Development of a scalable strategy for reconstructing cell-type determined connectome of the mammalian brain

开发可扩展的策略来重建哺乳动物大脑的细胞类型决定的连接组

• 批准号: 10088842
• 负责人: Dawen Cai
• 金额: $ 391.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-14 至 2024-09-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10088842
• 关键词: Animals; Antigens; Architecture; Axon; Brain; Brain Diseases; Brain Stem; Cell Nucleus; Cells; Cerebral cortex; Data Set; Development; Disease; Disease model; Electron Microscopy; Electrophysiology (science); Fluorescence; Genes; Heterogeneity; Image; Immune; Inhibitory Synapse; Knowledge; Label; Measures; Mental Health; Molecular; Molecular Abnormality; Morphology; Mus; Names; Nature; Neuronal Plasticity; Neurons; Pathway interactions; Pattern; Property; Protocols documentation; Publishing; Resolution; Sampling; Speed; Structure; Synapses; System; Technology; Thalamic structure; To specify; Transgenic Organisms; Ultrafine; Validation; Vibrissae; analysis pipeline; anatomic imaging; barrel cortex; base; brain cell; cell type; connectome; cost efficient; density; exhaustion; inhibitory neuron; light microscopy; microscopic imaging; molecular subtypes; multimodality; multiple datasets; nervous system disorder; neural circuit; neurotechnology; new technology; reconstruction; software development; success; theories

Abstract In order to fully understand the structural substrates underlying the brain function, it is central to curate multiple attributes of the same neurons. The important attributes include, but limited to morphology, connection properties and molecular patterns, such as the expression of functional genes and the distribution of synaptic densities. Light microscopy-based neuronal tracing has contributed our fundamental understanding of the heterogeneity of neuronal morphology. Aligning morphology reconstructions of extremely sparsely labeled neurons from multiple brain samples onto a common coordinate system permitted systematic comparison of the receptive dendritic fields and the projective axonal arbors of distinct neuronal subtypes. However, connection partners of neurons cannot be identified from the light microscopy-based reconstructions due to the nature of sparse sampling and limited resolution. On the other hand, electron microscopy-based reconstructions label all the cell nondifferential but permit recognition of ultra-fine structures, including synaptic contacts, which in theory permits mapping the complete connectome between all neurons. However, it is technically and economically challenging to scale lossless electron microscopy to a large sample, such as the mouse brain. In addition, molecular information is often lost in sample processing. In this project, we propose to develop a scalable strategy that combines several novel technologies to permit reconstructing a molecular connectome of the mammalian brain by light microscopy. Being able to simultaneous profile neuronal morphology, connectivity and molecular properties throughout the whole mouse brain will clarify our understanding of the heterogeneity of brain cells and advance our knowledge about the overall architecture of the mammalian brain with unprecedented resolution and scale.

抽象的 为了充分了解大脑功能的结构基础，核心是策划 相同神经元的多个属性。重要的属性包括但不限于形态、 连接特性和分子模式，例如功能基因的表达和 突触密度的分布。基于光学显微镜的神经元追踪为我们做出了贡献 对神经元形态异质性的基本理解。对齐形态 将来自多个大脑样本的极其稀疏标记的神经元重建到一个共同的 坐标系允许对感受树突场和投影树突场进行系统比较 不同神经元亚型的轴突乔木。然而，神经元的连接伙伴不能 由于稀疏采样的性质，从基于光学显微镜的重建中识别出 分辨率有限。另一方面，基于电子显微镜的重建标记了所有细胞 非差异性，但允许识别超精细结构，包括突触接触，理论上 允许绘制所有神经元之间的完整连接组。然而，从技术上和 将无损电子显微镜扩展到大样本（例如小鼠）在经济上具有挑战性 脑。此外，分子信息在样品处理中经常丢失。在这个项目中，我们建议 开发一种可扩展的策略，结合多种新技术来重建 通过光学显微镜观察哺乳动物大脑的分子连接组。能够同时分析 整个小鼠大脑的神经元形态、连接性和分子特性将 阐明我们对脑细胞异质性的理解并增进我们对脑细胞异质性的认识 哺乳动物大脑的整体结构具有前所未有的分辨率和规模。