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: 10414815
• 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 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10414815
• 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.

项目概要/摘要 寻求 K99/R00 独立之路奖的目标是让自己成为一个独立的人 首席研究员研究正常和大脑中脑回路的结构功能关系 拟议的项目是由高分辨率了解人脑的需求驱动的。 高通量工具和我在神经影像生物医学光学方面的丰富经验，旨在建立一个 重建人类小脑电路和神经结构的多功能工具，了解 小脑退行性疾病的破坏性影响，并结合 MRI 模型寻找新的生物标志物 这可能会影响临床评估。 尽管自圣地亚哥·拉蒙·卡哈尔 (Santiago Ramón y Cajal) 的开创性工作以来，光学显微镜取得了巨大进步 绘制轴突束，我们对 80-1000 亿个神经元如何连接在一起形成复杂的知识 目前，人类大脑的功能仍然有限，还没有可以绘制地图的体积显微镜技术。 在这里，我建议开发一种具有高度完整性的人脑电路和架构。 连接组显微镜（VOCM），以前所未有的分辨率重建人类小脑 VOCM 是基于全局视角绘制连接性和神经架构的。 偏振敏感光学相干断层扫描和振动切片机对大规模离体大脑进行成像 重要的是，该技术允许在微米级分辨率下进行体积重建。 超高精度，无组织变形；因此克服了所有组织学 100 年来的挑战； 基于追踪长纤维束和检查人脑中复杂的皮质折叠的方法。 VOCM生成的高质量数据将适合MRI模型，构建超高分辨率图谱 人类小脑提供当前 MRI 工具无法提供的解剖标签。 该项目通过应用VOCM，进一步探索小脑多系统疾病的3D病理模式。 小脑萎缩型（MSA-C）是一种致命的神经退行性疾病，表现为严重的小脑和 尽管脑干萎缩的发生率很少，但 MSA-C 与其他疾病具有共同的表型特征。 研究 MSA-C 的神经解剖学基础和病理轨迹可以帮助研究神经系统疾病。 增进我们对小脑疾病和小脑受影响疾病的影响的了解。 该项目将描述与神经退行性疾病相关的架构和电路中断的特征 然后，我们将使用高分辨率的离体数据集进行体内预测，并允许进行 MRI 否则不可能进行评估。 拟议的研究是在马萨诸塞州总医院 (MGH) 马蒂诺斯中心进行的，该中心是一家 开发尖端生物医学技术并与大型社区互动的理想环境 我组建了一支强大的导师团队：Bruce Fischl博士，主任。 马蒂诺斯中心计算核心；马蒂诺斯中心光学部门主任 David Boas 博士； 和 MGH 共济失调科主任 Jeremy Schmahmann 博士，我将利用 MRI 建模的正式培训。 和分析，小脑相关脑疾病和神经病理学，神经解剖学课程。 神经生物学和中枢神经疾病补充了我的生物医学光学背景并提高了我的水平 有关重要神经科学问题的知识将为我提供准备。 启动独立研究计划和进一步写作所需的技能、新工具和有趣的数据 R00 阶段完成后的研究资助我预计该研究将极大地推进我们的工作。 脑科学的最新知识，对临床革命产生影响，并倡导公众意识 更多人群的大脑健康。

项目成果

Near-Infrared Light Triggered-Release in Deep Brain Regions Using Ultra-photosensitive Nanovesicles.

使用超光敏纳米囊泡在大脑深部区域触发近红外光释放。

• 发表时间: 2020-05-25
• 作者: Xiong, Hejian;Li, Xiuying;Kang, Peiyuan;Perish, John;Neuhaus, Frederik;Ploski, Jonathan E;Kroener, Sven;Ogunyankin, Maria O;Shin, Jeong Eun;Zasadzinski, Joseph A;Wang, Hui;Slesinger, Paul A;Zumbuehl, Andreas;Qin, Zhenpeng
• 通讯作者: Qin, Zhenpeng

Optical coherence tomography of arteriolar diameter and capillary perfusion during spreading depolarizations.

扩散去极化期间小动脉直径和毛细血管灌注的光学相干断层扫描。

• 发表时间: 2021-09
• 作者: Anzabi, Maryam;Li, Baoqiang;Wang, Hui;Kura, Sreekanth;Sakadžić, Sava;Boas, David;Østergaard, Leif;Ayata, Cenk
• 通讯作者: Ayata, Cenk

Quantitative optical coherence microscopy of neuron morphology in human entorhinal cortex.

人内嗅皮层神经元形态的定量光学相干显微镜。

• 发表时间: 2023
• 作者: Wang, Hui;Gong, Dayang;Augustinack, Jean C;Magnain, Caroline
• 通讯作者: Magnain, Caroline

Optical measurement of microvascular oxygenation and blood flow responses in awake mouse cortex during functional activation.

功能激活过程中清醒小鼠皮层微血管氧合和血流反应的光学测量。

• 发表时间: 2022-03
• 作者: Şencan, İkbal;Esipova, Tatiana;Kılıç, Kıvılcım;Li, Baoqiang;Desjardins, Michèle;Yaseen, Mohammad A;Wang, Hui;Porter, Jason E;Kura, Sreekanth;Fu, Buyin;Secomb, Timothy W;Boas, David A;Vinogradov, Sergei A;Devor, Anna;Sakadžić, Sava
• 通讯作者: Sakadžić, Sava