Origin of Cortical Species-specific Distinctions

皮质物种特异性差异的起源

• 批准号: 10392885
• 负责人: PASKO RAKIC
• 金额: $ 75.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392885
• 关键词: 3-Dimensional; Anisotropy; Area; Astrocytes; Automobile Driving; Axon; Bioinformatics; Biological; Birth; Brain; Brain imaging; Breeding; Bromodeoxyuridine; CM-DiI; Calcium; Candidate Disease Gene; Cell Line; Cells; Cerebral cortex; Cerebrum; Characteristics; Clinical; Cluster Analysis; Cognition Disorders; Complement; Consumption; Contracts; Data; Development; Disease; Drug abuse; Dyes; Embryo; Event; Evolution; Explosion; Exposure to; FGF2 gene; Fibroblast Growth Factor; Fibroblasts; Gene Cluster; Gene Expression; Genes; Genetic; Genetic Determinism; Goals; Grant; Growth; Human; Image; Immunohistochemistry; Label; Lead; Ligands; Light; Link; Logistics; Macaca; Mammals; Methodology; Methods; Molecular; Monkeys; Morphogenesis; Motor; Mus; Nature; Neuroepithelial; Neuroglia; Neurons; Neuropil; Oligodendroglia; Pathogenesis; Pathologic; Pathway Analysis; Pattern; Pharmacotherapy; Phenotype; Positioning Attribute; Predisposition; Prefrontal Cortex; Prevention; Primates; Primordium; Process; Proteins; Radial; Regulatory Element; Research; Resolution; Rodent; Role; Sampling; Sensory; Skin; Specificity; Surface; Synapses; System; Testing; Time; Work; addiction; cognitive capacity; cognitive function; comparative; cost; experimental study; fetal; frontal lobe; gene network; gliogenesis; in utero; induced pluripotent stem cell; innovation; insight; lipophilicity; multiphoton microscopy; nerve stem cell; neurogenesis; neuropsychiatric disorder; neurotrophic factor; newborn neuron; nonhuman primate; notch protein; overexpression; prenatal exposure; primate development; relating to nervous system; response; single cell mRNA sequencing; single-cell RNA sequencing; somatosensory; stem cells; subventricular zone; theories; transcriptome; transcriptomics; white matter

Project Summary The principal goal of this new grant cycle is to uncover the origin and nature of uniqueness of the cerebral cortex of the human, and non-human primates (NHP), particularly the association areas such as the prefrontal cortex, that underlie the highest level of our cognitive capacities and are thought to be undermined in neuropsychiatric disorders including drug abuse. Although basic principles of cortical development in all mammals are similar, there are important quantitative and qualitative evolutionary innovations that were introduced in primates since their split from the rodent lineage about 60 million years ago. Thus, our strategy will be to study in parallel the developmental events in the NHP (macaque) and human skin-cell-derived iPSC cortex-mimicking cultures by using the most advanced molecular and cell biological methods available, including comparative high resolution single-cell mRNA sequencing, advanced confocal and light-sheet imaging, and in utero and ex utero functional manipulation of neural stem cells. We will complete and further augment our ongoing high-resolution single-cell mRNA sequencing and gain insight through bioinformatic gene network analysis in three species: macaque, human, and mouse. We will first investigate the genetic determinants of primate- specific stem cell subtypes, using gene clustering analysis at the transcriptome level, and determine how this impacts the cortical expansion process through functional studies (Aim #1). As a next step, we will examine genes and regulatory elements involved in emergence of areal and laminar specific distinction in monkey embryonic cortex and human iPSC 3D cortex mimicking cultures, generated from skin fibroblasts, to identify unique signatures of human and nonhuman primate-specific gene expression in evolutionarily new cortical areas such as prefrontal cortex (Aim #2). Finally, we will examine how cortical neuropil and the growth and patterning of white matter contribute to cortical area differences and drive primate-specific cortical gyrification (Aim #3). Although the proposed research is time-consuming, logistically difficult and costly, it is essential if we are to understand the biological basis of our humanity and the pathogenesis of some high order cognitive disorders, including drug abuse. We have established primate precisely timed breeding facilities at Yale, as well as mastered and modified essential methodology and already have obtained a substantial amount of high impact information which alone, or in combination, can give insight into elusive neuropsychiatric disorders and neuronal susceptibility to prenatal exposure to drugs of therapy and abuse.

项目摘要 这个新的资助周期的主要目标是揭示独特性的起源和本质 人类和非人类灵长类动物（NHP）的大脑皮层，特别是 像前额皮质这样的区域，是我们认知能力的最高层次的基础 并且被认为在包括药物滥用的神经精神障碍中被破坏。虽然 所有哺乳动物皮层发育的基本原则是相似的， 数量和质量的进化创新，引入灵长类动物，因为他们 从啮齿类动物中分离出来因此，我们的战略将是研究 在NHP（猕猴）和人皮肤细胞衍生的iPSC中平行的发育事件 采用最先进的分子和细胞生物学方法， 包括比较高分辨率的单细胞mRNA测序，先进的 共聚焦和光片成像，以及子宫内和子宫外神经功能操纵 干细胞我们将完成并进一步增强我们正在进行的高分辨率单细胞mRNA 通过生物信息学基因网络分析，在三个物种中进行测序并获得洞察力： 猕猴、人类和小鼠。我们将首先研究灵长类动物的遗传决定因素- 特定干细胞亚型，在转录组水平上使用基因聚类分析，以及 通过功能研究确定这如何影响皮质扩张过程（目标#1）。 作为下一步，我们将研究基因和调控元件参与出现的区域， 猴胚胎皮层和人iPSC 3D皮层中的层特异性区别 模拟培养，从皮肤成纤维细胞产生，以确定人类和 非人类灵长类动物特异性基因在进化上新的皮质区域表达， 前额皮质（目标#2）。最后，我们将研究皮层神经元和生长， 白色物质的图案有助于皮质区域的差异，并驱动灵长类动物特异性 皮质脑回化（目标#3）。虽然拟议的研究是耗时的，后勤 困难和昂贵，如果我们要了解我们人类的生物基础， 一些高级认知障碍的发病机制，包括药物滥用。我们有 在耶鲁大学建立了灵长类动物精确定时的繁殖设施， 基本的方法，并已获得了大量的高影响力 这些信息单独或结合起来，可以深入了解难以捉摸的神经精神病学 疾病和神经元对产前暴露于治疗和滥用药物的易感性。