The Missing Circuit: The First Brainwide Connectivity Map for Mouse

缺失的电路：第一个鼠标全脑连接图

• 批准号: 8085811
• 负责人: PARTHA Pratim MITRA
• 金额: $ 91.45万
• 依托单位: COLD SPRING HARBOR LABORATORY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8085811
• 关键词: Architecture; Autistic Disorder; Automation; Brain; Brain Diseases; Communities; Computational Technique; Consensus; Data Storage and Retrieval; Development; Disease; Disease model; Etiology; Funding Mechanisms; Genome; Injection of therapeutic agent; Institutes; Knowledge; Laboratories; Mammals; Maps; Methods; Microscopy; Modeling; Mus; Neuroanatomy; Neurosciences; Rattus; Research; Scanning; Schizophrenia; Slide; Staging; Techniques; Time; Tracer; United States National Institutes of Health; Vertebral column; Vertebrates; Work; base; cost; drug development; experience; instrument; meetings; mouse model; neuropsychiatry; neurotropic virus; open source; public health relevance; software development; therapy development

DESCRIPTION (provided by applicant): Brain function is dictated by its circuitry, yet we know little about its wiring architecture: in the most-studied mammal (rat), only an estimated 10-30% of the long range circuit connections have been probed. There is growing consensus that it is time to close this gap by generating brainwide connectivity maps for model vertebrates. The mouse is the starting species of choice: mouse models form the backbone of research into the etiology of neuropsychiatric disorders, have the most-studied genome of any mammal, and are key to the early stages of drug development. Over the last two years, we have organized several meetings involving the neuroanatomy community to gain in-depth understanding of the technical and scientific challenges of such a project. Based on this experience, we propose to produce the first brainwide connectivity map of mouse, through the development of an automated pipeline of experimental and computational techniques-- a "connectivity scanner". Our proposal is timely and is enabled by advances in automated wide-field slide scanning microscopy, decreasing data-storage costs, and established tract-tracing methods using injections of classical tracers and neurotropic viruses. The need for brain-wide scope and scalability rule out other approaches. To demonstrate the translational utility of the approach, we will also analyze disease model mice (autism and schizophrenia), to understand alterations in the connectivity map compared to the reference map generated in the project. The project does not fit neatly into an existing funding mechanism at the NIH, but has the potential to fundamentally impact the entire neuroscience community. The transformative potential is twofold: by generating the first mammalian brainwide connectivity map, we provide the neuroscientific community with a landmark reference map which can be used in a wide variety of contexts. Secondly, our emphasis on open source software development, cost optimization and duplicability will result in an affordable, integrated instrument which other academic laboratories will be able to implement. In this way it borrows from, yet differs significantly from, the model offered by the Allen Institute, which has previously demonstrated the potential of industrial automation for neuroscience. PUBLIC HEALTH RELEVANCE: The study of mouse models of neuropsychiatric disorders provides hope for the development of therapies for these burdensome illnesses, but progress has been slow due to the lack of knowledge about how the mouse brain is wired. This project aims to close this gap by generating the first brain-wide wiring diagram of mouse, using automating techniques that are known to work but are labor- intensive. If successful, the project has the potential to fundamentally transform our understanding of brain function and brain disorders.

描述（由申请人提供）：大脑功能由其电路决定，但我们对其布线架构知之甚少：在研究最多的哺乳动物（大鼠）中，估计仅探测了 10-30% 的长距离电路连接。人们越来越一致认为，是时候通过生成模型脊椎动物的全脑连接图来缩小这一差距了。小鼠是首选的起始物种：小鼠模型构成了神经精神疾病病因学研究的支柱，拥有哺乳动物中研究最多的基因组，并且是药物开发早期阶段的关键。在过去的两年里，我们组织了几次涉及神经解剖学界的会议，以深入了解此类项目的技术和科学挑战。基于这一经验，我们建议通过开发实验和计算技术的自动化管道——“连接扫描仪”来制作第一个小鼠全脑连接图。我们的建议是及时的，并且是通过自动化宽视野载玻片扫描显微镜的进步、降低数据存储成本以及使用经典示踪剂和嗜神经病毒注射建立的纤维束追踪方法来实现的。对全脑范围和可扩展性的需求排除了其他方法。为了证明该方法的转化效用，我们还将分析疾病模型小鼠（自闭症和精神分裂症），以了解连接图与项目中生成的参考图相比的变化。该项目并不完全符合美国国立卫生研究院现有的资助机制，但有可能从根本上影响整个神经科学界。变革潜力是双重的：通过生成第一个哺乳动物全脑连接图，我们为神经科学界提供了一个具有里程碑意义的参考图，可以在各种背景下使用。其次，我们对开源软件开发、成本优化和可复制性的重视将带来其他学术实验室能够实施的经济实惠的集成仪器。通过这种方式，它借鉴了艾伦研究所提供的模型，但又与之显着不同，该模型此前已经证明了工业自动化在神经科学领域的潜力。 公共健康相关性：对神经精神疾病小鼠模型的研究为开发治疗这些繁重疾病的疗法带来了希望，但由于缺乏对小鼠大脑如何连接的了解，进展缓慢。该项目旨在通过使用已知有效但劳动密集型的自动化技术生成第一个小鼠全脑接线图来缩小这一差距。如果成功，该项目有可能从根本上改变我们对大脑功能和大脑疾病的理解。