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：
9311373
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/9311373
关键词：
Address Adenosine Affect Alzheimer&apos s Disease Angiotensin II Astrocytes Automobile Driving Bilateral Blood Pressure Blood Vessels Brain Caliber 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 Recruitment Activity Regulation Rest Risk Signal Transduction Slice Stroke Synapses Synaptic Transmission Testing Vascular Diseases Vascular resistance artery stenosis 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 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

尽管人们付出了很多努力来理解与活动引起的变化相关的机制脑血流量（CBF）即功能性充血和神经血管耦合，目前了解较少考虑到慢性脑灌注不足，控制基础 CBF 和静息神经活动的过程。导致认知障碍我们小组有兴趣研究细胞机制稳态血管张力的变化以及由此引起的灌注会影响我们的中枢神经功能。假设是定义生理性血管-胶质-神经元耦合（VGNC）的构成机制是使用多学科方法，我们将实现以下三个目标：目标 1：测试假设疾病中异常的星形胶质细胞 Ca2+ 信号传导会损害 VGNC。将灌注状态整合到大脑中，并通过释放胶质递质信号来调整静息神经元 VGNC 损伤使大脑面临谷氨酸兴奋性毒性、炎症和相应活动的风险。我们将使用 GLAST-CreERT2 小鼠（体内和体外）测量星形胶质细胞。 Ca2+ 事件响应管腔内 ↑ 或 ↓ 引起的实质小动脉血管反应性变化对照和脑灌注不足（双侧颈总动脉狭窄）的脑切片中的流量/压力将使用药理学方法来定义关键信号机制（即 P2Y1 和 TRPV4 通道）。介导 VGNC 目的2。检验血管反应性变化直接相关的假设。随着静息皮质锥体神经元活动的变化，最佳的能量平衡需要达到一定程度。使用体内和体外方法，神经元活动与血液灌注适当匹配。确定压力/流量实质小动脉直径变化如何影响控制中的静息神经元活动小鼠以及使用血管紧张素 II 依赖性高血压和脑血管疾病的血管疾病模型体外灌注不足：测量动脉直径、神经膜电位、放电率和在血流动力学挑战之前、期间和之后获得突触电流（例如↑或↓流量/压力）体内加压 PA 引起：静息神经活动响应全身引起的血液变化。目的 3. 测试血管反应性变化的假设。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网络。利用同时发生的实质小动脉直径变化和电生理神经元活动我们将确定压力/流量引起的实质小动脉血管反应性变化的影响具体来说，我们将确定皮质 GABA 能中间神经元功能和神经网络。 GABA能中间神经元亚型在 VGNC 期间驱动神经网络反应，无论中间神经元反应需要星形胶质细胞 Ca2+ 变化作为中间步骤，以及中间神经元反应是否疾病状况发生改变。 1