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: 10653987
• 负责人: R CLAY REID
• 金额: $ 172.84万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10653987
• 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; 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; Work; anatomic imaging; brain cell; brain magnetic resonance imaging; brain tissue; brain volume; cell type; experimental study; human tissue; improved; in vivo; innovation; light microscopy; meter; multi-photon; multimodality; multiphoton imaging; neural; neural circuit; neuromechanism; nonhuman primate; novel; optical imaging; postsynaptic; programs; 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.

项目摘要/摘要 在过去的十年里，哺乳动物神经科学的三个领域取得了革命性的进展。 首先，随着新技术的出现，我们从大量神经元群体中进行记录的能力大大增强 电极技术和改进的多光子成像。第二，对他们大脑连接的研究 整体，连接学，已经作为一个领域进入了自己的领域。最近，世界上发生了一场革命 神经元类型的分类，主要是通过探测细胞中哪些基因被翻译成RNA(转录学)进行的。 缺乏一种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。 和人类。 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， 建议的两个主题是：(1)“标记单个神经元的新方法，使细胞 功能电路的组件可以探索“和(2)”创新方法，以桥接规模 实验方法。可以在更广泛的范围内探索神经活动的分子和细胞机制的研究 我们鼓励在不同的背景下进行交流。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，结合转录转录，区域间连接和功能研究 在多个尺度上，从单个神经元到整个大脑。我们将构建必要的工具来创建集成的 将六种模式组合成一个公共参照系的个体大脑图谱：(1)功能磁共振成像，以 以0.5-1 mm的分辨率测量大脑区域的功能特性，(2)广域光学成像，以绘制体图 皮质表面神经元活动的分辨率为~100微米，(3)多光子钙成像，以映射 跨多个皮质区域的单个神经元的神经元活动，(4)扩散张量成像(DTI)，以映射 白质内的轴索以0.5-1 mm的分辨率，(5)“轴突连接”，以绘制 从传出细胞体到突触后靶点的单个有髓轴突，以及(6)多路FISH 对其生理和投射目标已确定的相同细胞进行转录鉴定。 前三种模式的数据将被收集，首先是对猕猴的体内研究，并与 随后用最后三种方式对脑组织进行了分析。只有最后三个步骤将用于 对人脑组织的研究，尽管原则上可以从研究机构获得功能磁共振成像 为前瞻性研究提供适当的计划。

项目成果

Axonal organelle buildup from loss of AP-4 complex function causes exacerbation of amyloid plaque pathology and gliosis in Alzheimer's disease mouse model.

AP-4 复合物功能丧失导致的轴突细胞器堆积导致阿尔茨海默病小鼠模型中淀粉样斑块病理和神经胶质增生的恶化。

• DOI: 10.1101/2024.03.31.587499
• 发表时间: 2024
• 期刊: bioRxiv : the preprint server for biology
• 作者: Orlowski,Alex;Karippaparambil,Joseph;Paumier,Jean-Michel;Ghanta,Shraddha;Pallares,Eduardo;Tandukar,Jamuna;Gao,Ruixuan;Gowrishankar,Swetha
• 通讯作者: Gowrishankar,Swetha