Quantifying the developmental trajectory of autism-associated brain overgrowth using 3D cellular resolution imaging

使用 3D 细胞分辨率成像量化自闭症相关大脑过度生长的发育轨迹

基本信息

批准号：
10657348
负责人：
Jason Louis Stein
金额：
$ 42.58万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-23 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10657348
关键词：
3-Dimensional Address Algorithms Anecdotes Area Biological Markers Biological Process Brain Brain Mapping Brain region Cell Nucleus Cells DNA Sequence Alteration Data Set Detection Development Embryo Exhibits Genetic Growth Heterozygote Histone H3 Human Human Resources Image Image Analysis Individual Joints Label Light Macrocephaly Magnetic Resonance Imaging Maps Measures Methods Microscope Microscopy Mus Mutant Strains Mice Mutation Nature Neocortex Neuroglia Neuronal Differentiation Neurons Pathology Patients Positioning Attribute Resolution Structure Surface Techniques Technology Therapeutic Time Tissues Visual Visualization autism spectrum disorder brain overgrowth brain tissue cell type computerized tools cortex mapping critical period experience experimental study image registration imaging Segmentation improved large datasets light microscopy loss of function mutation microscopic imaging mouse model mutant neocortical nerve stem cell neurodevelopment neurogenesis neuroimaging neuropsychiatric disorder neuropsychiatry postnatal serial imaging spatiotemporal tool

项目摘要

Project Summary/Abstract Brain development involves the organized differentiation of neural progenitors into neurons and glia, tightly orchestrated in both temporal and spatial domains. Alterations in embryonic brain development can manifest as altered post-natal brain structure and function, leading to neuropsychiatric illness. Recent advances in tissue clearing technology and light-sheet microscopy have allowed for rapid cellular resolution image acquisition in intact whole brains. The ability to analyze these large datasets has lagged behind the ability to acquire them, resulting in their most common use as visual anecdotes rather than quantified results. In this proposal, we will develop computational tools to specifically quantify the developmental trajectories of individual cell-types in the entire brain. We will apply tissue clearing technology and light-sheet microscopy to study how development is altered in autism-associated CHD8 heterozygous mutant mice. Heterozygous CHD8 loss of function mutations result in macrocephaly in both human patients and mouse models. We will first acquire whole brain cellular resolution images of neural progenitor and neuronal cell-types across critical time- periods of neocortical neurogenesis in wild-type and Chd8+/- mice. We will then develop longitudinal image registration algorithms to map the developmental trajectories of neocortical development. Finally, we will quantify cell-type distributions within annotated areas of the developing neocortex. Completing the aims of this proposal will elucidate the cellular basis and spatial localization of brain overgrowth in autism.

项目摘要/摘要大脑发育涉及神经祖细胞对神经元和神经胶质的组织分化，紧密在时间和空间域中精心策划。胚胎脑发育的改变可以表现出来随着产后大脑结构和功能的改变，导致神经精神疾病。最近的进步组织清除技术和灯页显微镜已允许快速蜂窝分辨率图像完整的全脑中获取。分析这些大数据集的能力落后于获取它们，导致它们作为视觉轶事最常用而不是量化的结果。在这个提案，我们将开发计算工具，以专门量化整个大脑中的单个细胞类型。我们将应用组织清除技术和灯页显微镜研究如何改变自闭症相关的CHD8杂合突变小鼠的发育。杂合CHD8 功能突变的丧失导致人类患者和小鼠模型的脑畸形。我们将首先在关键时间 - 野生型和CHD8 +/-小鼠的新皮质神经发生周期。然后，我们将发展纵向图像绘制新皮质发展的发展轨迹的注册算法。最后，我们会的量化开发新皮层的注释区域内的细胞类型分布。完成目标提案将阐明自闭症中大脑过度生长的细胞基础和空间定位。