Signals and targets underlying mechanisms for neurovascular coupling in the brain

描述（由申请人提供）：本研究的主要重点是描述大脑皮层功能性充血的细胞机制。功能性充血是神经元、星形胶质细胞和大脑微循环之间交流的一种功能。导致适当充血反应的信号通路紊乱与许多疾病有关，包括高血压、中风、偏头痛和扩散性抑郁症，仅举几例。虽然功能性充血在几秒钟内发生，但介导这种快速信号反应的潜在机制仍有待确定。该项目将解决三个主要目标：首先，确定星形胶质细胞是否是神经血管耦合的中介（目的1）。其次，确定星形胶质细胞与实质小动脉沟通并诱导血管舒张的机制是否源于Ca2+激活的K+ (BK)通道的快速激活以及K+释放到星形胶质细胞终足和血管细胞之间的狭窄空间。此外，为了确定环氧二碳三烯酸是否有助于星形细胞终足中BK通道的激活，从而放大星形细胞与血管之间的信号交流（目的2）。第三，确定高血压期间神经血管单元是否发生功能和结构改变（目的3）。我们假设，在神经元刺激后，星形胶质细胞内Ca2+的升高激活了星形胶质细胞终足的BK通道，导致终足和血管细胞之间的空间快速释放K+（一种强血管扩张剂）。Ca2+的增加也增加了环氧二碳三烯酸的产生，它作用于星形细胞终足的BK通道，进一步激活这些通道。由于神经元、星形胶质细胞和实质小动脉的功能和解剖变化是相互联系的，因此了解生理条件下神经-胶质-血管网络内的交流模式将有助于了解诸如高血压等影响构成神经血管单元的这三种细胞成分中的一种或多种的病理。

DESCRIPTION (provided by the applicant): The main focus of this study is to characterize the cellular mechanisms underlying functional hyperemia in the cerebral cortex. Functional hyperemia occus as a function of the communication between neurons, astrocytes and the cerebral microcirculation. Disturbances in the signaling pathways leading to the proper hyperemic response have been linked to a number of pathologies including hypertension, stroke, migraine, and spreading depression, to mention a few. Although functional hyperemia occurs within seconds, the underlying mechanisms mediating such rapid signaling response are still to be defined. This project will address three major aims: First, to determine if astrocytes are intermediaries in neurovascular coupling (Aim 1). Second, to determine if the mechanism by which astrocytes communicate with parenchymal arterioles, to induce vasodilation, results from the rapid activation of Ca2+-activated K+ (BK) channels and the release of K+ into the narrow space between the astrocytic endfoot and vascular cells. Also to determine if epoxyeicosatrienoic acids contribute to the activation of BK channels in the astrocytic endfeet amplifying the signaling communication between astrocytes and blood vessels (Aim 2). Third, to determine if both functional and structural alterations occur in the neurovascular unit during hypertension (Aim 3). We hypothesize that following neuronal stimulation, the rise in intracellular Ca2+ in the astrocytes activated BK channels in astrocytic endfeet resulting in the rapid release of K+ (a strong vasodilator) in the space between the endfoot and the vascular cells. The rise in Ca2+ also increases the production of epoxyeicosatrienoic acids which act on BK channels in the astrocytic endfeet further activating these channels. Because functional and anatomical changes in neurons, asttrocytes and parenchymal arterioles are linked to one another, an understanding of the modes of communication within the neural-glial-vascular network under physiological conditions will provide insights on pathologies, such as hypertension, which affect one or more of these three cellular components constituting the neurovascular unit.