Functionally guided adult whole brain cell atlas in human and NHP

人类和 NHP 的功能引导成人全脑细胞图谱

• 批准号: 10523848
• 负责人: Ed Lein
• 金额: $ 2286.45万
• 依托单位: ALLEN INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-22 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523848
• 关键词: ATAC-seq; Acute; Adult; Anatomy; Animal Model; Architecture; Atlases; Automobile Driving; Basic Science; Behavior; Behavioral; Biological Assay; Biomedical Research; Brain; Brain Diseases; Brain region; Callithrix; Cell Nucleus; Cell physiology; Cells; Characteristics; Classification; Clinical; Communities; Complex; Consensus; Consent; Coupled; Data; Data Analyses; Development; Didelphidae; Disease; Enhancers; Ensure; Foundations; Freezing; Functional Imaging; Functional Magnetic Resonance Imaging; Genes; Genetic; Genomics; Goals; Hippocampus (Brain); Histologic; Human; Image; Individual; Knowledge; Label; Link; Macaca; Magnetic Resonance Imaging; Mammals; Maps; Measures; Methods; Modeling; Molecular; Molecular Analysis; Molecular Profiling; Monkeys; Moods; Morphology; Mus; Nerve Tissue; Neurons; Neurosciences; Ontology; Organism; Outcome; Pan Genus; Pattern; Perception; Phenotype; Population; Primates; Property; Reference Standards; Regulator Genes; Research; Resected; Resources; Rodent; Salvelinus; Sampling; Slice; Specimen; Structure; Subcellular Anatomy; Taxonomy; Techniques; Technology; Tissues; Variant; Visualization software; Work; base; brain cell; brain circuitry; brain tissue; cell type; cohort; comparative; computerized data processing; data integration; data management; data mining; data resource; data standards; data visualization; electrical property; end of life; epigenomics; human disease; human model; human subject; human tissue; in vivo; in vivo imaging; inter-individual variation; member; multimodality; nervous system disorder; neuroethics; neuroimaging; nonhuman primate; patch sequencing; sex; single cell technology; study population; tool; transcriptome; transcriptome sequencing; transcriptomics

Progress in treating brain disorders has been frustratingly slow, in large part due to the extraordinary complexity of the human brain and its inaccessibility to study. Remarkable advances in technologies for studying individual cells, most notably single cell genomics, have revolutionized the study of complex nervous tissues and have been used to map cellular diversity across the entire mouse brain with cell types defined by their specific patterns of gene usage and gene regulatory mechanisms. These highly scalable methods have been successfully applied to brain tissue from human and other species and are ready to be applied to whole brains from humans and non-human primates. A major challenge with studying the human brain is bridging fields and scales from functional MRI and macroscale connectomics to histological, cellular and molecular analyses. Bridging these domains is essential to creating a transformative new cell atlas that will describe the cellular and molecular underpinnings of the functional organization of the human brain. An important recent development from single cell genomic analysis is that cell types can be aligned across species and are highly conserved across mammals from mice to humans, although more similar in evolutionarily closer primates than in rodents. This finding amplifies the value of primate species in helping to understand human brains and infer cellular properties that cannot be measured in humans. The current proposal brings together a unique team of world leaders to tackle the challenge of creating a new human and non-human primate cell atlas linked to functional brain architecture. Single cell transcriptomic, epigenomic and spatial transcriptomics will be used to classify and spatially map cell types across the entire human, macaque and marmoset brain, sampling based on brain maps derived from structural and functional imaging. Function-localizing fMRI in macaques will allow the direct analysis of cellular correlates of functional topography. Advances in spatial transcriptomics will allow an unprecedented whole primate brain map of cell types. Unique access to macaque tissues for analysis of cellular anatomy and physiology allows the characterization of molecularly-defined cell types in many brain regions. Similar techniques will be applied to living neurosurgically-derived human brain tissues, coupled with enhancer-AAV based tools to allow selective genetic labeling of cell types. Finally, profiling regions central to perception, behavior and mood across many individuals and diverse mammals will link genetic, environmental and evolutionary factors to cellular variation. The outcome of these efforts will produce a new reference classification for cell types across the whole human and NHP brain, spatial maps of molecularly defined cell types, and phenotypic characterization of fundamental brain cell types. The classification will align homologous cell types from mice, marmosets, macaques and humans, allowing inference and comparison of cellular properties across species. Furthermore, data will be aligned in common coordinate frameworks, allowing creation of new atlases spanning structural, functional, cellular and molecular information. All data and analyses will be distributed to the research community, including a formal cell ontology of cell types across species and visualization tools for broad community access.

治疗大脑疾病的进展一直令人沮丧地缓慢，在很大程度上是由于大脑异常复杂， 人类大脑及其难以研究的问题。研究单个细胞的技术取得了显着进步， 特别是单细胞基因组学，已经彻底改变了复杂神经组织的研究，并已被用于绘制细胞图谱。 整个小鼠大脑的多样性，细胞类型由其特定的基因使用和基因调控模式定义 机制等这些高度可扩展的方法已成功应用于人类和其他物种的脑组织 并准备应用于人类和非人类灵长类动物的整个大脑。一个主要的挑战是研究 人类大脑正在桥接从功能性MRI和宏观连接组学到组织学、细胞学和 分子分析桥接这些结构域对于创建一个变革性的新细胞图谱至关重要，该图谱将描述 人类大脑功能组织的细胞和分子基础。一个重要的最近 从单细胞基因组分析发展而来的是，细胞类型可以在物种之间进行比对，并且是高度保守的 从小鼠到人类的哺乳动物，尽管在进化上更接近的灵长类动物中比啮齿类动物更相似。这一发现 放大了灵长类物种在帮助理解人类大脑和推断细胞特性方面的价值， 在人类中测量。 目前的提案汇集了一个独特的世界领导人团队，以应对创造新人类的挑战， 非人类灵长类动物细胞图谱与功能性大脑结构有关。单细胞转录组学、表观基因组学和空间 转录组学将用于对整个人类、猕猴和绒猴的细胞类型进行分类和空间定位。 大脑，基于来自结构和功能成像的大脑地图进行采样。猕猴的功能定位功能磁共振成像 将允许直接分析功能地形的细胞相关性。空间转录组学的进步将使 这是一张前所未有的灵长类大脑细胞类型图。获取猕猴组织进行细胞分析的独特途径 解剖学和生理学允许表征许多脑区域中的分子定义的细胞类型。类似 技术将应用于活的神经细胞衍生的人脑组织，再加上增强子-AAV为基础的工具， 以允许对细胞类型进行选择性遗传标记。最后，分析大脑中感知、行为和情绪的中心区域， 许多个体和不同的哺乳动物将遗传、环境和进化因素与细胞变异联系起来。 这些努力的结果将为整个人类和NHP的细胞类型产生新的参考分类。 脑，分子定义的细胞类型的空间图，以及基本脑细胞类型的表型表征。的 分类将比对来自小鼠、绒猴、猕猴和人类的同源细胞类型，允许推断和 比较不同物种的细胞特性。此外，数据将在共同的坐标框架内进行调整， 允许创建跨越结构、功能、细胞和分子信息的新图谱。所有数据和分析 将分发给研究界，包括跨物种和可视化的细胞类型的正式细胞本体 广泛的社区访问工具。