The Missing Circuit: The First Brainwide Connectivity Map for Mouse

描述（由申请人提供）：脑功能由其电路决定，但我们对其布线结构知之甚少：在研究最多的哺乳动物（大鼠）中，估计只有10-30%的长距离电路连接已被探测。越来越多的人一致认为，现在是时候通过为模型脊椎动物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，拥有任何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”，来制作第一个小鼠全脑连接图。我们的建议是及时的，并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，并建立了使用经典示踪剂和嗜神经病毒注射的跟踪跟踪方法。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，连接图的变化。该项目并不完全符合NIH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，可用于各种各样的情况。其次，我们强调开放源码软件开发、成本优化和可复制性，这将导致其他学术实验室能够实施一种负担得起的综合仪器。在这方面，它借鉴了艾伦研究所提供的模型，但又有很大的不同。艾伦研究所之前已经证明了工业自动化对神经科学的潜力。 公共卫生相关性：对神经精神疾病小鼠模型的研究为开发这些负担沉重的疾病的治疗方法提供了希望，但由于缺乏对小鼠大脑如何连接的了解，进展缓慢。这个项目的目的是通过使用已知的工作但劳动密集型的自动化技术来生成第一个老鼠的大脑布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。

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.