Origin of Cortical Species-specific Distinctions

项目摘要 这个新的赠款周期的主要目标是揭示独特性的起源和本质 人类和非人灵长类(NHP)的大脑皮层，特别是 前额叶皮质等区域是我们认知能力的最高水平的基础 并被认为在包括药物滥用在内的神经精神障碍中受到破坏。虽然 所有哺乳动物的皮质发育的基本原理都是相似的，有重要的 在灵长类动物中引入的数量和质量的进化创新 大约在6000万年前从啮齿动物谱系中分离出来。因此，我们的战略将是在 NHP(猕猴)和人类皮肤细胞来源的IPSC的平行发育事件 利用最先进的分子和细胞生物学方法模拟皮质培养 可用，包括相对高分辨率的单细胞mRNA测序，高级 共聚焦和光片成像以及神经的宫内和宫外功能操作 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mRNAs 对三个物种进行测序并通过生物信息基因网络分析获得洞察力： 猕猴、人类和老鼠。我们将首先研究灵长类的遗传决定因素- 在转录组水平上使用基因聚类分析特定的干细胞亚型，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，我们将研究与面积形成有关的基因和调控因素。 猴胚胎皮质和人iPSC 3D皮质的板层特异性差异 模仿皮肤成纤维细胞产生的培养物，以识别人类和 非人灵长类特异基因在进化上新的皮质区域的表达，如 前额叶皮质(目标2)。最后，我们将研究皮质神经膜如何与生长和 白质的图案化有助于皮质区域的差异，并驱动灵长类动物特有的 皮质回变(目标3)。虽然拟议的研究是耗时的，但在后勤方面 困难和昂贵，如果我们要了解人类的生物学基础和 一些高级认知障碍的发病机制，包括药物滥用。我们有 在耶鲁建立了灵长类精确定时的繁育设施，并进行了掌握和修改 基本方法论，已经取得了相当大的影响力 这些信息单独或结合在一起，可以洞察难以捉摸的神经精神病学 疾病和神经元对产前暴露于药物治疗和滥用的易感性。

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.