Doctoral Dissertation Improvement: Defining Evolutionary Units in the Neocortex: A Quantitative Assesment of Morphogenetic Patterns in the Embryonic Human Brain

博士论文改进：定义新皮质中的进化单位：胚胎人脑形态发生模式的定量评估

• 批准号: 0648822
• 负责人: Theodore Schurr
• 金额: $ 0.75万
• 依托单位: University of Pennsylvania
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-15 至 2007-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0648822&HistoricalAwards=false
• 关键词: Doctoral; Dissertation; Improvement; Defining; Evolutionary

This project investigates the nature of the developmental program that compartmentalizes the human neocortex, pre-natally, into what has been interpreted, post-natally, as functionally distinct cortical divisions. Specifically, this project examines the spatio-temporal pattern of cell proliferation (morphogenesis) that gives rise to the neocortex. This pattern indexes the morphological level at which genes partition this brain structure during embryonic development. Overall, the genetic partition(s) of the neocortex can be understood as internally cohesive, independently modifiable, evolutionary units. The delineation of these units is, thus, central for understanding how the human neocortex was transformed evolutionarily and how evolved cognitive/behavioral adaptations are mapped out in its architecture. For example, do small genetic changes regularly induce general, system-wide effects on the functional architecture of this brain structure and, thus, on many of the cognitive traits it mediates, or, instead, does the neocortex accumulate evolutionary changes in a much more specific, piece-meal, trait-by-trait fashion? The results of this project will advance a critical framework that will enable researchers to test hypotheses about cognitive/behavioral adaptation against the developmental organization of the neocortex. Embryonic development involves complex spatio-temporal morphogenetic changes that have been impossible to analyze with traditional 2-dimensional histological methods alone. To understand these changes, it is essential to accurately visualize the embryonic brain in 3-dimensions and, because they occur in time, in 4-dimensions. This project employs an innovative approach that synthesizes a number of cutting-edge computational techniques to create a digital, histology based, 4-dimensional model that reveals, visually and mathematically, the morphogenesis of the embryonic brain. The model is constructed from high-resolution digital representations of embryonic specimens from the Carnegie Collection of Embryology and the Yakovlev-Haleem Neuroanatomical Collection. The outcome of this project will contribute the first rigorous quantitative characterization of the embryonic morphogenesis of the human brain. In addition to providing invaluable research experience and training for the Co-PI, the approach developed in this project will pioneer several exciting avenues of future trans-disciplinary research. These include neuro-anatomical atlases for studying pre-natal morphological variation, and systematic manipulation of morphogenetic variables to explore the anatomical outcomes of different kinds of developmental modifications in virtual space. In addition, this approach can be applied to any other structure of the human embryo and to other species, thereby allowing cross-species pre-natal comparative studies. Moreover, it will enable the synthesis of quantitative pre-natal human morphogenetic data with theoretical and empirical 3D gene expression models based on experimental animals. The realization of this project will have a broad impact on the way in which future human embryonic research is carried out. Making sense of the enormous quantities of gene sequence data from the human genome project will involve, amongst other things, characterizing their expression and function during pre-natal development. However, the kinds of experimental manipulations routinely executed by developmental biologist are prohibitive in humans. The ability to integrate multiple explanatory dimensions in a single holistic framework makes the approach developed in this project particularly well suited for non-invasive human developmental research in the future.

该项目研究了发育程序的性质，该程序将出生前的人类新皮质划分为出生后被解释为功能不同的皮质分区。 具体来说，该项目研究了产生新皮质的细胞增殖（形态发生）的时空模式。 这种模式指示了胚胎发育过程中基因划分大脑结构的形态水平。 总体而言，新皮质的遗传分区可以被理解为内部凝聚力、独立可修改的进化单元。 因此，这些单元的划分对于理解人类新皮质如何进化转变以及如何在其架构中映射进化的认知/行为适应至关重要。 例如，微小的基因变化是否会定期对大脑结构的功能结构产生一般性的、全系统的影响，从而影响它介导的许多认知特征，或者，新皮质是否会以更广泛的方式积累进化变化？具体的、零散的、逐个特征的时尚？ 该项目的结果将推进一个关键框架，使研究人员能够测试有关新皮质发育组织的认知/行为适应的假设。胚胎发育涉及复杂的时空形态发生变化，仅用传统的二维组织学方法无法进行分析。 为了理解这些变化，必须在 3 维中准确地可视化胚胎大脑，并且因为它们及时发生，所以必须在 4 维中准确地可视化。 该项目采用创新方法，综合多种尖端计算技术，创建基于组织学的数字 4 维模型，以视觉和数学方式揭示胚胎大脑的形态发生。 该模型是根据来自卡内基胚胎学收藏和雅科夫列夫-哈利姆神经解剖学收藏的胚胎标本的高分辨率数字表示构建的。 该项目的成果将首次对人脑胚胎形态发生进行严格的定量表征。除了为联合首席研究员提供宝贵的研究经验和培训之外，该项目开发的方法还将开创未来跨学科研究的几个令人兴奋的途径。 其中包括用于研究产前形态变异的神经解剖图谱，以及对形态发生变量的系统操作，以探索虚拟空间中不同类型发育修饰的解剖结果。 此外，这种方法可以应用于人类胚胎的任何其他结构和其他物种，从而允许跨物种的产前比较研究。 此外，它将能够将定量的产前人类形态发生数据与基于实验动物的理论和经验 3D 基因表达模型进行合成。该项目的实现将对未来人类胚胎研究的开展方式产生广泛影响。 要理解人类基因组计划中的大量基因序列数据，除其他外，还需要表征它们在产前发育过程中的表达和功能。 然而，发育生物学家常规执行的各种实验操作对人类来说是令人望而却步的。 将多个解释维度整合到一个整体框架中的能力使得该项目中开发的方法特别适合未来的非侵入性人类发育研究。