Brainbow: Novel tools for studying the development of neuronal circuits

Brainbow：研究神经元回路发育的新工具

• 批准号: 7497848
• 负责人: WILLIAM J BOSL
• 金额: $ 25.05万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497848
• 关键词: Adult; Age; Algorithms; Animals; Antibodies; Ataxia; Automation; Axon; Brain; Cell membrane; Cells; Cerebellar Diseases; Cerebellar Mossy Fibers; Cerebellum; Chromosome Pairing; Color; Complex; Computers; Cytoplasm; Data; Data Set; Dendrites; Detection; Development; Dimensions; Disease; Embryo; Epitopes; Fluorescence; Gene Mutation; Goals; Human; Image; Image Analysis; Image Enhancement; Imagery; Individual; Investigation; Knowledge; Label; Laboratories; Lead; Manuals; Maps; Methods; Microscopy; Mus; Nervous system structure; Neurologic; Neurons; Numbers; Pathway interactions; Property; Proteins; Public Health; Research; Research Proposals; Staging; Synapses; Techniques; Testing; Time; Transgenic Mice; Transgenic Organisms; Work; computerized; digital; granule cell; improved; interest; mossy fiber; mouse model; nervous system development; neural circuit; neuronal cell body; neuronal circuitry; novel; presynaptic; prevent; programs; protein expression; reconstruction; software development; tool

DESCRIPTION (provided by applicant): The organization of the human brain relies upon precise connectivity among hundreds of billions of neurons. The vast majority of these connections are established during nervous system development, when neurons find and connect to appropriate targets. To date, detailed studies of neuronal circuit development and maturation have been hampered due to technical limitations that prevent the clear visualization of many interacting neurons. New "Brainbow" transgenic mice, however, use random expression of multiple fluorescent proteins to allow for the clear identification of multiple individual components within complex neuronal circuits. These new tools greatly enhance one's ability to study neuronal connectivity and its development by allowing one to extract previously inaccessible information about specific neural circuits. Using confocal imaging methods, clear circuit diagrams can be constructed by direct visualization of the axons and dendrites of many interacting neurons throughout the nervous system. However, existing methods of image analysis are not sufficient for large Brainbow datasets, requiring new advancements in current techniques. This research proposal aims to create and utilize computer algorithms for automating the reconstruction of large neuronal datasets, and to generate new Brainbow mouse lines for improved analysis. These new tools will then be used to conduct a thorough investigation into how neuronal circuitry develops in the young cerebellum, and how cerebellar circuitry may form abnormally in an ataxic mouse model of the developmental cerebellar disease known as ataxia telangectasia. These studies will help to provide a better understanding of how neuronal circuits develop and function in the mammalian brain. PUBLIC HEALTH RELEVANCE The goal of this work is to understand how circuits form in the developing brain. There are a great deal of human disorders that arise when neurological development goes awry; a better understanding of brain circuitry can lead to appropriate treatments for disease. This research will develop new tools that will help us to understand the developmental mechanisms that lead to normal and abnormal connectivity within the brain.

描述（由申请人提供）：人类大脑的组织依赖于数千亿神经元之间的精确连接。这些连接中的绝大多数是在神经系统发育期间建立的，当神经元找到并连接到适当的目标时。迄今为止，由于技术限制，阻碍了许多相互作用的神经元的清晰可视化，神经元回路发育和成熟的详细研究受到阻碍。然而，新的“Brainbow”转基因小鼠使用多种荧光蛋白的随机表达，以允许在复杂的神经元回路中清楚地识别多个单独的成分。这些新工具大大提高了研究神经元连接及其发展的能力，使人们能够提取以前无法获得的有关特定神经回路的信息。使用共聚焦成像方法，可以通过直接可视化整个神经系统中许多相互作用的神经元的轴突和树突来构建清晰的电路图。然而，现有的图像分析方法对于大型Brainbow数据集是不够的，需要在当前技术中取得新的进展。该研究计划旨在创建和利用计算机算法来自动重建大型神经元数据集，并生成新的Brainbow小鼠线以改进分析。然后，这些新工具将用于对年轻小脑中神经元回路如何发育以及小脑回路如何在发育性小脑疾病（称为共济失调毛细血管扩张症）的共济失调小鼠模型中异常形成进行彻底调查。这些研究将有助于更好地了解哺乳动物大脑中神经元回路的发育和功能。这项工作的目标是了解回路如何在发育中的大脑中形成。当神经系统发育出现问题时，会出现大量的人类疾病;更好地了解大脑回路可以导致疾病的适当治疗。这项研究将开发新的工具，帮助我们了解导致大脑正常和异常连接的发育机制。