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

项目总结/摘要 大脑发育涉及神经祖细胞有组织地分化为神经元和神经胶质， 在时间和空间两个方面都是如此。胚胎大脑发育的改变可以表现为 出生后大脑结构和功能的改变，导致神经精神疾病。的最新进展 组织清除技术和光片显微镜允许快速细胞分辨率图像 在完整的大脑中获得。分析这些大型数据集的能力已经落后于 获得它们，导致它们最常见的用途是视觉轶事，而不是量化结果。在这 建议，我们将开发计算工具，以具体量化的发展轨迹， 整个大脑中的单个细胞类型。我们将应用组织清除技术和光片显微镜， 研究自闭症相关CHD 8杂合子突变小鼠的发育如何改变。杂合子CHD 8 功能丧失突变导致人类患者和小鼠模型中的大头畸形。我们将首先 在关键时间内获取神经祖细胞和神经元细胞类型的全脑细胞分辨率图像， 在野生型和Chd 8 +/-小鼠中的新皮层神经发生期。我们将展开纵向图像 配准算法来绘制新皮层发育的发育轨迹。最后我们将 量化发育中的新皮层的注释区域内的细胞类型分布。为了实现这一目标， 该提案将阐明自闭症大脑过度生长的细胞基础和空间定位。

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.