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

与压力相关的激素肾上腺素和去甲肾上腺素长期以来一直被认为可以介导全身血管的收缩，以帮助将富含氧气的血液重新引导到最需要的区域。然而，目前尚不清楚大脑的去甲肾上腺素系统是否具有类似的功能。在这个应用程序中，我建议检查的作用，去甲肾上腺素介导的脑血管收缩在血流再分配响应特定的大脑区域激活。我将首先在全球范围内使用内在光学成像通过一个大的开口在头骨上有或没有激活的大脑去甲肾上腺素能系统，以评估去甲肾上腺素的影响的血流模式。然后，我将使用激光扫描显微镜技术更深入地研究去甲肾上腺素能效应背后的细胞机制，也可以通过头骨中的开口，在特殊的转基因小鼠中，可以评估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）的反应。 脑血流的典型研究是在麻醉条件下进行的，这阻止了去甲肾上腺素能系统的任何潜在作用的观察。去甲肾上腺素能系统通过调节大脑的行为状态将我们与环境联系起来，因此只有在几乎有意识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能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，将补充现有的知识，去甲肾上腺素在调节组织代谢中的作用，并强调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.