Quantitative Imaging of Mouse Brain Development

摘要： 大脑发育是一个高度动态但精确编排的过程。使用转基因小鼠 模型，我们正在揭开控制关键细胞事件的复杂机制的过程 发育中的大脑。高通量成像工具将极大地促进这一领域的研究，因为它可以表征大脑 宏观/中观水平的表型，并指导后续的细胞和 分子水平。在这个项目中，多种新的磁共振成像(MRI)技术将被 从中期开始对发育中的小鼠大脑进行非侵入性的广泛表型检测 胚胎期到青春期。目标表型包括宏观脑形态和结构 连通性，微结构组织，神经元迁移和分化，以及出生后的大脑活动。 提出的技术包括快速成像序列、新颖的图像对比度、优化的成像 线圈/夹持器和图像分析工具，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，以实现高通量在体多对比磁共振成像 发育中的小鼠大脑。我们将收集多对比MRI数据来构建活体MRI图谱 发育小鼠脑以辅助小鼠脑表型分析和 使用sas4-/-鼠标，这是 小头畸形，以测试该技术的性能。 在目标2中，我们将使用新的扩散磁共振技术来 描述发育中大脑的宏观形态、连通性和微观结构组织。 特别是，高角分辨率扩散成像(HARDI)将被用于分辨复杂的组织 微结构组织和重建主要大脑区域之间的连接，以及新的振荡 梯度扩散磁共振成像技术将用于检测发育中的皮质细胞的变化。 与神经元迁移有关。磁共振弥散成像与弥散关系的详细研究 标志物和特定的组织学标志物将决定它们对潜在的发育的敏感性 流程。在目标3中，我们将使用新型的锰(Mn2+)增强磁共振作为另一种组织对比，这 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 发育中的小鼠大脑。我们将研究胚胎和胚胎中Mn2+增强MRI的对比模式。 用新生小鼠脑内神经元分化的模式观察组织学数据来确定 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，并建立将这些影响降至最低的方案。在目标2和目标3中， 这些技术还将被用来表征三种脑部表型异常的突变小鼠模型。 由神经元迁移和分化缺陷引起。成像技术和所获得的知识 这个项目将极大地提高我们定量描述突变小鼠表型的能力 从而实现对大脑发育和紊乱的深入了解。

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.