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“脑代谢耦合”-以及能量供应和废物清除的血流动力学调节-称为“脑血管耦合”-通过间接替代标记物测量大脑活动。了解局部脑活动与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成像数据至关重要。我的主要研究兴趣是了解和阐明在正常和刺激诱导的脑活动中脑血流量的调节机制。在这一宏大任务的几个关键方面中，我在第一年指导了研究工作，研究了两种主要的信号通路——一氧化氮（NO）通路和前列腺素（PGE2）通路，已知它们参与将大脑活动的变化转化为血管反应。

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.