Photoacoustic Microscopy of the Awake Mouse Brain

清醒小鼠大脑的光声显微镜

• 批准号: 10106311
• 负责人: Song Hu
• 金额: $ 19.59万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-14 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10106311
• 关键词: Photoacoustic; Microscopy; Awake; Mouse; Brain

PROJECT SUMMARY A long-standing technical challenge in neuroscience is high-resolution functional and molecular imaging of the awake mouse brain. The need is evident and pressing, because anesthesia can significantly reduce the overall brain activity and alter multiple forms of brain dynamics. The profound effects of anesthesia may confound the readouts of conventional microscopies, which require preparations of anesthetized animals, and thus impose significant limitations on the interpretation and translation of basic neuroscience findings. Moreover, incapable of imaging the awake brain for direct comparison with the anesthetized counterpart, conventional microscopies are of very limited utility in examining the important yet elusive roles of general anesthesia in the progression of multiple life-threatening brain disorders (e.g., ischemic stroke and Alzheimer's disease, which are the leading causes of death and disability in the United States). In addressing this challenge, recent efforts have extended the scope of fluorescence microscopy to the awake brain. While this molecular imaging technology advances and rapidly expands our understanding of the neural activities underlying behavior, high-resolution functional imaging of the coevolving hemodynamics falls far behind. This project aims to bridge the increasing technology gap by developing a first-of-a-kind photoacoustic microscopy (PAM) instrumentation for functional imaging of cerebral hemodynamics and metabolism at high spatiotemporal resolution in awake mice. The unprecedented speed of the proposed awake-brain PAM (1 MHz A-line rate), enabled by the innovative designs of wide-field optical-mechanical hybrid scan and MHz-repetition-rate dual-wavelength Raman laser, will exceed that of the existing multi-parametric PAM by two orders of magnitude and will enable spatiotemporal visualization of the functional and metabolic responses of the brain to neural stimulations and disease onsets without the influence of anesthesia. The complementary algorithms for statistical, spectral and correlation analysis of the same PAM dataset will further push the technology envelope by enabling simultaneous and comprehensive quantification of the total concentration and oxygen saturation of hemoglobin, blood flow and perfusion, and metabolic supply and demand at the microscopic level. This technology innovation will open up new and exciting opportunities in basic and translational neuroscience, including the mechanistic study of anesthetic neuroprotection in ischemic stroke proposed in this project. In turn, this stroke study will provide an ideal setting to assess the potential of awake-brain MHz-PAM in the context of a clinically important brain disease and pave the way for future studies of neurovascular coupling and neuromodulation in the awake brain. These efforts, together, hold the potential to establish PAM as a new enabling technology in brain research.

项目摘要 神经科学中的长期技术挑战是高分辨率的功能和分子成像 清醒的老鼠大脑。需求是显而易见和紧迫的，因为麻醉可以大大减少整体 大脑活动并改变多种形式的大脑动力学。麻醉的深刻作用可能会混淆 需要制备麻醉动物的常规显微镜的读数，因此施加 基本神经科学发现的解释和翻译的重大局限性。而且，无能为力 成像清醒大脑以直接与麻醉的对应物进行直接比较 在检查全身麻醉在进展中的重要但难以捉摸的作用方面的实用性非常有限 多种威胁生命的脑疾病（例如，缺血性中风和阿尔茨海默氏病，这是领先的 美国的死亡和残疾原因）。在应对这一挑战时，最近的努力已扩大 荧光显微镜与清醒大脑的范围。而这种分子成像技术的进步 并迅速扩展我们对高分辨率功能的神经活动的理解 共同进化的血液动力学的成像远远落后。该项目旨在弥合不断增长的技术 通过开发首个光声学显微镜（PAM）仪器的差距，以进行功能成像 在清醒小鼠的高时空分辨率下，脑血液动力学和代谢。前所未有的 拟议的醒目 - 脑PAM的速度（1 MHz A-Line速率），由宽场设计实现 光学机电混合动力扫描和MHz重复速率双波长拉曼激光将超过 现有的多参数通过两个数量级，将使时空可视化 大脑对神经刺激和疾病的功能和代谢反应而没有影响 麻醉。同一PAM的统计，光谱和相关分析的互补算法 数据集将通过同时且全面的量化来进一步推动技术信封 血红蛋白的总浓度和氧饱和度，血流和灌注以及代谢供应 和在微观水平上的需求。这项技术创新将在 基本和转化神经科学，包括缺血性麻醉神经保护的机械研究 该项目提出的中风。反过来，这项中风研究将为评估潜力提供理想的环境 在临床上重要的脑部疾病的背景下，清醒的MHz-PAM为未来的研究铺平了道路 清醒大脑中神经血管耦合和神经调节的作用。这些努力共同发挥了潜力 将PAM确立为大脑研究中的新技术。