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.

项目总结 神经科学中一个长期存在的技术挑战是高分辨率的功能和分子成像 唤醒小鼠的大脑。这一需求是显而易见和紧迫的，因为麻醉可以显著减少总体 大脑活动和改变多种形式的大脑动力学。麻醉的深远影响可能会使 常规显微镜的读数，这需要麻醉动物的准备，从而强制 在解释和翻译基本神经科学发现方面存在重大限制。而且，没有能力 对清醒的大脑进行成像，以便与麻醉的对应物进行直接比较，即常规显微镜 在检查全身麻醉在肿瘤进展中的重要而难以捉摸的作用方面的作用非常有限。 多种危及生命的脑部疾病(例如，缺血性中风和阿尔茨海默病，它们是 美国的死亡和残疾原因)。在应对这一挑战方面，最近的努力扩大了 将荧光显微镜的范围扩展到清醒的大脑。随着这种分子成像技术的进步 并迅速扩展了我们对潜在行为的神经活动的理解，高分辨率泛函 对共同进化的血流动力学的成像远远落后。该项目旨在为日益增长的技术搭建桥梁 GAP通过开发第一个用于功能成像的光声显微镜(PAM)仪器 清醒小鼠高时空分辨率下的脑血流动力学和代谢。史无前例的 建议的唤醒脑PAM(1 MHz A线速率)的速度，由广域的创新设计实现 光机混合扫描和MHz重复频率双波长拉曼激光器，将超过 现有的多参数PAM提高了两个数量级，并将使时空可视化成为可能 大脑对神经刺激和疾病发作的功能和代谢反应 麻醉剂的作用。同一PAM的统计、谱和相关分析的互补算法 DataSet将通过实现同步和全面量化进一步推动技术极限 血红蛋白的总浓度和血氧饱和度、血流量和灌注量以及代谢供应 以及微观层面的需求。这项技术创新将在以下领域开辟新的令人兴奋的机会 基础神经科学和翻译神经科学，包括麻醉神经保护在脑缺血中的机制研究 本项目中提出的中风。反过来，这项中风研究将提供一个理想的环境来评估潜在的中风 觉醒-脑MHz-PAM在一种临床重要脑部疾病的背景下，并为未来的研究铺平道路 清醒大脑中的神经血管耦合和神经调节。这些努力加在一起，蕴含着 将PAM确立为脑研究的一项新的使能技术。