Quantitative Imaging of Mouse Brain Development

小鼠大脑发育的定量成像

• 批准号: 9886288
• 负责人: Daniel H Turnbull
• 金额: $ 61.9万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9886288
• 关键词: 3-Dimensional; 4D MRI; Adolescence; Anatomy; Area; Atlases; Axon; BRAIN initiative; Biological Models; Brain; Brain Injuries; Brain region; Cellularity; Complex; Computational Technique; Consumption; Data; Defect; Development; Developmental Biology; Developmental Process; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Embryo; Embryonic Development; Event; Genes; Genetic; Genetic study; Goals; Histologic; Histology; Human; Image; Image Analysis; Imaging Device; Imaging Techniques; Knockout Mice; Knowledge; Location; Magnetic Resonance Imaging; Manganese; Maps; Measurement; Microcephaly; Midbrain structure; Modeling; Molecular; Monitor; Morphology; Mouse Strains; Mus; Mutant Strains Mice; Neonatal; Neurodevelopmental Disorder; Neuronal Differentiation; Neurons; Pattern; Phenotype; Physics; Process; Protocols documentation; Research; Resolution; Signal Transduction; Structure; TP53 gene; Techniques; Technology; Time; Tissues; Toxic effect; United States National Institutes of Health; Wild Type Mouse; automated image analysis; base; brain abnormalities; brain morphology; contrast imaging; cortex mapping; fetal; imaging biomarker; in utero; in vivo; innovation; interest; longitudinal analysis; migration; mind control; mouse development; mouse model; mutant mouse model; neonatal brain development; neuronal patterning; new technology; novel; performance tests; postnatal; prenatal; programs; quantitative imaging; spatiotemporal; stem; tool

Abstract: Brain development is a highly dynamic yet precisely orchestrated process. Using genetically modified mouse models, we are in the process of unveiling the complex mechanisms that control critical cellular events in the developing brain. High-throughput imaging tools will greatly benefit studies in this area by charactering brain phenotypes at the macroscopic/mesoscopic levels and directing subsequent examinations at the cellular and molecular levels. In this project, multiple novel magnetic resonance imaging (MRI) techniques will be developed to non-invasively exam a wide range of phenotypes in the developing mouse brain from mid- embryonic stage to adolescence. The target phenotypes include macroscopic brain morphology and structural connectivity, microstructural organization, neuronal migration and differentiation, and postnatal brain activity. The proposed techniques include fast imaging sequences, novel image contrasts, optimized imaging coils/holder, and image analysis tools, many of which stem from on our existing expertise. In Aim 1, we will develop imaging tools to achieve high-throughput in vivo multi-contrast MRI of the developing mouse brain. We will collect multi-contrast MRI data to construct an in vivo MRI atlas of the developing mouse brain to assist mouse brain phenotype analysis and use the sas4-/- mouse, a model of microcephaly, to test the performance of the technique. In Aim 2, we will use novel diffusion MRI techniques to characterize macroscopic morphology, connectivity, and microstructural organization in the developing brain. In particular, high angular resolution diffusion imaging (HARDI) will be used to resolve complex tissue microstructural organization and reconstruct connectivity between major brain regions, and the new oscillating gradient diffusion MRI technique will be used to exam changes in cellularity in the developing cortex associated with neuronal migration. Detailed examination of the relationships between diffusion MRI-based markers and specific histological markers will determine their sensitivity to the underlying developmental processes. In Aim 3, we will use novel Manganese (Mn2+)-enhanced MRI as another tissue contrast, which reflects postnatal brain activity and potentially neuronal differentiation in the embryonic brain, to examine the developing mouse brain. We will examine the contrast patterns of Mn2+-enhanced MRI in the embryonic and neonatal mouse brain with the patterns of neuronal differentiation observed in histological data to determine the sensitivity of Mn2+-enhanced MRI to neuronal differentiation. In addition, we will investigate potential toxic effects of Mn2+ on brain development, and establish protocols that minimize these effects. In Aims 2 and 3, the techniques will also be used to characterize three mutant mouse models with abnormal brain phenotypes resulting from defects in neuronal migration and differentiation. The imaging techniques and knowledge gained in this project will greatly enhance our ability to quantitatively characterize the phenotypes of mutant mouse models in order to achieve a deep understanding of brain development and disorders.

抽象的： 大脑发育是一个高度动态但精确协调的过程。使用转基因小鼠 模型中，我们正在揭示控制关键细胞事件的复杂机制。 正在发育的大脑。高通量成像工具通过表征大脑将大大有利于该领域的研究 宏观/介观水平的表型，并指导随后的细胞和细胞检查 分子水平。在该项目中，将采用多种新颖的磁共振成像（MRI）技术 开发用于非侵入性地检查发育中的小鼠大脑中的各种表型 胚胎期至青春期。目标表型包括宏观脑形态和结构 连接性、微观结构组织、神经元迁移和分化以及出生后大脑活动。 所提出的技术包括快速成像序列、新颖的图像对比度、优化成像 线圈/支架和图像分析工具，其中许多源于我们现有的专业知识。 在目标 1 中，我们将开发成像工具来实现高通量体内多对比 MRI 正在发育的小鼠大脑。我们将收集多对比 MRI 数据来构建体内 MRI 图集 开发小鼠大脑以协助小鼠大脑表型分析和 使用 sas4-/- 鼠标，其型号为 小头畸形，以测试该技术的性能。 在目标 2 中，我们将使用新颖的扩散 MRI 技术来 表征发育中大脑的宏观形态、连接性和微观结构组织。 特别是，高角分辨率扩散成像（HARDI）将用于解析复杂的组织 微观结构组织并重建主要大脑区域之间的连接，以及新的振荡 梯度扩散 MRI 技术将用于检查发育中皮层细胞结构的变化 与神经元迁移有关。基于扩散 MRI 之间关系的详细检查 标记和特定组织学标记将决定它们对潜在发育的敏感性 流程。在目标 3 中，我们将使用新型锰 (Mn2+) 增强 MRI 作为另一种组织对比， 反映出生后大脑活动和胚胎大脑中潜在的神经元分化，以检查 正在发育的小鼠大脑。我们将检查胚胎和胚胎时期 Mn2+ 增强 MRI 的对比模式 新生小鼠大脑通过组织学数据观察神经元分化模式来确定 Mn2+增强MRI对神经元分化的敏感性。 此外，我们将调查潜在的有毒物质 Mn2+ 对大脑发育的影响，并建立尽量减少这些影响的方案。在目标 2 和 3 中， 技术还将用于表征三种具有异常大脑表型的突变小鼠模型 由神经元迁移和分化缺陷引起。所获得的成像技术和知识 在这个项目中将大大增强我们定量表征突变小鼠表型的能力 模型，以深入了解大脑发育和疾病。