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

基本信息

批准号：
9011238
负责人：
Vivek Jay Srinivasan
金额：
$ 28.66万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-01 至 2020-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): 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.

描述（由应用提供）：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，但由于体内微分辨率，很难研究。光学方法，例如两光子显微镜图像微米尺度上的表面皮层，但是这些常规显微镜方法的分辨率迅速降低了600微米的成像深度。标准的全脑磁共振成像（MRI）方法尚未提供细胞水平的分辨率，并且通常昂贵。这是在微观水平上直接评估深层皮质和皮层灌注以及细胞损伤的方法的紧迫，从而弥合了现有的浅表光学显微镜和宏观成像之间的间隙。该建议将开发并应用新颖的光学成像技术和参与方法，以直接研究疾病的遗传小鼠模型中的皮质下（海马和白质）细胞和血管变化，而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；将这些与测量神经元细胞活力，髓鞘，斑块分布，萎缩相结合；最后，纵向图像深皮层的时间过程在阿尔茨海默氏病小鼠模型中，海马损伤直至2 mm。这些技术将在治疗和生物标志物发现方面的临床前实验研究中产生宽度的影响，并将推进对白质损伤和皮质下痴呆的研究。此处提出的最初发展，验证和演示将催化这些新技术的宽度采用，以在小鼠脑中无创地研究皮质下病理生理学。