The developmental origins and fate of neurons in the gyrencephalic neocortex

环脑新皮质神经元的发育起源和命运

• 批准号: 10597691
• 负责人: Tarik F Haydar
• 金额: $ 22.31万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10597691
• 关键词: Acceleration; Anatomy; Applications Grants; Brain; Cells; Comparative Study; Complex; Data; Data Set; Development; Dorsal; Electroporation; Etiology; Family suidae; Ferrets; Gene Delivery; Gene Expression; Generations; Genetic; Genomics; Goals; Growth; Human; Imaging Techniques; Infant; Label; Laboratories; Methods; Miniature Swine; Modeling; Modernization; Molecular; Molecular Profiling; Monkeys; Morphology; Mus; Neocortex; Neuroanatomy; Neurodevelopmental Disorder; Neuroglia; Neurons; Operative Surgical Procedures; Pilot Projects; Plasmids; Pongidae; Population; Primates; Process; Radial; Rattus; Rodent; Slice; Specific qualifier value; Sus scrofa; System; Techniques; Time; Ventricular; Visualization; Work; cell type; cellular imaging; cognitive ability; density; fetal; fluorescence imaging; frontal lobe; genetic manipulation; in utero; in vivo; interdisciplinary approach; migration; neocortical; nerve stem cell; neurophysiology; perinatal period; porcine model; postnatal; precursor cell; prenatal; progenitor; protein biomarkers; self-renewal; single cell sequencing; skills; subventricular zone; tool; transcriptomics; treatment strategy

SUMMARY/ABSTRACT: Diverse networks of neurons and glia produce the advanced computational power of the mammalian brain. Neural precursor cell (NPC) populations present in the ventricular and subventricular zones (VZ and SVZ) of the prenatal brain generate all neurons and glia either directly, or indirectly via intermediate progenitors. While there has been a rapid increase in understanding the cell diversity and underlying genetic mechanisms of these precursor cells, most of this work has been accomplished in the lissencephalic rodent. Some recent findings in gyrencephalic species indicate that NPC types and their developmental mechanisms are tuned differently in species with larger brains. For example, recent studies have discovered that, unlike in rodents, the density of basal radial glial cells (bRGCs) is significantly higher in primate brain, but the neuroanatomical and neurophysiological advantage(s) of this difference have not been established. Similarly, large numbers of neurons migrating to the frontal lobe are present in the human infant brain but are not found in mouse; neither the mechanisms underlying their prenatal generation nor their processes of integration into the neocortex have been identified. While single cell transcriptomic data has opened new windows into the gene expression underlying this diversity, the ability to not only confirm species-specific differences but to also interrogate their effects in vivo is hampered by the lack of an appropriate model. Piglets are a powerful model with which to study complex brain development because they have a highly evolved gyrencephalic neocortex. Our previous studies found that the cytoarchitecture of the porcine SVZ is exceptionally similar to its human counterpart. Consistent with the human infant cortex, young neurons in the piglet SVZ migrate to the frontal cortex and differentiate into neurons in a region-specific manner. Finally, our recent collaborative single cell sequencing study has uncovered cell populations with unique molecular profiles within the piglet SVZ that are not found in rodent SVZ. Thus, we hypothesize that elucidating the diversity and fate potential of the porcine VZ and SVZ neural precursors will accelerate our understanding of human neuronal diversity, cortical circuit complexity and cognitive ability. Our project will establish an in vivo gene delivery method to visualize NPC dynamics and neuronal specification in the fetal piglet VZ and SVZ (Aim 1); and visualize late-migrating neurons and cell populations derived from the postnatal piglet SVZ (Aim 2). Establishment of a system in which a large gyrencephalic brain can be studied using modern genetic and cellular imaging techniques would significantly impact our understanding of normal human brain development and provide a critical tool for elucidating the etiology for neurodevelopmental disorders. This advance will enable key comparative studies with other datasets from gyrencephalic and lissencephalic species and allow genomic/cellular understanding of early brain development in a model that shares important developmental and anatomical similarities to the human brain.

总结/摘要： 不同的神经元和神经胶质网络产生了哺乳动物大脑的高级计算能力。 神经前体细胞（NPC）群体存在于脑室和脑室下区（VZ和SVZ）， 出生前脑直接或间接通过中间祖细胞产生所有神经元和胶质细胞。虽然 对细胞多样性和这些疾病的潜在遗传机制的理解迅速增加， 前体细胞，这项工作的大部分已经在无脑啮齿动物中完成。最近的一些发现， 脑回型物种表明NPC类型及其发育机制在不同的 拥有更大大脑的物种例如，最近的研究发现，与啮齿动物不同， 基底放射状胶质细胞（bRGCs）在灵长类动物脑中显著较高，但神经解剖学和 这种差异的神经生理学优势尚未确立。同样，大量的 迁移到额叶的神经元存在于人类婴儿的大脑中，但在小鼠中没有发现; 它们在出生前产生的机制，以及它们整合到新皮层的过程， 被识别。虽然单细胞转录组学数据为研究基因表达打开了新的窗口， 在这种多样性的基础上，不仅能够确认物种特异性差异，而且能够询问它们的 由于缺乏合适的模型，体内效应受到阻碍。小猪是一个强大的模型， 复杂的大脑发育，因为他们有高度进化的脑回新皮层。我们以前的研究 发现猪SVZ的细胞结构与人类SVZ非常相似。一致 与人类婴儿皮层一样，小猪SVZ中的年轻神经元迁移到额叶皮层并分化为 神经元以特定区域的方式。最后，我们最近的合作单细胞测序研究发现， 在仔猪SVZ中具有独特分子特征的细胞群，在啮齿动物SVZ中未发现。因此我们 假设阐明猪VZ和SVZ神经前体的多样性和命运潜力将 加速我们对人类神经元多样性、皮层回路复杂性和认知能力的理解。我们 该项目将建立一种体内基因传递方法，以可视化NPC动力学和神经元特异性， 胎猪VZ和SVZ（目标1）;并可视化来自于VZ的晚期迁移神经元和细胞群。 出生后仔猪SVZ（Aim 2）。一个大型脑回研究系统的建立 使用现代遗传和细胞成像技术将大大影响我们对正常 人类大脑发育，并提供了一个重要的工具，阐明神经发育的病因学 紊乱这一进展将使关键的比较研究与其他数据集从脑回和 无脑物种，并允许在模型中对早期脑发育进行基因组/细胞理解， 与人类大脑在发育和解剖学上有着重要的相似之处。