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: 9343056
• 负责人: Vivek Jay Srinivasan
• 金额: $ 33.52万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/9343056
• 关键词: Address; Adoption; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Atrophic; Benign; Biological Markers; Blood Vessels; Blood capillaries; Blood flow; Brain; Brain imaging; Brain region; Cell Survival; Cerebrovascular Circulation; Cerebrum; Corpus Callosum; Coupling; Data; Dementia; Deposition; Development; Disease; Disease Progression; Disease model; Experimental Models; Functional disorder; Funding; Future; Genetic; Genetic Models; Graph; Hippocampus (Brain); Image; Imagery; Imaging technology; Injection of therapeutic agent; Injury; Kinetics; Magnetic Resonance Imaging; Measures; Memory; Metabolic; Metabolism; Methods; Microscope; Microscopic; Microscopy; Monitor; Mus; Natural History; Nerve Degeneration; Neurons; Neuropil; Optical Methods; Optics; Oxygen; Pathology; Penetration; Perfusion; Play; Proteins; Recovery; Regulation; Research Project Grants; Resolution; Rodent; Rodent Model; Role; Senile Plaques; Stroke; Structure; System; Techniques; Technology; Testing; Therapeutic; Thinness; Time; Tracer; Transgenic Organisms; Traumatic Brain Injury; United States National Institutes of Health; Validation; Vascular Dementia; Visible Radiation; Water; Work; absorption; base; biomarker discovery; brain tissue; capillary; cell injury; cerebral blood volume; cerebral capillary; cognitive function; cranium; experimental study; imaging modality; imaging study; imaging system; improved; in vivo; in vivo imaging; in vivo optical imaging; innovation; microscopic imaging; minimally invasive; mouse model; myelination; nervous system disorder; neural circuit; neuron loss; neuronal cell body; neurophysiology; neurovascular; neurovascular coupling; novel; optical imaging; pre-clinical; prevent; public health relevance; rapid technique; two-photon; white matter; white matter injury

 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（由申请人提供）：皮质下病理学是衰老、阿尔茨海默病和血管性痴呆的常见特征，但在体内用微米分辨率研究是极其困难的。诸如双光子显微镜的光学方法在微米级对表层皮层成像，但是这些常规显微镜方法的分辨率在超过600微米成像深度时迅速降低。标准的全脑磁共振成像（MRI）方法尚未提供细胞级分辨率，并且实施起来往往成本高昂。因此，迫切需要在微观水平上直接评估深层皮质和皮质下灌注和细胞损伤的方法，从而弥合现有表面光学显微镜和宏观成像之间的差距。该提案将开发和应用新的光学成像技术和相关方法，直接研究遗传性疾病小鼠模型中的皮质下（海马和白色物质）细胞和血管变化，而不需要荧光蛋白的转基因表达。我们建议开发和验证在单个毛细血管水平上量化传输时间分布的方法;联合收割机将这些方法与测量神经元细胞活力、髓鞘形成、斑块分布、萎缩的方法相结合;最后，纵向成像深部皮质的时间过程。 这些技术将在治疗学和生物标志物发现的临床前实验研究中产生广泛的影响，并将推进白色物质损伤和皮质下痴呆的研究。初步的发展，验证和示范提出这里将促进这些新技术的广泛采用，研究皮层下的病理生理非侵入性小鼠大脑。