The Missing Circuit: The First Brainwide Connectivity Map for Mouse

描述(申请人提供)：大脑功能由其电路决定，但我们对其连接结构知之甚少：在研究最多的哺乳动物(老鼠)中，估计只探测到10%-30%的长距离电路连接。越来越多的人达成共识，认为现在是时候通过为模型脊椎动物制作全脑连接地图来缩小这一差距了。小鼠是最初选择的物种：小鼠模型形成了神经精神疾病病因学研究的骨干，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，我们建议通过开发一种实验和计算技术的自动化管道--“连接扫描仪”--来制作第一个大脑范围的鼠标连接地图。我们的建议是及时的，得益于自动化广域玻片扫描显微镜的进步，数据存储成本的降低，以及使用经典示踪剂和嗜神经病毒注射的已建立的轨迹追踪方法。对全脑范围和可伸缩性的需求排除了其他方法。为了展示这种方法的翻译效用，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地图相比，连接地图中的变化。该项目不能很好地融入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。变革的潜力是双重的：通过生成第一个哺乳动物脑部连通性地图，我们为神经科学界提供了一个里程碑式的参考地图，可以在各种环境中使用。其次，我们对开源软件开发、成本优化和可复制性的重视将产生一个负担得起的、集成的仪器，其他学术实验室将能够实施。在这种方式上，它借鉴了艾伦研究所提供的模型，但与之有很大的不同。艾伦研究所之前已经证明了工业自动化在神经科学中的潜力。 与公共卫生相关：对神经精神障碍的小鼠模型的研究为这些负担沉重的疾病的治疗方法的开发提供了希望，但由于缺乏关于小鼠大脑如何连接的知识，进展缓慢。这个项目旨在通过使用已知有效但劳动密集型的自动化技术，生成第一个大脑范围的鼠标接线图来弥合这一差距。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.