A Computational Framework for Mapping Long Range Genetic Circuits

绘制长距离遗传电路的计算框架

• 批准号: 7845097
• 负责人: JULIE RUTH KORENBERG
• 金额: $ 49.68万
• 依托单位: UNIVERSITY OF UTAH
• 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 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7845097
• 关键词: 3-Dimensional; Address; Affect; Algorithms; Alzheimer' s Disease; American; Amygdaloid structure; Animal Model; Animals; Area; Argipressin; Autistic Disorder; Axon; Behavior; Biological Neural Networks; Biology; Brain; Brain Mapping; Brain Stem; Cell Nucleus; Cells; Cholera Toxin; Clinical; Clinical Research; Cognition; Collaborations; Computer software; Data; Data Set; Devices; Disease; Doctor of Philosophy; Drug Delivery Systems; Emerging Technologies; Emotional; Emotions; Employee Strikes; Fluorescence; Functional Magnetic Resonance Imaging; Gene Expression; Generations; Genes; Genetic; Goals; Hereditary Disease; Hippocampus (Brain); Human; Hypothalamic structure; Image; Imagery; Immunohistochemistry; Informatics; Information Storage; Injection of therapeutic agent; Institutes; Knowledge; Limbic System; Link; Macaca; Macaca fascicularis; Magnetic Resonance Imaging; Mammals; Manuals; Maps; Medicine; Mental disorders; Methods; Microscopy; Mus; Neuroanatomy; Neurobiology; Neurologic; Neurons; Neuropeptides; Neurosciences Research; Noise; Nucleus Accumbens; Occupations; Oxytocin; Parkinson Disease; Pathway interactions; Primates; Proteins; Public Health; Rabies virus; Reporting; Research; Research Personnel; Resolution; Retina; Schizophrenia; Signal Transduction; Slice; Social Behavior; Social Behavior Disorders; Software Tools; Solutions; Son; Structure; Synapses; System; Techniques; Technology; Tracer; Travel; Universities; Utah; Variant; Vasopressins; Williams Syndrome; addiction; base; career; computer framework; depression; digital; emotion regulation; fluorescence imaging; forging; image reconstruction; image registration; innovation; insight; instrumentation; light microscopy; neural circuit; new technology; next generation; nonhuman primate; novel; prevent; programs; reconstruction; relating to nervous system; scientific computing; social; software development; tool; white matter

DESCRIPTION (provided by applicant): This application addresses broad Challenge Area: (06) Enabling Technologies and specific Challenge Topic: 06-MH-103 New technologies for neuroscience research. Develop technologies for neuroscience research that are software-based, (e.g., informatics tools, implementation of data analytic algorithms), hardware-based (e.g., instrumentation or devices), or biology-based (e.g., driven by conditional gene expression or bioactive agents). Contact: Michael F. Huerta, Ph.D., 301-443-1815, [e-mail] Establishing a network diagram of the brain is one of the major challenges of modern neurobiology and medicine, particularly a diagram of genetic connectivity. Nowhere is this need more clear than for the social-emotional system, where dysregulation of circuitry has been implicated in the most devastating mental illnesses, depression, schizophrenia and autism. This proposal seeks to deploy the next generation neurobiologic technologies and novel software tools needed to generate gene-specific 3-dimensional reconstructions from serial sections of long range axon projections or wiring diagrams of the limbic system, at the axon level and on the size scale of primate brain. This software will fill two striking gaps that have seriously hindered the generation of maps of primate brain circuitry. Blocked by lack of existing software for both aligning sequential sections and for handling large datasets, current circuit reconstruction methods cannot handle axon projections that travel through more than a single, typical ~30¿m section. Therefore, although there are elegant emerging approaches to tract tracing, current technology permits only visualization of cells in a single section of a mouse hippocampus but prevents providing answers to the critical questions at the systems level. The long range links to other cortical or subcortical structures involved in regulation of emotion or cognition, particularly at the scale needed for primate systems cannot yet be visualized. Moreover, there are no programs for making the leap between axon projections and larger tracts defined by DTI or MRI. The current proposal takes advantage of a unique multidimensional collaboration among the Scientific Computing and Imaging Institute (SCI) experts in image reconstruction and three-dimensional visualization (Tasdizen, Jones) who have recently (Anderson, 2009) developed a computational framework for 3-dimensional neurocircuitry of the retina and in fluorescence image reconstruction (Roysam), experts in non-human primate brain circuitry and neuroanatomy (Angelucci, Hof), experts in animal and human DTI/ MRI (Hsu), and experts in multicolor fluorescence imaging of axon projections (Korenberg, Angelucci). This unique collaborative project will help to maintain two junior investigators and three early career investigators, and will create seven new research jobs in the fields of neurobiology and computation. The four aims will: 1) Generate high signal- to-noise multicolor fluorescence images of neuropeptide projections in the macaque limbic system (hypothalamus- a subset of limbic targets) at axon resolution, 2) Acquire and store images of more than 400 serial sections in mosaic 2 ¿m stacks equal to158 terabytes, 3) Reconstruct the hypothalamic- projections found with arginine-vasopressin and a Williams syndrome gene product to a subset of limbic targets from serial images into a single continuous dataset, and 4) Automatically reconstruct axon pathways to their targets. The goal is to create and integrate this novel set of software and neurobiologic technologies that will accelerate wiring the brain of mammals. These technologies will provide the critical missing framework necessary for image acquisition, manipulation of terabyte datasets, serial section reconstruction, automatic and manual tract tracing, and gene specific wiring diagrams or connectomes at the scale of primate brains and for bridging the gap between axon projections and high resolution tracts obtained by MRI and DTI of non-human primates and humans. of this research to public health: Establishing a network diagram of the brain is one of the major challenges of modern neurobiology and medicine, particularly a diagram of genetic connectivity. Nowhere is this need clearer than for the brain system controlling social behavior and emotion, where dysregulation of circuitry has been implicated in the most devastating mental illnesses, depression, schizophrenia and autism that together affect more than 13 million Americans. Creating solutions to understand these brain systems will broadly accelerate unraveling the connectivity of many circuits that are disturbed in other neurologic diseases, including those involved in Parkinson's, Alzheimer's, and addiction. In summary, the tools we are creating will transform the field of mental illness by providing genetic links to the underlying brain circuitry. This knowledge will provide insights into new drug targets to prevent, treat, and ultimately cure mental illness.

