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

这个项目调查了发育程序的性质，该程序在出生前将人类新皮质划分为出生后被解释为功能上不同的皮质分区。具体地说，这个项目研究了细胞增殖(形态发生)的时空模式，这种模式导致了新皮质的产生。这一模式标明了胚胎发育过程中基因分割大脑结构的形态水平。总体而言，新大脑皮层的遗传划分(S)可以理解为内部凝聚的、独立修改的进化单位。因此，这些单位的描绘对于理解人类新皮质是如何进化转化的，以及如何在其架构中描绘出进化的认知/行为适应是至关重要的。例如，小的基因变化是否会定期对这一大脑结构的功能架构产生普遍的、系统范围的影响，从而影响它所调节的许多认知特征，或者，相反，新皮质是否以更具体的、零碎的、逐个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/行为适应与新皮质发育组织的假说。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。要理解这些变化，必须准确地将胚胎大脑在3维空间中可视化，因为它们发生在时间上，所以是在4维空间中。这个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馆和雅科夫列夫-哈利姆神经解剖学收藏馆的胚胎标本的高分辨率数字表示构建的。该项目的成果将有助于首次对人类大脑的胚胎形态发生进行严格的量化表征。除了为合作项目提供宝贵的研究经验和培训外，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。这些包括用于研究出生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，以探索不同类型的发育修改在虚拟空间中的解剖结果。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，从而允许进行跨物种的出生前比较研究。此外，它还将能够利用基于实验动物的理论和经验3D基因表达模型来合成定量的出生前人类形态发生数据。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，将涉及表征它们在出生前发育期间的表达和功能。然而，发育生物学家经常进行的那种实验操作在人类身上是令人望而却步的。在一个整体框架中整合多个解释维度的能力使本项目开发的方法特别适合于未来的非侵入性人类发展研究。

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.