The First Comprehensive Neural Connectivity Map of Mouse

第一个全面的小鼠神经连接图

• 批准号: 7939770
• 负责人: PARTHA Pratim MITRA
• 金额: $ 50万
• 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 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7939770
• 关键词: Address; Adult; Architecture; Area; Atlases; Attention; Autistic Disorder; Automation; Brain; Brain Diseases; Brain imaging; Budgets; Communities; Computational Technique; Computer software; Consensus; Data; Data Analyses; Data Set; Data Storage and Retrieval; Databases; Disease; Economics; Engineering; Etiology; Experimental Designs; Foundations; Functional disorder; Gene Expression; Genetic Polymorphism; Genome; Genomics; Goals; Grant; Head Start Program; Human Genome Project; Image; Individual; Injection of therapeutic agent; Institutes; Knowledge; Laboratories; Light Microscope; Maps; Methods; Microscope; Microscopy; Modeling; Mus; Mutant Strains Mice; Neural Network Simulation; Neuroanatomy; Neurosciences; Occupations; Online Systems; Phenotype; Population Study; Preparation; Process; Protocols documentation; Rattus; Recovery; Research; Research Infrastructure; Sampling; Scanning; Schizophrenia; Site; Slice; Slide; Techniques; Testing; Three-Dimensional Image; Time; TimeLine; Tracer; Translational Research; Validation; Variant; Vertebrates; Viral; Virus; Work; base; cost; design; experience; image reconstruction; innovation; instrument; male; meetings; mouse model; neurodevelopment; neuropsychiatry; open source; programs; relating to nervous system; research study; retrograde transport; scale up; software development; success; symposium; theories; therapy development; tissue processing

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area (15): Translational Science and specific Challenge Topic, 15- MH-103 Mapping the Neural Connectivity of a Mouse Model. 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. The present Challenge Topic validates the growing consensus that it is time to close this gap by generating brainwide connectivity maps for model vertebrates. 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 have designed and have begun to build and test an automated pipeline of experimental and computational techniques for achieving this goal. Our proposal 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 engineered viruses. The experimental plan can be summarized as follows. The mouse brain is divided into ~200 regions based on classical neuroanatomical and regional gene-expression data. For each region we inject one mouse with classical tracers and one mouse with viral tracers. From the injection site, the tracers are transported anterogradely to the area's projection targets and retrogradely to areas which project to the injection site. In this way, individual projections are revealed multiple times. In order to acquire this information, we will section the entire brain from each mouse and image the sections using an automated slide-scanning microscope. The resulting 2D slice-images will be combined in software to produce a 3D reconstructed brain image for each injection. Finally the 3D images from all of the individual injections will be combined by spatially registering them to the Allen Reference Atlas, ultimately generating a unified brainwide neural connectivity map. Generating the first unbiased, brainwide connectivity map in the mouse will have broad neuroscientific implications. The study of neural development, neural network modeling, evolutionary neuroanatomy, and associative and integrative brain function will benefit tremendously from finally having this landmark reference map to meaningfully constrain theories and aid in experimental design and interpretation of results. Relationships between gene expression and connectivity can be probed by analyzing the gene-expression maps generated by the Allen Institute in combination with the connectivity maps generated by this project. The baseline neural connectivity map generated in the present study will serve as a foundation for subsequently studying circuit polymorphisms across mutant mouse lines. The ability to objectively quantify alterations in connectivity in mouse models of neuropsychiatric disorders such as autism and schizophrenia will aid our understanding of their etiology and pathophysiology. Finally, 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, so that this approach can be rapidly applied to a wide variety of neuroscientific problems. NARRATIVE 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, automating techniques that are known to work but are labor-intensive. If successful, the project has the potential to fundamentally transform our understanding of the architecture of the normal and disordered brain.

描述（由申请人提供）：此申请应解决广泛的挑战领域（15）：翻译科学和特定挑战主题，15-MH-103映射鼠标模型的神经连接性。大脑功能是由其电路决定的，但我们对其接线架构一无所知：在最研究的哺乳动物（大鼠）中，估计只有10-30％的远程电路连接探测了。目前的挑战主题验证了日益增长的共识，即该通过为模型脊椎动物生成精心的连接图来缩小这一差距了。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，以深入了解此类项目的技术和科学挑战。根据这一经验，我们设计并开始构建和测试实现这一目标的实验和计算技术的自动管道。我们的建议是通过使用经典示踪剂和工程病毒的注射量来实现自动宽视野滑梯扫描显微镜，降低数据存储成本以及建立的道路追踪方法的进展来实现的。实验计划可以总结如下。基于经典的神经解剖学和区域基因表达数据，小鼠大脑分为〜200个区域。对于每个区域，我们将一只小鼠注入经典的示踪剂和一只小鼠带有病毒示踪剂。从注射部位，示踪剂被直接运输到该地区的投影目标，并逆转到投射到注射部位的区域。这样，单个预测被多次揭示。为了获取此信息，我们将使用自动滑动扫描显微镜从每只鼠标分开整个大脑，并为部分进行图像。所得的2D切片图像将在软件中合并，为每次注射产生3D重建的大脑图像。最后，来自所有个人注射的3D图像将通过空间将其注册到Allen参考地图集，最终生成统一的Brainwide神经连接图。在小鼠中生成第一个无偏见的，遍布头脑的连通图将具有广泛的神经科学含义。对神经发育，神经网络建模，进化神经解剖学以及联想和整合大脑功能的研究将受益匪浅，从最终拥有这个具有里程碑意义的参考图到有意义地限制理论并有助于实验设计和结果解释。可以通过分析艾伦研究所（Allen Institute）与该项目产生的连通图产生的基因表达图来探测基因表达与连通性之间的关系。本研究中产生的基线神经连通图将是随后研究突变小鼠系的电路多态性的基础。在自闭症和精神分裂症等神经精神疾病的小鼠模型中，客观地量化连通性变化的能力将有助于我们理解其病因学和病理生理学。最后，我们强调开源软件开发，成本优化和重复性将导致其他学术实验室能够实施的负担得起的集成工具，以便可以将这种方法迅速应用于各种神经科学问题。 叙事的神经精神疾病的小鼠模型的研究为这些繁重疾病的疗法开发提供了希望，但是由于缺乏对小鼠大脑的连线方式的知识，进步速度很慢。该项目的目的是通过生成鼠标的首个大脑范围的接线图来缩小这一差距，这些接线图是可行的，但具有劳动力密集的自动化技术。如果成功，该项目有可能从根本上改变我们对正常和无序大脑结构的理解。