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.

这项研究的主要焦点是描述功能性充血的细胞机制。 大脑皮层。功能性充血眼球是神经元之间通讯的功能， 星形胶质细胞和脑微循环。信号通路中的干扰导致适当的 充血反应与许多病理因素有关，包括高血压、中风、偏头痛、 以及蔓延的抑郁症，仅举几例。虽然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。这个项目将 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(AIM)的中介 1)。其次，为了确定星形胶质细胞与实质小动脉沟通的机制， 诱导血管扩张，结果是快速激活钙激活的钾(BK)通道和释放 K+进入星形细胞端足和血管细胞之间的狭窄空间。还可以确定是否 环氧二十碳三烯酸参与激活星形细胞终足的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，要确定两者是否都 高血压期间神经血管单位发生功能和结构变化(目标3)。我们 假设在神经元刺激后，星形胶质细胞内钙离子的升高激活了BK 星形细胞终足中的通道导致K+(一种强血管扩张剂)在其间的间隙迅速释放 端足和血管细胞。钙离子的升高也增加了环氧二十碳三烯酸的产量 作用于星形细胞末端的BK通道的酸，进一步激活这些通道。因为 神经元、星形胶质细胞和实质小动脉的功能和解剖变化是一脉相承的 另一种是对神经-神经-胶质-血管网络内通讯模式的理解 生理条件将提供对影响一种或多种疾病的病理的洞察，例如高血压 这三种细胞成分组成了神经血管单位。