描述（由申请人提供）：本申请涉及广泛的挑战领域：（06）使能技术和特定的挑战主题：06-MH-103神经科学研究的新技术。开发基于软件的神经科学研究技术（例如，信息学工具，数据分析算法的实现），基于硬件的（例如，仪器或设备），或基于生物学的（例如，由条件基因表达或生物活性剂驱动）。联系人：Michael F. Huerta博士，301-443-1815，[e-mail]建立大脑网络图是现代神经生物学和医学的主要挑战之一，特别是遗传连接图。没有什么比社会情绪系统更清楚地表明这种需要了，在这个系统中，电路失调与最具破坏性的精神疾病，抑郁症，精神分裂症和自闭症有关。该提案旨在部署下一代神经生物学技术和新的软件工具，需要从长距离轴突投影或边缘系统接线图的连续切片中生成基因特异性三维重建，在轴突水平和灵长类动物大脑的大小尺度上。这个软件将填补两个显著的空白，这两个空白严重阻碍了灵长类动物大脑回路地图的生成。由于缺乏用于对齐连续切片和处理大型数据集的现有软件，目前的电路重建方法无法处理通过超过单个典型的~30 μ m切片的轴突投影。因此，虽然有优雅的新兴方法来跟踪，目前的技术只允许可视化的细胞在一个单一的部分小鼠海马，但防止提供答案的关键问题在系统层面上。与其他参与情绪或认知调节的皮层或皮层下结构的长距离联系，特别是灵长类系统所需的规模，目前还无法可视化。此外，还没有程序可以在轴突投射和DTI或MRI定义的更大的神经束之间进行跳跃。目前的提案利用了科学计算和成像研究所（SCI）专家在图像重建和三维可视化方面的独特多维合作（Tasdizen，Jones）最近，（安德森，2009）开发了用于视网膜的三维神经回路和荧光图像重建的计算框架（Roysam），非人类灵长类动物脑回路和神经解剖学专家（Angelucci，霍夫），动物和人类DTI/ MRI专家（Hsu），以及轴突投射荧光成像专家（Korenberg，Angelucci）。这个独特的合作项目将有助于维持两名初级研究人员和三名早期职业研究人员，并将在神经生物学和计算领域创造七个新的研究工作。这四个目标将：1）生成猕猴边缘系统中神经肽投射的高信噪比荧光图像（下丘脑-边缘系统目标的子集）在轴突分辨率，2）采集和存储图像的400多个连续切片的马赛克2？m堆叠等于158太字节，3）重建下丘脑-精氨酸发现的投射-将加压素和威廉姆斯综合征基因产物与来自连续图像的边缘靶的子集结合到单个连续数据集中，（4）自动重建轴突通路。我们的目标是创建和整合这套新的软件和神经生物学技术，以加速哺乳动物大脑的布线。这些技术将提供关键的缺失的框架所需的图像采集，操作的TB数据集，连续切片重建，自动和手动束跟踪，和基因特异性布线图或连接组的灵长类动物的大脑的规模和桥接轴突投影之间的差距差距和高分辨率的磁共振成像和DTI获得的非人类灵长类动物和人类的道。建立大脑网络图是现代神经生物学和医学的主要挑战之一，特别是遗传连接图。控制社会行为和情绪的大脑系统是最需要这种需求的，其中电路失调与最具破坏性的精神疾病，抑郁症，精神分裂症和自闭症有关，这些疾病共同影响了1300多万美国人。创造理解这些大脑系统的解决方案将广泛加速解开许多在其他神经系统疾病中受到干扰的电路的连接，包括帕金森氏症，阿尔茨海默氏症和成瘾。总之，我们正在创造的工具将通过提供与潜在大脑回路的遗传联系来改变精神疾病领域。这些知识将为预防、治疗并最终治愈精神疾病的新药靶点提供见解。