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）：本申请解决了广泛的挑战领域 (15)：转化科学和特定挑战主题，15-MH-103 绘制小鼠模型的神经连接。大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，估计仅探测了 10-30% 的长程电路连接。当前的挑战主题验证了日益增长的共识，即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。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，我们设计并开始构建和测试一个自动化的实验和计算技术管道，以实现这一目标。我们的建议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工程病毒注射建立的纤维束追踪方法来实现的。实验计划可概括如下。根据经典神经解剖学和区域基因表达数据，小鼠大脑被分为约 200 个区域。对于每个区域，我们向一只小鼠注射经典示踪剂，向另一只小鼠注射病毒示踪剂。从注射部位，示踪剂被顺行输送到该区域的投射目标，并逆行输送到投射到注射部位的区域。通过这种方式，各个投影会被多次揭示。为了获取这些信息，我们将对每只小鼠的整个大脑进行切片，并使用自动幻灯片扫描显微镜对切片进行成像。生成的 2D 切片图像将在软件中组合，为每次注射生成 3D 重建大脑图像。最后，所有单独注射的 3D 图像将通过空间注册到 Allen 参考图谱进行组合，最终生成统一的全脑神经连接图。在小鼠中生成第一个无偏见的全脑连接图将具有广泛的神经科学意义。最终拥有这个具有里程碑意义的参考图来有意义地约束理论并帮助实验设计和结果解释，神经发育、神经网络建模、进化神经解剖学以及联想和综合大脑功能的研究将受益匪浅。通过分析艾伦研究所生成的基因表达图谱并结合该项目生成的连接图谱，可以探讨基因表达和连接性之间的关系。本研究中生成的基线神经连接图将作为随后研究突变小鼠系的电路多态性的基础。客观量化自闭症和精神分裂症等神经精神疾病小鼠模型中连通性变化的能力将有助于我们了解其病因学和病理生理学。最后，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种经济实惠的集成仪器，其他学术实验室将能够实施，以便这种方法可以快速应用于各种神经科学问题。 叙述对小鼠神经精神疾病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。该项目旨在通过生成第一个小鼠全脑接线图以及已知有效但劳动密集型的自动化技术来缩小这一差距。如果成功，该项目有可能从根本上改变我们对正常和紊乱大脑结构的理解。