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

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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.