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.

这项研究的主要重点是表征在功能充血中的细胞机制 大脑皮层。功能性充血与神经元之间的通信的关系， 星形胶质细胞和脑微循环。信号通路的干扰导致适当的 多血症反应与许多病理有关，包括高血压，中风，偏头痛， 并散布抑郁症，以提到一些。尽管功能性充血发生在几秒钟内 介导这种快速信号反应的基本机制仍有待定定义。这个项目将 解决三个主要目的：首先，确定星形胶质细胞是否是神经血管耦合中的中介（AIM 1）。其次，确定星形胶质细胞与实质动脉沟通的机制是否是否 诱导血管舒张，这是由Ca2+激活的K+（BK）通道的快速激活以及释放 K+进入星形胶质细胞和血管细胞之间的狭窄空间。也确定是否 环氧酸性酸会导致星形胶质细胞端口中BK通道的激活，从而扩大了 星形胶质细胞和血管之间的信号通信（AIM 2）。第三，确定是否兼有 高血压期间神经血管单位发生功能和结构改变（AIM 3）。我们 假设在神经元刺激之后，星形胶质细胞中细胞内Ca2+的上升激活了BK 星形胶质细胞端的通道导致K+快速释放（强力降压剂）在之间 终脚和血管细胞。 Ca2+的上升还增加了环氧酸性的产生 在星形胶质细胞终端中作用于BK通道的酸进一步激活这些通道。因为 神经元，asttrocytes和实质动脉的功能和解剖学变化与一个相关 另一个是对神经胶质血管网络中沟通方式的理解 生理状况将提供有关高血压等病理的见解，这些病理影响一个或多个 在这三个构成神经血管单元的细胞成分中。