Volumetric optical connectome microscopy of human cerebellar circuitry

人体小脑回路的体积光学连接组显微镜

• 批准号: 10245316
• 负责人: Hui Wang
• 金额: $ 24.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-08 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10245316
• 关键词: 3-Dimensional; Activities of Daily Living; Advocate; Affect; Anatomy; Architecture; Ataxia; Atlases; Atrophic; Autopsy; Award; Awareness; Axon; Back; Biological Markers; Biomedical Technology; Boa; Brain; Brain Diseases; Brain Stem; Cell Nucleus; Cerebellar Ataxia; Cerebellar Diseases; Cerebellum; Characteristics; Clinical; Clinical Research; Clinical assessments; Cognitive; Communities; Complement; Complex; Data; Data Set; Degenerative Disorder; Development; Diagnosis; Disease; Disease Progression; Emotional; Environment; Face; Failure; Fiber; General Hospitals; Goals; Histology; Human; Image; Incidence; Individual; Interdisciplinary Study; Interneurons; Intervention; Knowledge; Label; Lead; Lobule; Location; Magnetic Resonance Imaging; Maps; Massachusetts; Measures; Mentors; Methods; Microscopic; Microscopy; Modeling; Morphology; Multiple System Atrophy; Nerve Degeneration; Neuroanatomy; Neurobiology; Neurodegenerative Disorders; Neurons; Neurosciences; Optical Coherence Tomography; Optics; Output; Pathologic; Pathology; Pathway interactions; Pattern; Phase; Phenotype; Population; Principal Investigator; Research; Research Personnel; Research Project Grants; Resolution; Role; Sampling; Scanning; Science; Slice; Spinocerebellar Ataxias; Structure; Techniques; Technology; Testing; Therapeutic Intervention; Tissues; Training; Training Programs; Work; Writing; base; brain circuitry; brain health; brain tissue; clinical diagnostics; cognitive function; connectome; experience; gray matter; histological stains; human disease; in vivo; light microscopy; microscopic imaging; multidisciplinary; nervous system disorder; neuroimaging; neuropathology; novel marker; polarized light; preservation; programs; reconstruction; scale up; skills; tool; ultra high resolution; white matter

Project Summary/Abstract The goal in seeking a K99/R00 Pathway to Independence Award is to establish myself as an independent principal investigator to study the structural-functional relationship of the brain circuitry in normal and brain disorders. The proposed project, driven by the need for understanding the human brain with high-resolution high-throughput tools and my extensive experience in biomedical optics for neuroimaging, aims to establish a versatile tool to reconstruct the circuitry and neuronal architecture in human cerebellum, understand the disruptive impacts of cerebellar degenerative disease, and combine with MRI models to seek novel biomarkers that will potentially influence the clinical assessment. Despite the tremendous advances of light microscopy since Santiago Ramón y Cajal's pioneering work in drafting axonal tracts, our knowledge on how the 80-100 billions of neurons connect together to form complex functions in human brain is still limited. Presently, there is no volumetric microscopy technique that can map the circuitry and architecture of human brain with high integrity. Here I propose to develop a volumetric optical connectome microscopy (VOCM), for reconstructing the human cerebellum with unprecedented resolution and scales, and mapping the connectivity and neuronal architectures from a global perspective. VOCM is based on a polarization sensitive optical coherence tomography and a vibratome slicer to image large-scale ex vivo brain at a micrometer-scale resolution. Importantly, this technology allows volumetric reconstruction preserving an ultra-high accuracy without tissue distortions; therefore overcomes the 100 years challenge of all histology based methods in tracing long fiber tracts and inspecting sophisticated cortical folding in the human brain. The high-quality data generated by VOCM will be fit into MRI models to construct an ultra-high resolution atlas of human cerebellum to provide anatomical labels that are not available in current MRI tools. By applying VOCM, the project further explores 3D pathological patterns of cerebellar disorder. Multiple system atrophy cerebellar type (MSA-C) is a fatal neurodegenerative disease manifested by severe cerebellar and brainstem atrophy. Despite its rare incidence, MSA-C shares common phenotypic characteristics with other neurological diseases. Studying the neuroanatomical substrates and pathological trajectory of MSA-C could advance our understanding of the impact of cerebellar disorders and cerebellar affected diseases. Particularly, the project will characterize the architecture and circuitry disruptions associated with neurodegeneration in MSA-C. We will then use the high-resolution ex vivo dataset to make predictions in vivo, and allow an MRI assessment that would not be possible otherwise. The proposed research is conducted at Martinos Center, Massachusetts General Hospital (MGH), which is an ideal environment developing cutting edge biomedical technologies and interacting with a large community of experts with multidisciplinary background. I have formed a strong mentoring team: Dr. Bruce Fischl, director of the Computational Core at Martinos Center; Dr. David Boas, director of the Optics Division at Martinos Center; and Dr. Jeremy Schmahmann, director of the MGH Ataxia Unit. I will leverage formal trainings in MRI modeling and analysis, cerebellar related brain diseases and neuropathology. The coursework on neuroanatomy, neurobiology and central nervous diseases complement my biomedical optics background and advance my knowledge on important neuroscience questions. The proposed trainings and research will prepare me with necessary skills, new tools, and intriguing data to launch an independent research program and writing further research grants after the completion of the R00 phase. I expect that the research will dramatically advance our current knowledge on brain science, have an impact on clinical revolutions, and advocate public awareness of brain health in greater populations.

