Clinically unscreened vasculo-glial-neuronal coupling is critical for physiological brain function

临床上未经筛选的血管-胶质-神经元耦合对于生理脑功能至关重要

基本信息

批准号：
9884817
负责人：
JESSICA A FILOSA
金额：
$ 33.25万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9884817
关键词：
Address Adenosine Affect Alzheimer&apos s Disease Angiotensin II Astrocytes Automobile Driving Bilateral Blood Pressure Blood Vessels Brain Caliber Carotid Stenosis Cerebrovascular Circulation Cerebrovascular system Cerebrum Chelating Agents Chronic Clinic Clinical Common carotid artery Communication Coupling Data Development Disease Electrophysiology (science)Energy Supply Equilibrium Event GLAST Protein Giant Cells Glucose Glutamates Goals Homeostasis Hyperemia Hypertension Impaired cognition Impairment In Vitro Inflammation Interneuron function Interneurons Lead Link Location Maintenance Measurement Measures Mediating Membrane Potentials Modality Modeling Monitor Mus Neurodegenerative Disorders Neurons Oxidative Stress Oxygen Pathology Pathway interactions Perfusion Pharmacology Physiological Population Process Regulation Rest Risk Signal Transduction Slice Stroke Synapses Synaptic Transmission Testing Vascular Diseases Vascular resistance blood perfusion cerebral hypoperfusion cerebrovascular constriction energy balance excitotoxicity experimental study hemodynamics hippocampal pyramidal neuron hypoperfusion improved in vivo interdisciplinary approach interest neuronal excitability neurovascular coupling neurovascular unit novel parenchymal arterioles pressure recruit response

项目摘要

While much effort has been devoted to the understanding of mechanisms linked to activity-evoked changes in cerebral blood flow (CBF) namely, functional hyperemia and neurovascular coupling, less is understood about the processes controlling basal CBF and resting neuronal activity. Considering that chronic brain hypoperfusion contributes to cognitive impairments our group is interested in studying the cellular mechanisms by which changes in steady-state vascular tone, and thus perfusion, affect resting neuronal function. Our central hypothesis is that constitutive mechanisms defining physiological vasculo-glial-neuronal coupling (VGNC) are impaired in disease. Using a multidisciplinary approach we will address the following three aims: Aim1: Test the hypothesis that aberrant astrocytes Ca2+ signaling in disease impairs VGNC. Astrocytes constitutively integrate perfusion status to the brain and, through the release of gliotransmitter signals, adjust resting neuronal activity accordingly. Impairments in VGNC places the brain at risk for glutamate excitotoxicity, inflammation and oxidative stress. Using GLAST-CreERT2; R26-lsl-GCaMP3 mice (in vivo and in vitro) we will measure astrocytic Ca2+ events in response to parenchymal arteriole vascular reactivity changes evoked by ↑or↓ in lumen flow/pressure in brain slices from control and cerebral hypoperfused (bilateral common carotid artery stenosis) mice. A pharmacological approach will be used to define key signal mechanisms (i.e. P2Y1 and TRPV4 channel) mediating VGNC. Aim2. Test the hypothesis that changes in vascular reactivity are directly associated with changes in resting cortical pyramidal neuron activity. Optimal energy balance requires that the degree of neuronal activity be properly matched with blood perfusion. Using in vivo and in vitro approaches, we will determine how pressure/flow parenchymal arteriole diameter changes impact resting neuronal activity in control mice and in models of vascular disease using Angiotensin II-dependent hypertension and cerebral hypoperfusion. In vitro: measurements of arteriolar diameter, neuronal membrane potential, firing rates and synaptic currents are obtained before, during and after a hemodynamic challenge (e.g. ↑or↓ flow/pressure) evoked to pressurized PA. In vivo: resting neuronal activity in response to systemic-evoked changes in blood pressure will be assessed. Aim3. Test the hypothesis that changes in vascular reactivity recruit, via an astrocyte Ca2+-dependent pathway, GABAergic interneurons to regulate cortical neuronal networks. Using simultaneous parenchymal arteriole diameter changes with electrophysiological neuronal activity recordings we will determine the effect pressure/flow-evoked parenchymal arteriole vascular reactivity changes has on cortical GABAergic interneuron function and neuronal networks. Specifically, we will identify the GABAergic interneuron subtype driving neuronal network responses during VGNC, whether interneuron responses require astrocyte Ca2+ changes as an intermediate step and whether interneuron responses are altered in disease conditions. 1

虽然已经大力致力于理解与活动引起的变化相关的机制脑血流（CBF），即功能性充血和神经血管耦合，对控制基本CBF和静息神经元活动的过程。考虑到慢性大脑灌注不足有助于认知障碍我们的小组有兴趣研究细胞机制稳态血管张力的变化，因此会影响静止的神经元功能。我们的中心假设是定义物理Vasculo-Glial-神经元偶联（VGNC）的构型机制是疾病受损。使用多学科方法，我们将解决以下三个目标：AIM1：测试假设疾病中异常星形胶质细胞Ca2+信号损害VGNC。星形胶质细胞组成性整合大脑的灌注状态，并通过释放Gliotransmitter信号，调整静息神经元相应的活动。 VGNC的障碍使大脑处于谷氨酸兴奋性，感染和氧化应激。使用Glast-Creert2; R26-LSL-GCAMP3小鼠（体内和体外）我们将测量星形胶质细胞 Ca2+事件响应聚chandyal动脉血管反应性的变化↑或管腔中的↓ 来自对照和脑置液的脑切片流量/压力（双侧共同颈动脉狭窄）老鼠。药物方法将用于定义关键信号机制（即P2Y1和TRPV4通道）中介VGNC。 AIM2。测试假设血管反应性的变化是直接相关的随着静息皮层神经元活性的变化。最佳能源平衡要求学位神经元活性与血液灌注适当匹配。使用体内和体外方法，我们将确定压力/流动副群体直径如何变化影响对照中的静息神经元活性小鼠和血管疾病模型中使用血管紧张素II依赖性高血压和脑灌注不良。体外：小动脉直径的测量，神经元膜电位，发射速率和在血液动力学挑战之前，之中和之后获得突触电流（例如↑或↓流/压力）唤起加压PA。体内：响应系统性诱发的血液变化而静止的神经元活性压力将被评估。 AIM3。测试通过一个假设，即通过A 星形胶质细胞CA2+依赖性途径，GABA能中间神经元调节皮质神经元网络。使用简单的副型副型动脉直径随电物质神经元活性而变化记录我们将确定效应压力/流动诱发的副副群小动物血管反应性的变化具有皮质GABA能中间神经元功能和神经元网络。具体来说，我们将确定 gabaergic intreneron子类型在VGNC期间驱动神经元网络响应，无论interneuron是否反应需要星形胶质细胞Ca2+变化作为中间步骤，以及中间响应是否为疾病状况改变。 1