Functional and cell-type specific axonal pathways in the primate brain

灵长类动物大脑中的功能和细胞类型特异性轴突通路

• 批准号: 10272370
• 负责人: R CLAY REID
• 金额: $ 153.57万
• 依托单位: ALLEN INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10272370
• 关键词: Alzheimer' s disease patient; Anatomy; Antibodies; Area; Atlases; Autopsy; Axon; BRAIN initiative; Biological Assay; Brain; Brain Diseases; Calcium; Cells; Censuses; Classification; Data; Data Set; Development; Diffusion Magnetic Resonance Imaging; Disease Marker; Electrodes; Functional Imaging; Functional Magnetic Resonance Imaging; Genes; Goals; Histologic; Human; Image; Individual; Institutes; Institution; Label; Macaca; Magnetic Resonance Imaging; Maps; Measures; Methodology; Methods; Modality; Molecular; Neurodegenerative Disorders; Neurons; Neurosciences; Optics; Parietal; Pathway interactions; Phase; Physiology; Play; Population; Primates; Program Appropriateness; Property; Prospective Studies; Protocols documentation; RNA; RNA Probes; Recording of previous events; Research; Resolution; Role; Specificity; Stream; Surface; Techniques; Technology; Testing; Tissues; Translating; United States National Institutes of Health; Visual Cortex; Visual system structure; Work; anatomic imaging; brain cell; brain tissue; brain volume; cell type; experimental study; human tissue; improved; in vivo; innovation; light microscopy; multimodality; multiphoton imaging; neural circuit; neuromechanism; nonhuman primate; novel; optical imaging; postsynaptic; programs; relating to nervous system; success; tool; transcriptomics; white matter

Project Summary/Abstract Over the past decade, there have been transformative advances in three areas of mammalian neuroscience. First, our ability to record from large populations of neurons has dramatically increased with the advent of new electrode technologies and improved multiphoton imaging. Second, the study of brain connections in their entirety, connectomics, has come into its own as a field. Most recently, there has been a revolution in the classification of neuronal types, largely by probing which genes are translated into RNA in cells (transcriptomics). What is lacking is a way to bring these three fields together, particularly in the studies of non-human primates and humans. The goal of the current RFA is to create innovative tools for use in humans and non-human primates. In particular, two suggested topics are to develop: (1) “novel methods for tagging individual neurons such that cellular components of a functional circuit can be explored” and (2) “innovative approaches to bridge scales of experimental approach. Studies that can explore molecular and cellular mechanisms of neural activity in broader contexts are encouraged.” To achieve these goals, we present an innovative approach to characterize neuronal cell types in macaques and humans, combining transcriptomics, inter-areal connectivity and functional studies at multiple scales, from individual neurons to entire brains. We will build the necessary tools to create integrated atlases of individual brains that combine six modalities into a common reference frame: (1) functional MRI, to measure functional properties of brain areas at 0.5-1 mm resolution, (2) widefield optical imaging, to map bulk neuronal activity at the cortical surface with ~100 µm resolution, (3) multiphoton calcium imaging, to map neuronal activity in individual neurons across multiple cortical areas, (4) diffusion tensor imaging (DTI), to map axonal tracts in the white matter with 0.5-1 mm resolution, (5) “axonal connectomics”, to map projections of individual myelinated axons from efferent cell bodies to their postsynaptic targets, and (6) multiplexed FISH, to assay transcriptomic identities of the same cells whose physiology and projection targets have been defined. Data from first three modalities will be collected, starting with in vivo studies of macaques and correlated with subsequent analysis of brain tissue with the last three modalities. Only the last three steps will be used in the study of human brain tissue, although functional MRI could, in principle, be obtained from research institutions with appropriate programs for prospective studies.

项目总结/摘要 在过去的十年中，哺乳动物神经科学的三个领域取得了变革性的进展。 首先，我们记录大量神经元的能力随着新的神经元的出现而急剧增加。 电极技术和改进的多光子成像。第二，研究他们的大脑连接， 整体性，连接组学，已经成为一个领域。最近，有一场革命， 神经元类型的分类，主要是通过探测哪些基因在细胞中被翻译成RNA（转录组学）。 目前缺乏的是将这三个领域结合在一起的方法，特别是在非人类灵长类动物的研究中 还有人类 目前RFA的目标是创造用于人类和非人类灵长类动物的创新工具。特别是， 两个建议的主题是发展：（1）“标记单个神经元的新方法， 可以探索功能电路的组件”和（2）“桥接 实验方法研究可以探索神经活动的分子和细胞机制， 背景受到鼓励”。为了实现这些目标，我们提出了一种创新的方法来表征神经元 猕猴和人类的细胞类型，结合转录组学，区域间连接和功能研究 从单个神经元到整个大脑。我们将构建必要的工具， 将联合收割机的六种模式结合到一个共同的参考框架中的个体大脑图谱：（1）功能性MRI， 以0.5-1 mm的分辨率测量脑区域的功能特性，（2）宽视野光学成像，以映射体积 皮质表面的神经元活动，分辨率约为100 µm，（3）多光子钙成像，以绘制 （4）扩散张量成像（DTI），以映射跨多个皮层区域的单个神经元中的神经元活动， 白色物质中的轴突束，分辨率为0.5-1 mm，（5）“轴突连接组学”，用于绘制 从传出细胞体到其突触后靶点的单个有髓鞘轴突，和（6）多重FISH， 测定其生理学和投射靶已经被定义的相同细胞的转录组学身份。 将收集前三种方式的数据，从猕猴的体内研究开始，并与 用最后三种方式对脑组织进行后续分析。只有最后三个步骤将在 虽然功能性磁共振成像技术原则上可以从研究机构获得， 进行适当的前瞻性研究。