Deciphering the Cerebral Microinfarct and its Role in Vascular Cognitive Impairment

项目摘要。 许多临床研究表明，脑微梗死可能与血管认知有关。 损害和痴呆症(VCID)。然而，这些小而普遍的病变导致 全脑神经功能障碍仍不清楚。我们的中心假设是微梗塞损伤会导致 神经损伤远远超出组织学和放射学中可见的限制性病变核心 考试。这些远程影响，当累积起来时，是一种机制，通过这种机制，微梗塞导致大量... 大脑功能的大规模破坏和认知能力下降。拟议研究的基本原理是使用一种 小鼠模型，可以控制微梗塞的时间和位置，以便更好地了解 它们如何导致大脑功能障碍。我们计划检查：i)功能的空间范围和时代性 单个微梗塞引起的损害，ii)多个微梗塞的累积效应，以及iii) 细胞/分子变化是其远程影响的基础。 我们的模型使用最先进的方法来控制靶向皮质穿透的光学遮挡 单个和多个小动脉精确地、非侵入性地形成小的缺血性损伤区域 它模仿了人类的微梗塞。然后，相关的损伤过程可以在体内研究随时间的变化 并行高分辨率双光子荧光钙成像和7T MRI显示 核磁共振或组织病理学可能看不到的大脑病理生理学。我们进一步使用行为 对微梗塞敏感以揭示其对感觉知觉和认知的影响的范式 功能。该项目的目标1验证了皮质微梗塞导致持续性神经元缺陷的假设 在它们在小鼠触觉感觉系统内的战略诱导之后，它们的损伤核心之外。它进一步 检查兴奋性-抑制性平衡的异常变化是否导致这些缺陷。目标2 项目测试的假设是多发性微梗塞的累积，在空间上分布在 两个大脑半球的皮质，足以引起皮质下白质变性(评估在 体内扩散磁共振成像和体外组织学检查)和认知任务中的损害。 这项工作将在几个方面补充VCID的临床研究。首先，它将提供详细的机制 关于微梗塞如何以及在多大程度上损害远程脑组织的信息。其次，它将澄清什么 微梗塞损伤的某些方面在MRI上是可见或不可见的，MRI是在 生活。第三，它将提供独特的在体MRI-体外组织病理学比较，以揭示潜在的 在灰质和白质损伤过程中导致MRI信号变化的生物过程。第四，它将建立 首个研究微梗死性病理机制的体内实验平台 评估新的治疗剂的效用。

Project Summary. Numerous clinical studies have shown that cerebral microinfarcts are likely contributors to vascular cognitive impairment and dementia (VCID). However, the mechanism by which these small, but prevalent lesions lead to brain-wide neural dysfunction remains unknown. Our central hypothesis is that microinfarct injury leads to neural impairments that extend well beyond the restricted lesion cores seen during histological and radiological examination. These remote effects, when accumulated, are a mechanism by which microinfarcts cause large- scale disruption of brain function and cognitive decline. The rationale of the proposed research is to use a mouse model where the timing and location of microinfarcts can be controlled in order to better understand how they cause brain dysfunction. We plan to examine: i) the spatial extent and chronicity of functional impairments induced by individual microinfarcts, ii) the cumulative effects of multiple microinfarcts, and iii) the cellular/molecular changes that underlie their remote effects. Our model uses state-of-the-art methods for controlled optical occlusion of targeted cortical penetrating arterioles, individually and in multiples, to precisely and non-invasively form small regions of ischemic injury that mimic human microinfarcts. The associated injury processes can then be studied in vivo over time using parallel high-resolution two-photon fluorescence calcium imaging and 7T MRI to reveal detailed aspects of brain pathophysiology that are potentially invisible to MRI or histopathology. We further use behavioral paradigms that are sensitive to microinfarcts to uncover their effects on sensory perception and cognitive function. Aim 1 of the project tests the hypothesis that cortical microinfarcts induce sustained neuronal deficits beyond their lesion core following their strategic induction within the mouse vibrissa sensory system. It further examines whether aberrant change in excitatory-inhibitory balance contributes to these deficits. Aim 2 of the project tests the hypothesis that the accumulation of multiple microinfarcts, spatially distributed throughout the cortices of both cerebral hemispheres, is sufficient to cause subcortical white matter degeneration (assessed in vivo with diffusion MRI tractography and ex vivo with histology) and impairment in cognitive tasks. This work will complement clinical research on VCID in several ways. First, it will provide detailed mechanistic information on how, and to what extent, microinfarcts impair remote brain tissues. Second, it will clarify what aspects of microinfarct injury are visible or invisible to MRI, the primary means to detect these lesions during life. Third, it will provide unique in vivo MRI-ex vivo histopathology comparisons to reveal the underlying biological processes that cause MRI signal change during gray and white matter injury. Fourth, it will establish a first-of-its-kind in vivo experimental platform to study mechanisms of microinfarct-induced pathology and to gauge the utility of new therapeutic agents.