Role of the locus coeruleus-norepinephrine network in the regulation of cerebral blood flow

长期以来，与压力相关的激素肾上腺素和去甲肾上腺素一直被认为可以调节全身血管的收缩，以帮助将富氧血液重新引导到最需要的区域。然而，目前尚不清楚大脑中的去甲肾上腺素系统是否具有类似的功能。在这项应用中，我建议研究去甲肾上腺素介导的脑血管收缩在响应特定脑区激活的血流重新分配中的作用。我将首先在全球范围内使用内部光学成像技术在有或没有激活大脑去甲肾上腺素系统的情况下通过颅骨上的一个大开口来表征血液流动模式，以评估去甲肾上腺素的影响。然后，我将使用激光扫描显微镜技术，也通过头骨上的开口，在特殊的转基因小鼠身上更深入地研究去甲肾上腺素作用背后的细胞机制，这种转基因小鼠能够评估反应中的星形胶质细胞和周细胞(已知与血管相关的支持性脑细胞类型)。 对大脑血流的典型研究是在麻醉条件下进行的，这种条件阻止了观察到去甲肾上腺素系统的任何潜在作用。去甲肾上腺素系统通过调节大脑的行为状态将我们与环境联系起来，因此只有在几乎清醒的未麻醉动物中才能完全发挥作用。这些研究首次系统分析了去甲肾上腺素系统在脑血流调节中的作用。更好地了解去甲肾上腺素在脑血流调节中的作用，将补充现有关于去甲肾上腺素在调节组织代谢中的作用的知识，并突出与其他血流调节途径的潜在相互作用。

The stress related hormones adrenaline and noradrenaline have long been known to mediate constriction of blood vessels throughout the body in order to help redirect the oxygen rich blood to areas of greatest need. It is not known, however, whether the noradrenaline systems of the brain serve a similar function. In this application, I propose to examine the role of noradrenaline-mediated constriction of brain blood vessels in blood flow redistribution in response to specific brain region activation. I will first characterize blood flow patterns on a global scale using intrinsic optical imaging through a large opening in the skull with or without activation of the brains noradrenergic system to evaluate the impact of noradrenaline. I will then delve more deeply into the cellular mechanisms behind the noradrenergic effects using laser scanning microscopy techniques, also through an opening in the skull, in special genetically modified mice that enable evaluation of astrocytes and pericytes (supportive brain cell types known to be associated with blood vessels) in the response. Typical studies of blood flow in the brain are performed under anesthetized conditions that prevents observation of any potential role for the noradrenergic system. The noradrenergic system connects us to our environment by modulating the brain's behavioral state and is thus only fully functional in nearly conscious unanesthetized animals. These studies respresent the first systematic analysis of the role of the noradrenergic system in brain blood flow regulation. Better understanding of the role noradrenaline plays in brain blood flow regulation will complement existing knowledge regarding the role of noradrenaline in regulating tissue metabolism and highlight the potential interplay with other blood flow regulatory pathways.