Signals and targets underlying mechanisms for neurovascular coupling in the brain

描述(由申请人提供)：这项研究的主要焦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、星形胶质细胞和脑微循环之间通讯的一种功能。导致适当充血反应的信号通路的紊乱与许多病理疾病有关，包括高血压、中风、偏头痛和扩散性抑郁，仅举几例。尽管功能性充血在几秒钟内就会发生，但调节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：第一，确定星形胶质细胞是否是神经血管偶联的中介(目标1)。其次，为了确定星形胶质细胞与实质小动脉沟通、诱导血管扩张的机制是否源于钙激活的钾(BK)通道的快速激活和K的释放进入星形细胞终足和血管细胞之间的狭窄空间。此外，为了确定环氧二十碳三烯酸是否有助于激活星形细胞末端的BK通道，放大星形胶质细胞和血管之间的信号交流(目标2)。第三，确定高血压期间神经血管单位是否同时发生功能和结构变化(目标3)。我们推测，在神经元刺激后，星形胶质细胞内钙的升高激活了星形胶质细胞终足的BK通道，导致K(一种强血管扩张剂)在终足和血管细胞之间的间隙迅速释放。钙的升高也增加了环氧二十碳三烯酸的产生，环氧二十碳三烯酸作用于星形细胞末端的BK通道，进一步激活了这些通道。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，了解生理条件下神经-神经胶质-血管网络内的通信模式将有助于深入了解病理，如高血压，这些疾病会影响构成神经血管单位的这三个细胞成分中的一个或多个。

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.