Microvascular Function and Neuroplasticity after Stroke

中风后，大脑启动一个精细的修复过程，涉及神经元连接的重新连接和 中风周围存活组织的重组。就像神经元一样，血管系统也经历了戏剧性的 重组。血管生成等机制被认为可以在共存的情况下改善血流 炎症细胞黏附和慢性收缩等机制会阻碍血流。目前还不清楚是如何做到的 这些机制相互作用，影响卒中慢性期的梗塞周围血流灌注，以及它们可能的作用方式。 在恢复过程中影响脑功能的重新定位。我们的长期目标是确定关键因素， 影响梗塞周围存活神经元的重新连接和重新映射，并以一种方式对它们进行调制 这加强了复苏进程。为了实现这一目标，该项目的重点是 了解中风后微血管的变化如何影响神经元连接的可塑性。作为一名 模型，我们将在小鼠触觉系统中创建光血栓形成的中风，以模仿小的、可存活的中风 常见于人类。神经血管单位的组成部分，包括突触前和突触后神经元 结构和微血管，将使用体内双光子技术在功能恢复的几周内进行动态跟踪 激光扫描显微镜。我们将使用一种新型的薄头骨颅窗，以避免假冒 手术引起的炎症的影响，从而使观察脑重构成为可能。 颅内环境。我们的中心假设是，微血管血流的异常可能对 影响中风慢性期的神经元重新连接。我们进一步假设，康复范例 促进功能恢复，减轻微血管功能障碍，改善神经元重塑。这些 假说将通过三个具体目标进行检验。在目标1中，我们计划确定现有的 神经元可塑性的基准，即树突棘和轴突数量，受到慢性、 卒中引起的微血管密度和灌注量的变化。在目标2和目标3中，我们计划确定如何 重复使用康复训练和大脑皮层电刺激对这些指标有影响。我们期待着 这项工作将对慢性微血管变化在中风康复中的作用提供洞察力。它将进一步 开发一种新的基于成像的实验框架，用于未来的机制研究。

The brain initiates an exquisite process of repair after a stroke, involving rewiring of neuronal connections and reorganization of surviving tissue around the stroke. As with neurons, the vasculature also undergoes dramatic reorganization. Mechanisms such as angiogenesis are postulated to improve blood flow while co-existing mechanisms such as inflammatory cell adhesion and chronic constriction can impede flow. It is unknown how these mechanisms interplay to affect peri-infarct perfusion in the chronic stages of stroke, and how they might influence the remapping of brain function during recovery. Our long-term goal is to determine key factors that influence the rewiring and remapping of surviving neurons in peri-infarct areas, and to modulate them in a way that enhances the recovery process. The focus of this project, toward the achievement of this goal, is to understand how microvascular changes after stroke influence the plasticity of neuronal connections. As a model, we will create photothrombotic strokes in the mouse vibrissa system to mimic small, survivable strokes often seen in humans. Components of the neurovascular unit, including pre- and postsynaptic neuronal structures and microvessels, will be tracked dynamically over weeks of functional recovery using in vivo twophoton laser-scanning microscopy. We will use a novel thinned-skull cranial window that avoids the spurious effects of surgically induced inflammation, thus enabling the observation of brain remodeling in a natural intracranial environment. Our central hypothesis is that anomalies in microvascular blood flow can negatively influence neuronal rewiring in chronic stages of stroke. We further hypothesize that rehabilitative paradigms to enhance functional recovery alleviate microvascular dysfunction and improve neuronal remodeling. These hypotheses will be tested through three specific aims. In Aim 1, we plan to determine whether existing benchmarks of neuronal plasticity, i.e., dendritic spine and axon bouton number, are influenced by chronic, stroke-induced changes in microvascular density and perfusion. In Aims 2 and 3, we plan to determine how rehabilitative training by repetitive use and cortical electrical stimulation impacts these indices. We expect that this work will provide insight on the role of chronic microvascular changes in stroke recovery. It will further develop a novel imaging-based experimental framework for future mechanistic studies.