Investigation of Modulators of Cerebrovascular Coupling

现代功能性神经成像方法，如正电子发射断层扫描（PET）和功能性磁共振成像（fMRI），依赖于神经元电活动与局部代谢需求变化的耦合-称为“代谢耦合”-以及能量供应和废物清除的血液动力学调节-称为“脑血管耦合”-通过此类活动的间接替代标记来测量大脑活动。了解局部脑活动和测量的主要生理标志物之间的关系对于正确解释和量化功能性神经影像数据至关重要。我的主要研究兴趣是理解和阐明正常和刺激诱导的脑活动过程中脑血流的调节机制。在这个宏伟的广泛任务的几个关键方面，我在第一年就指导了研究工作，调查两个主要的信号通路-一氧化氮（NO）通路和前列腺素（PGE 2）通路，已知参与将大脑活动的变化转化为血管反应。 第一个实验集中在使用大鼠和小鼠和功能性MRI，结合同步电生理记录，以测量血液动力学反应和增加的电活动刺激的躯体感觉皮层，之前和之后使用的有效和特异性抑制剂的一氧化氮合酶（NOS）和环氧合酶-2（考克斯-2）。初步结果显示，分别抑制考克斯-2或NOS后，对体感刺激的血流动力学反应显著降低（50-90%），电活动降低最小。这些结果证实了NO和PGE 2是脑血管耦联的重要介质的假设。这些结果已提交出版。 一些合作者在这个项目中提供了重要的帮助。德国科隆马克斯-普朗克神经学研究所的Mathias Hoehn教授帮助开发了大鼠体感刺激和记录磁铁中SEP的协议。在NINDS中，NINDS的列奥纳多贝鲁西奥博士一直在合作开发双光子共聚焦技术，以直接可视化皮质微血管。NIA的Francesca Bosetti博士帮助进行了测量考克斯-2活性的分析。例如，在Francesca Bosetti博士的实验室中，在对照和实验大鼠中测量了考克斯-2的基础活性，显示美洛昔康对考克斯-2的抑制至少为64%。

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.