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.

这个项目调查了发育程序的本质，该程序划分了人类新皮层，在出生前，被解释为出生后，作为功能不同的皮层分裂。具体来说，该项目研究了细胞增殖（形态发生）的时空模式，从而产生新皮层。这种模式表明在胚胎发育过程中，基因划分大脑结构的形态学水平。总的来说，新皮层的遗传分区可以被理解为内部凝聚力，独立修改的进化单位。因此，这些单位的描述对于理解人类新皮层是如何进化转化的，以及进化的认知/行为适应是如何在其结构中绘制出来的，是至关重要的。例如，小的基因变化是否有规律地对这个大脑结构的功能结构产生普遍的、全系统的影响，从而影响它所介导的许多认知特征，或者，相反，新皮层是否以一种更具体的、零碎的、逐特征的方式积累进化变化？这个项目的结果将推进一个关键的框架，使研究人员能够测试关于认知/行为适应的假设，反对新皮层的发育组织。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是不可能分析的。为了理解这些变化，有必要在三维空间中准确地可视化胚胎大脑，因为它们是在时间上发生的，所以在四维空间中也是如此。该项目采用了一种创新的方法，综合了许多尖端的计算技术，创建了一个基于组织学的数字4维模型，从视觉和数学上揭示了胚胎大脑的形态发生。该模型是由来自卡内基胚胎学收藏和Yakovlev-Haleem神经解剖学收藏的胚胎标本的高分辨率数字表示构建的。这个项目的结果将有助于人类大脑胚胎形态发生的第一个严格的定量表征。除了为Co-PI提供宝贵的研究经验和培训外，该项目开发的方法将为未来的跨学科研究开辟几条令人兴奋的途径。其中包括用于研究产前形态变异的神经解剖学地图集，以及系统地操纵形态发生变量以探索虚拟空间中不同类型发育修饰的解剖学结果。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，它将使定量产前人类形态发生数据与基于实验动物的理论和经验三维基因表达模型的合成成为可能。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的影响。从人类基因组计划中获取大量的基因序列数据，其中包括描述它们在产前发育过程中的表达和功能。然而，由发育生物学家常规执行的各种实验操作在人类中是禁止的。在单一整体框架中整合多个解释维度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展研究。