Investigation of the Modulators of Cerebrovascular Coupl

脑血管耦合调节剂的研究

• 批准号: 7324734
• 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/7324734
• 关键词: Investigation; Modulators; Cerebrovascular; Coupl

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 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 stimulation induced brain activity. I have directed research efforts in the first two years 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 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). In the case of the NO, we set out to investigate the effect of the inhibition of neuronally derived NO on the spatial and temporal profiles of hemodynamic and neuronal responses to functional brain stimulation. Cerebral blood flow (CBF), volume (CBV), blood oxygenation level dependent (BOLD) signal, and SEP to forepaw stimulation were recorded in alpha-chloralose anesthetized rats via MRI and epidural EEG before and after administration of a bolus of 7-nitroindazole (7-NI), a potent in vivo inhibitor of neuronal nitric oxide synthase (nNOS). 7-NI produced a significant attenuation of the activation-elicited CBF, CBV and BOLD responses, without affecting the baseline perfusion level. The average CBF response was nulled, while the BOLD and the CBV responses decreased to approximately 30% of their respective amplitudes before 7-NI administration. The average SEP amplitude decreased to about 60% of its pretreatment value, indicating a pharmacologically-induced uncoupling between neuronal and hemodynamic responses to functional activation. We thus concluded that neuronally-produced NO has a critical role in the cerebrovascular coupling. These results were published in the Journal of Cerebral Blood Flow and Metabolism (1). Similar experiments were carried out to investigate the role of cyclooxygenase-2 (COX-2) in the cerebrovascular coupling. Hemodynamic (CBF and BOLD) and neuronal (SEP) responses to forepaw stimulation were measured in alpha-chloralose-anesthetized rats before and after intravenous administration of Meloxicam (MEL), a preferential COX-2 inhibitor, and following a bolus of prostaglandin E2 (PGE2), a prominent vasodilatatory product of COX-2 catalyzed metabolism of arachidonic acid. Both MEL and PGE2 had a significant effect on the activation-elicited CBF and BOLD responses, without affecting the baseline perfusion. Meloxicam decreased brain COX enzymatic activity by 57% and decreased the stimulation-induced CBF response to 32% and BOLD to 46% of their respective pre-drug amplitudes. In turn, PGE2 bolus resulted in a partial recovery of functional hyperemia, with the CBF response recovering to 52% and the BOLD response to 56% of their values prior to MEL administration. There was no concomitant decrease in either amplitudes or latencies of SEP components. These findings suggest a modulatory role of COX-2 products in the cerebrovascular coupling and provide evidence for existence of a functional metabolic buffer. These results were published in the journal Neuroimage (2). To complement the pharmacological studies, the differential role of NMDA and AMPA receptors on the cerebrovascular coupling was investigated in a collaborative project with the Max-Planck Institute for Neurological Research in Cologne, Germany (3), while the effects of GABA where investigated with the lab of Dr. Jun Shen in NIMH (4). In addition to the above mentioned pharmacological manipulations, we have been using state-of-the-art optical imaging methods such as two-photon laser-scanning microscopy to directly visualize the cortical microvasculature and observe its reactivity to global vasodilators, such as carbon dioxide, as well as to stimulus-induced changes in vessel diameter and in red blood cell velocity. In a recent study (5), cortical vessels traversing the top 200 microns of the somatosensory cortex were visualized in alpha-chloralose-anesthetized Sprague?Dawley rats equipped with a cranial window. Intraluminal vessel diameters, transit times of fluorescent dextrans and red blood cells (RBC) velocities in individual capillaries were measured under normocapnic and slightly hypercapnic conditions, a gentle increase in PaCO2 was sufficient to produce robust and significant increases in both arterial and venous vessel diameters, concomitant to decreases in transit times of a bolus of dye from artery to venule (14%, P < 0.05) and from artery to vein (27%, P < 0.05). On the whole, capillaries exhibited a significant increase in diameter (16 +/- 33%, P < 0.001, n = 393) and a substantial increase in RBC velocities (75 +/- 114%, P < 0.001, n = 46) with hypercapnia. However, the response of the cerebral microvasculature to modest increases in PaCO2 was spatially heterogeneous. The maximal relative dilatation (range: 5 ? 77%; mean +/- SD: 25 +/- 34%, P < 0.001, n = 271) occurred in the smallest capillaries (1.6 microns ? 4.0 microns resting diameter), while medium and larger capillaries (4.4 microns ? 6.8 microns resting diameter) showed no significant changes in diameter (P > 0.08, n = 122). In contrast, on average, RBC velocities increased less in the smaller capillaries (39 +/- 5%, P < 0.002, n = 22) than in the medium and larger capillaries (107 +/- 142%, P < 0.003, n = 24). Thus, the changes in capillary RBC velocities were spatially distinct from the observed volumetric changes and occurred to homogenize cerebral blood flow along capillaries of all diameters. Several experiments are currently in progress to follow-up on the findings of the above 3 studies. We are moving to a small non-human primate model in an attempt to close the gap between translational research and human applications. We are refining our methods for delivery of pharmacological agents and for detection of both the hemodynamics as well as the neuronal responses from the brain. We are developing sophisticated manganese-enhanced protocols to map functional brain regions with better spatial localization than hemodynamic based methods, with the added advantage of allowing in-vivo tracing of functionally specific pathways. Finally, we are further refining optical imaging techniques to directly visualize the cortical microvasculature and the red blood cells, to facilitate simultaneous measurements of stimulus-induced CBF, CBV and hematocrit changes.

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。叫什么?cerebrometabolic耦合吗?吗?以及能量供应和废物清除的血流动力学调节？叫什么?脑血管耦合吗?吗?通过这种活动的替代标记来测量大脑活动。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刺激诱导的脑活动中脑血流量的调节机制。我在头两年指导研究工作，研究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。