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: 7841408
• 负责人: JESSICA A FILOSA
• 金额: $ 23.79万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7841408
• 关键词: Acids; Address; Affect; Arts; 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

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.

描述（由申请人提供）：这项研究的主要重点是表征大脑皮层功能性充血的细胞机制。功能性充血与神经元，星形胶质细胞和脑微循环之间的通信相当。导致适当高血症反应的信号传导途径的干扰与许多病理有关，包括高血压，中风，偏头痛和扩散抑郁症，以提及一些病理。尽管功能性充血发生在几秒钟内，但介导这种快速信号反应的基本机制仍有待定义。该项目将针对三个主要目标：首先，确定星形胶质细胞是否是神经血管耦合中的中介（AIM 1）。其次，为了确定星形胶质细胞与实质小动脉的通信的机制是否是由Ca2+激活的K+（BK）通道快速激活以及K+释放到星形胶质细胞和血管细胞之间狭窄空间的原因。还要确定环氧酸性酸是否有助于在星形细胞端终下激活BK通道，从而扩大星形胶质细胞和血管之间的信号通信（AIM 2）。第三，为了确定高血压期间神经血管单位的功能和结构改变是否发生（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+的上升激活了星形胶质细胞端膜中的BK通道，从而导致终脚和血管细胞之间的空间中的K+（强力血管扩张剂）迅速释放。 Ca2+的升高还增加了在星形胶质细胞终端中的BK通道上作用的环氧钠酸的产生，从而进一步激活了这些通道。由于神经元的功能和解剖变化，抗震颤细胞和实质动脉相互联系，因此在生理条件下对神经 - 粘膜血管网络中的沟通方式的理解将提供对高血压的洞察力，例如高血压，例如高血压，这会影响这些三个细胞组件的Neurospastulting The Neurospastulter the Neurospastular the Neurospastular the Neurospastular the Neurospastular the Neurospastular the Neurospastular the Neurospastular the Neurospastular the NiT。