Investigation of Modulators of Cerebrovascular Coupling

脑血管耦合调节剂的研究

• 批准号: 7143928
• 负责人: afonso silva
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7143928
• 关键词: bioimaging /biomedical imaging; biological signal transduction; brain circulation; brain electrical activity; cerebrovascular imaging /visualization; cyclooxygenase inhibitors; electrophysiology; enzyme activity; functional magnetic resonance imaging; hemodynamics; laboratory mouse; laboratory rat; nitric oxide; nitric oxide synthase; positron emission tomography; prostaglandin E; prostaglandin endoperoxide synthase; somesthetic sensory cortex

Modern functional neuroimaging methods, such as Positron Emission Tomography (PET), and functional Magnetic Resonance Imaging (fMRI), rely on the coupling of neuronal electrical activity to changes in local metabolic demands--called "cerebrometabolic coupling"--and to the hemodynamic regulation of energy supply and waste removal--called "cerebrovascular coupling"--to measure brain activity through indirect surrogate markers of such activity. Understanding the relationship between local brain activity and the major physiological markers that are measured is of paramount importance for the correct interpretation and quantification of functional neuroimaging data. My main research interests are to understand and elucidate the mechanisms of regulation of cerebral blood flow during normal and stimulation induced brain activity. Amongst the several key aspects of this magnificently broad task, I have directed research efforts in the first year on investigating two major signaling pathways - the nitric oxide (NO)pathway, and the prostaglandin (PGE2) pathway, known to be involved in translating a change in brain activity into a vascular response. The first experiments have focused on the use of rats and mice and functional MRI, combined with simultaneous electrophysiological recordings, to measure the hemodynamic response and the increased electrical activity to stimulation of the somatosensory cortex, before and after the use of potent and specific inhibitors of nitric oxide synthase (NOS) and of cyclooxygenase-2 (COX-2). Preliminary results show a significant decrease (50-90%) of the hemodynamic response to somatosensory stimulation after inhibition of either COX-2 or NOS, respectively, with minimal decrease of electrical activity. Such results confirm the hypothesis that NO and PGE2 are important mediators of the cerebrovascular coupling. These results have been submitted for publication. A few collaborators have been of essential help in this project. Prof. Mathias Hoehn, of the Max-Planck Institute for Neurological Research, Cologne, Germany, has helped develop the protocol for somatosensory stimulation of the rat and for recording of SEPs in the magnet. In NINDS, Dr. Leonardo Belluscio in NINDS has been collaborating in developing 2-photon confocal techniques to directly visualize the cortical microvasculature. And Dr. Francesca Bosetti, NIA, has helped with assays to measure COX-2 activity. For example, in the lab of Dr. Francesca Bosetti, basal activity of COX-2 was measured in control and experimental rats showing at least 64% inhibition of COX-2 by meloxicam.

现代功能神经成像方法，如正电子发射断层扫描(PET)和功能磁共振成像(FMRI)，依赖于神经元电活动与局部代谢需求变化的耦合(称为脑代谢耦合)，以及与能量供应和废物清除的血液动力学调节的耦合(称为脑血管耦合)，通过此类活动的间接替代标记物来测量大脑活动。了解局部脑活动与所测量的主要生理标记物之间的关系对于正确解释和量化功能神经成像数据至关重要。我的主要研究兴趣是了解和阐明正常脑活动和刺激诱导脑活动中脑血流调节的机制。在这项极其广泛的任务的几个关键方面中，我在第一年指导了两个主要信号通路的研究工作-一氧化氮(NO)途径和前列腺素(PGE2)途径，已知这两个途径参与将大脑活动的变化转化为血管反应。 第一个实验集中于使用大鼠和小鼠以及功能磁共振，结合同步电生理记录，测量在使用有效和特定的一氧化氮合酶(NOS)和环氧合酶-2(COX-2)抑制剂前后，对刺激躯体感觉皮质的血流动力学反应和增加的电活动。初步结果显示，分别抑制COX-2或NOS后，体感刺激的血流动力学反应显著降低(50-90%)，电活动的下降幅度很小。这些结果证实了NO和PGE2是脑血管偶联的重要介质的假说。这些结果已提交发表。 一些合作者在这个项目中起到了重要的帮助作用。德国科隆Max-Planck神经研究所的Mathias Hoehn教授帮助开发了对大鼠的体感刺激和在磁铁中记录SEP的方案。在NINDS中，NINDS的Leonardo Belluscio博士一直在合作开发双光子共聚焦技术，以直接显示皮质微血管。NIA的Francesca Bosetti博士帮助进行了测量COX-2活性的分析。例如，在Francesca Bosetti博士的实验室中，在对照组和实验大鼠中测量了COX-2的基本活性，显示美洛昔康至少抑制COX-2的%。