The Missing Circuit: The First Brainwide Connectivity Map for Mouse

描述（由申请人提供）：大脑的功能是由它的电路决定的，但我们对它的线路结构知之甚少：在研究最多的哺乳动物（老鼠）中，估计只有10-30%的远程电路连接被探测到。越来越多的人一致认为，现在是时候通过为脊椎动物模型生成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，拥有所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。在过去的两年中，我们组织了几次涉及神经解剖学社区的会议，以深入了解这样一个项目的技术和科学挑战。基于这一经验，我们建议通过开发一种自动化的实验和计算技术——“连接扫描仪”——来绘制第一张小鼠全脑连接图。我们的建议是及时的，并且由于自动化宽视场载玻片扫描显微镜的进步，降低了数据存储成本，以及使用注射经典示踪剂和嗜神经病毒建立了通道追踪方法。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），以了解与项目中生成的参考图相比，连接图中的变化。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。这种转变的潜力是双重的：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，可以在各种情况下使用。其次，我们对开源软件开发、成本优化和可重复性的强调将导致其他学术实验室能够实现的负担得起的集成仪器。在这方面，它借鉴了艾伦研究所（Allen Institute）提供的模型，但与之有很大不同。艾伦研究所此前曾展示过工业自动化对神经科学的潜力。

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.