发抑郁行为的损伤（多巴胺能神经元的消融）。最后，在目标 4 中，我们将使用遗传命运图谱和 MIMS 来确定一系列非神经元组织中干细胞/祖细胞的周转和命运的变化，这些组织以我们的多等位基因报告系中的报告基因表达为标志。总之，我们的结果和遗传工具将为研究干细胞的分裂和分化以及组织更新作为一项综合的定量研究提供一个框架。