Vascular Signaling Plasticity - Novel Concepts and Tools for Studying Neurovascular Interactions in Health and Disease

总结 大脑需要大量的能量（约占身体总能量的20%）才能正常工作。 尽管如此，大脑缺乏能量储存，而是使用一种“及时”的能量输送系统， “功能性充血”，其中局部血流响应于神经元活动的尖峰而增加。这个过程 由一系列冗余的“神经血管耦合”机制支撑，这些机制共同确保了 血液流动对进食活动的反应。我们已经发现，这些机制显示出一种惊人的形式， 可塑性，其中神经元能量需求的慢性变化导致这些血管的重新编程， 信号机制，以增加或抑制血液的局部输送。我们称这种现象为血管 信号可塑性（VSP）。重要的是，VSP在阿尔茨海默病小鼠模型中被破坏，这意味着 该过程的丧失可能导致能量供给和需求之间的不匹配并损害神经元功能。 在这里，我们提出了一个研究计划，在该计划中，我们开发了VSP慢性成像的新工作流程， 清醒行为的动物，然后详细的分子分析的机制，基础VSP在 和我们想象的一样。这项工作将揭示一个以前未知和未知的机制，血液 大脑中的流量控制对神经元健康至关重要，开辟了该现象的新研究领域 的VSP。该项目的完成将提供一系列成像工具，使我们能够对血流进行成像， VSP方面的非侵入性在体内长时间，我们的工作将最终在发展一个 一种新的脑内皮特异性基因疗法，旨在保护或恢复痴呆症中的VSP， 保护神经元代谢和功能。

SUMMARY The brain requires a vast amount of energy (around 20% of the total generated in the body) to function normally. Despite this, the brain lacks energy stores and instead uses a ‘just-in-time’ energy delivery system known as ‘functional hyperemia’, in which local blood flow increases in response to spikes in neuronal activity. This process is underlain by a range of redundant ‘neurovascular coupling’ mechanisms that collectively ensure the fidelity of the blood flow response to feed activity. We have discovered that these mechanisms display a striking form of plasticity, in which chronic changes in neuronal energy requirements lead to reprogramming of these vascular signaling mechanisms to augment or dampen the local delivery of blood. We term this phenomenon vascular signaling plasticity (VSP). Importantly, VSP is disrupted in a mouse model of Alzheimer’s disease, implying that loss of this process may lead to a mismatch between energy supply and demand and impair neuronal function. Here, we propose a program of research in which we develop novel workflows for chronic imaging of VSP in awake behaving animals, followed by detailed molecular analyses of the mechanisms that underlie VSP in the same cells that we image. This work will reveal a previously unknown and unsuspected mechanism for blood flow control in the brain that is critical for neuronal health, opening a new field of research into the phenomenon of VSP. Completion of this project will deliver a range of imaging tools to enable us to image blood flow and aspects of VSP non-invasively over long periods in vivo, and our work will culminate in the development of a novel brain endothelium-specific gene therapy aimed at protecting or restoring VSP in dementia, thereby safeguarding neuronal metabolism and function.