Imaging Neuronal and Capillary Dysfunction Deep in the Rodent Brain in vivo Using 1700 NM Optical Coherence Microscopy and Tracer-Based Kinetics

使用 1700 NM 光学相干显微镜和基于示踪剂的动力学对啮齿动物大脑深处的神经元和毛细血管功能障碍进行体内成像

• 批准号: 10374266
• 负责人: Vivek Jay Srinivasan
• 金额: $ 33.35万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-07 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374266
• 关键词: Imaging; Neuronal; Capillary; Dysfunction; Deep

Abstract: Subcortical pathology is a common feature in aging, Alzheimer's disease and vascular dementia but has been extremely difficult to study with micron resolution in vivo. Optical methods such as two-photon microscopy image the superficial cortex at the micron-scale, but the resolution of these conventional microscopic methods degrades rapidly beyond 600 microns imaging depth. Standard whole-brain magnetic resonance imaging (MRI) methods do not yet provide cellular-level resolution and are often expensive to implement. Thus, there is a pressing need for methods to directly assess deep cortical and subcortical perfusion and cellular injury at the microscopic level, thus bridging the gap between existing superficial optical microscopy and macroscopic imaging. This proposal will develop and apply novel optical imaging technologies and accompanying methods to directly investigate subcortical (hippocampal and white matter) cellular and vascular changes in genetic mouse models of disease, without the need for transgenic expression of fluorescent proteins. We propose to develop and validate methods to quantify transit time distribution at the single capillary level; combine these with methods to measure neuronal cell viability, myelination, plaque distribution, atrophy; and finally, to longitudinally image the time course of deep cortical and hippocampal injury in a mouse model of Alzheimer's disease up to a depth of 2 mm. These techniques will have a widespread impact in preclinical experimental research in therapeutics and biomarker discovery, and will advance the study of white matter injury and subcortical dementia. The initial development, validation, and demonstration proposed here will catalyze the widespread adoption of these novel techniques to study subcortical pathophysiology non-invasively in the mouse brain.

抽象的： 皮层病理学是衰老，阿尔茨海默氏病和血管性痴呆的常见特征，但一直是 通过在体内分辨率下分辨率非常困难。光学方法，例如两光子显微镜 在微米尺度上对表面皮质进行图像，但是这些常规微观方法的分辨率 迅速降解超过600微米的成像深度。标准的全脑磁共振成像 （MRI）方法尚未提供细胞级分辨率，并且实施通常昂贵。因此，那里 是对直接评估深层皮质和皮质下灌注以及细胞损伤的迫切需求 显微镜水平，从而弥合了现有的浅表光学显微镜和宏观之间的差距 成像。该建议将开发并应用新颖的光学成像技术和随附的方法 直接研究遗传的皮质下（海马和白质）细胞和血管变化 小鼠疾病模型，无需荧光蛋白的转基因表达。我们建议 开发和验证在单个毛细管水平上量化运输时间分布的方法；结合这些 使用测量神经元细胞活力，髓鞘，斑块分布，萎缩的方法；最后，到 纵向图像阿尔茨海默氏症小鼠模型中深层皮质和海马损伤的时间过程 疾病深度为2毫米。这些技术将对临床前实验产生广泛影响 治疗和生物标志物发现研究，并将进步研究白质损伤和 皮质下痴呆。此处提出的最初发展，验证和示范将催化 这些新型技术广泛地采用了非侵入性研究下皮质病理生理学 小鼠大脑。