项目摘要/摘要 寻求K99/R00途径获得独立奖的目标是将自己确立为独立 主要研究者研究正常和大脑中脑电路的结构功能关系 疾病。拟议的项目是由高分辨率理解人脑的需求的驱动 高通量工具和我在生物医学光学上进行神经影像学的丰富经验，旨在建立一个 在人小脑中重建电路和神经元建筑的多功能工具，了解 小脑退行性疾病的破坏性影响，并与MRI模型相结合以寻求新型生物标志物 这可能会影响临床评估。 尽管自圣地亚哥·拉蒙（SantiagoRamón）y Cajal的开创性工作以来，光学显微镜取得了巨大进步 绘制轴突区域，我们了解8000亿个神经元如何连接在一起形成复杂的知识 人脑中的功能仍然有限。目前，没有可以映射的体积显微镜技术 具有高完整性的人脑的电路和结构。在这里，我建议开发体积光学 Connectome显微镜（VOCM），用于以前所未有的分辨率重建人小脑 从全球角度来看鳞片，并绘制连通性和神经元体系结构。 VOCM是基于 极化敏感的光学相干断层扫描和一个纤维化切片机，以形象大尺寸的离体大脑 在千分尺尺度的分辨率下。重要的是，该技术允许数量重建保存 没有组织变形的超高精度；因此克服了所有组织学的100年挑战 基于追踪长纤维区域和检查人脑中复杂的皮质折叠的方法。这 VOCM生成的高质量数据将适合MRI模型，以构建超高分辨率的地图集 人类小脑提供当前MRI工具中无法使用的解剖标签。 通过应用VOCM，该项目进一步探讨了小脑疾病的3D病理模式。多系统 小脑萎缩类型（MSA-C）是一种致命的神经退行性疾病，由严重的小脑和 脑干萎缩。尽管有罕见的事件，但MSA-C与其他共同的表型特征与其他 神经疾病。研究MSA-C的神经解剖底物和病理轨迹可能 促进我们对小脑疾病和小脑影响疾病的影响的理解。特别， 该项目将表征与神经变性相关的架构和电路中断 MSA-C。然后，我们将使用高分辨率EX VIVO数据集在体内进行预测，并允许MRI 否则不可能的评估。 拟议的研究是在马萨诸塞州综合医院（MGH）的马蒂诺斯中心进行的，这是 理想的环境开发尖端生物医学技术，并与大型社区互动 具有多学科背景的专家。我组成了一个强大的心理团队：布鲁斯·菲斯尔（Bruce Fischl）博士 马提尼斯中心的计算核心；马蒂诺斯中心（Martinos Center）光学部主任David Boas博士； MGH共济失调部门主任Jeremy Schmahmann博士。我将利用MRI建模的正式培训 和分析，小脑相关的脑疾病和神经病理学。神经解剖学的课程， 神经生物学和中枢神经疾病完成我的生物医学光学背景，并推进我的 有关重要神经科学问题的知识。拟议的培训和研究将为我做好准备 必要的技能，新工具和有趣的数据来启动独立研究计划并进一步撰写 R00阶段完成后的研究补助金。我希望这项研究将极大地推动我们的 当前关于脑科学的知识，对临床革命产生影响，并提倡公众对 人群中的大脑健康。