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

基本信息

批准号：
10429019
负责人：
Tarik F Haydar
金额：
$ 26.78万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
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/10429019
关键词：
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 Neurodevelopmental Disorder Neuroglia Neurons Operative Surgical Procedures Pilot Projects Plasmids Play Pongidae Population Primates Process Radial Rattus Rodent Role Slice Sus scrofa System Techniques Time Ventricular Work base cell type cellular imaging cognitive ability density fetal fluorescence imaging frontal lobe genetic manipulation in utero in vivo interdisciplinary approach lissencephaly 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

项目摘要

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.

摘要/摘要：神经元和神经胶质细胞的多样化网络产生了哺乳动物大脑的先进计算能力。神经前体细胞 (NPC) 群存在于脑室和室下区（VZ 和 SVZ）产前大脑直接或通过中间祖细胞间接产生所有神经元和神经胶质细胞。在那里人们对细胞多样性及其潜在遗传机制的了解迅速增加前体细胞，大部分工作已在无脑啮齿动物中完成。最近的一些发现环脑物种表明 NPC 类型及其发育机制在大脑较大的物种。例如，最近的研究发现，与啮齿类动物不同，灵长类动物大脑中的基底放射状胶质细胞（bRGC）明显较高，但神经解剖学和这种差异的神经生理学优势尚未确定。同样，大量迁移到额叶的神经元存在于人类婴儿大脑中，但在小鼠中没有发现；两者都不它们产前生成的机制或它们融入新皮质的过程已经已被识别。虽然单细胞转录组数据为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定的差异，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。仔猪是一个强大的研究模型复杂的大脑发育，因为它们具有高度进化的环脑新皮质。我们之前的研究发现猪 SVZ 的细胞结构与其人类对应物异常相似。持续的与人类婴儿皮质一样，仔猪 SVZ 中的年轻神经元迁移到额叶皮质并分化为神经元以区域特定的方式。最后，我们最近的合作单细胞测序研究发现仔猪 SVZ 内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、皮质回路复杂性和认知能力的理解。我们的项目将建立一种体内基因传递方法，以可视化 NPC 动态和神经元规范胎仔猪 VZ 和 SVZ（目标 1）；并可视化源自晚期迁移的神经元和细胞群产后仔猪 SVZ（目标 2）。建立可研究大型环脑的系统使用现代遗传和细胞成像技术将极大地影响我们对正常现象的理解人脑发育并为阐明神经发育的病因提供了重要工具失调。这一进展将使与来自环脑和脑的其他数据集的关键比较研究成为可能。无脑物种，并允许在模型中对早期大脑发育进行基因组/细胞理解与人脑在发育和解剖学上具有重要的相似性。