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

项目摘要/摘要 大脑发育包括神经前体细胞有组织地分化为神经元和神经胶质细胞，紧密地 在时间和空间领域都进行了协调。胚胎大脑发育的改变可以表现为 由于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使快速细胞分辨率成像成为可能。 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 获取它们，导致它们最常见的用途是视觉轶事，而不是量化的结果。在这 建议，我们将开发计算工具来具体量化 整个大脑中的单个细胞类型。我们将把组织透明技术和光片显微镜应用到 研究自闭症相关CHD8杂合突变小鼠的发育是如何改变的。杂合子CHD8 功能突变的丧失会导致人类患者和小鼠模型的巨头畸形。我们将首先 获取关键时间内神经前体和神经细胞类型的全脑细胞分辨率图像- 野生型和CHD8+/-小鼠的新皮质神经发生周期。然后我们将显影纵向图像 配准算法绘制新皮质发育的发展轨迹。最后，我们会 量化发育中新皮质注释区内的细胞类型分布。完成这项任务的目标 该提案将阐明自闭症患者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.