Signals and targets underlying mechanisms for neurovascular coupling in the brain

大脑神经血管耦合的信号和目标潜在机制

• 批准号: 8059688
• 负责人: JESSICA A FILOSA
• 金额: $ 29.4万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059688
• 关键词: Acids; Address; Affect; Astrocytes; Blood Vessels; Brain; Calcium; Calcium-Activated Potassium Channel; Cells; Cerebral cortex; Cerebrovascular Circulation; Cerebrum; Chronic; Communication; Coupling; Disease; Event; Glucose; Glutamates; Health; Hyperemia; Hypertension; Ions; Learning; Light; Link; Mediating; Mediator of activation protein; Metabolic; Microcirculation; Migraine; Muscle Cells; Nature; Neuroglia; Neurons; Neurotransmitters; Oxygen; Pathology; Pattern; Physiological; Potassium; Potassium Channel; Preparation; Process; Production; Property; Rattus; Research Personnel; Signal Pathway; Signal Transduction; Slice; Smooth Muscle Myocytes; Stroke; Synapses; Vasodilation; Vasodilator Agents; Work; arteriole; cell type; extracellular; gamma-Aminobutyric Acid; innovation; insight; intercellular communication; large-conductance calcium-activated potassium channels; multidisciplinary; neurovascular unit; programs; relating to nervous system; response; spreading depression; vasoconstriction

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.

本研究的主要重点是表征功能性充血的细胞机制， 大脑皮层功能性充血是神经元之间交流的一种功能， 星形胶质细胞和大脑微循环。信号通路的紊乱导致了 充血反应与许多病理学有关，包括高血压，中风，偏头痛， 和扩散性抑郁症虽然功能性充血发生在几秒钟内， 介导这种快速信号应答的潜在机制仍有待确定。该项目将 提出三个主要目标：首先，确定星形胶质细胞是否是神经血管偶联的中介（Aim 1）。第二，为了确定星形胶质细胞与实质小动脉沟通的机制， 诱导血管舒张，由Ca 2+激活的K+（BK）通道的快速激活和 K+进入星形胶质细胞端足和血管细胞之间的狭窄空间。同时也要确定 环氧二十碳三烯酸有助于激活星形胶质细胞终足中的BK通道， 星形胶质细胞和血管之间的信号传递（Aim 2）。第三，确定两者 在高血压期间，神经血管单元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Ca 2+升高激活了BK 星形胶质细胞终足中的通道导致K+（一种强血管扩张剂）在间隙中的快速释放 尾足和血管细胞。Ca 2+的增加也增加了环氧二十碳三烯酸的产生。 作用于星形胶质细胞末足中BK通道的酸进一步激活这些通道。因为 神经元、星形细胞和实质小动脉的功能和解剖学变化与一个 另一个是对神经-胶质-血管网络内通讯模式的理解， 生理条件将提供关于病理学的见解，例如高血压，其影响一个或多个 这三种细胞成分构成了神经血管单位。