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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的为了充分理解大脑功能的结构底物，策展人是核心同一神经元的多个属性。重要属性包括但仅限于形态学，连接性能和分子模式，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跟踪为我们的对神经元形态异质性的基本理解。对齐形态从多个脑样本中的极稀疏标记神经元重建到一个共同的坐标系统允许对树突状田地的系统比较和投影不同神经元亚型的轴突轴。但是，神经元的连接伙伴不能由于稀疏采样的性质和有限的分辨率。另一方面，基于电子显微镜的重建标记所有细胞非差异但允许识别包括突触接触在内的超细结构，从理论上讲，这允许映射所有神经元之间的完整连接组。但是，从技术上讲，在经济上具有挑战性的无损电子显微镜，例如小鼠脑。另外，样品处理中通常会丢失分子信息。在这个项目中，我们建议制定可扩展的策略，该策略结合了几种新型技术以允许重建哺乳动物大脑通过光学显微镜的分子连接组。能够同时简介整个小鼠大脑中的神经元形态，连通性和分子特性将澄清我们对脑细胞异质性的理解，并提高我们对哺乳动物大脑的整体结构具有前所未有的分辨率和规模。