Investigation of the Modulators of Cerebrovascular Coupling

脑血管耦合调节剂的研究

• 批准号: 8746798
• 负责人: Afonso Silva
• 金额: $ 101.75万
• 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/8746798
• 关键词: Address; Adopted; Afferent Pathways; Architecture; Arteries; Astrocytes; Blood; Blood Vessels; Blood capillaries; Brain; Brain imaging; Caliber; Cells; Cerebrovascular Circulation; Cerebrum; Complex; Cortical Column; Coupling; Data; Disease; Drainage procedure; Dyes; Electrophysiology (science); Energy Supply; Erythrocytes; Evolution; Excision; Functional Magnetic Resonance Imaging; Functional disorder; Future; Goals; Healthcare; Homeostasis; Human; Hyperemia; Hypertension; Individual; Interneurons; Investigation; Ischemic Stroke; Label; Laser Scanning Microscopy; Light; Magnetic Resonance Imaging; Measurement; Mediating; Mediator of activation protein; Microscopy; Molecular; Neuroglia; Neurons; Organ; PTGS2 gene; Pathway interactions; Penetration; Photons; Physiological; Plasma; Price; Process; Regulation; Relative (related person); Research; Resolution; Role; Sensory; Shapes; Signal Pathway; Signal Transduction; Specificity; Stroke; Techniques; Translating; Vascular blood supply; Veins; Work; base; capillary; cerebrovascular; feeding; hemodynamics; interest; millimeter; neurochemistry; neuroimaging; neurovascular unit; prevent; relating to nervous system; research study; response; soft tissue; two-photon; vasoactive agent; wasting

We are interested in establishing the physiological role of well-established neurochemical pathways (such as NO and COX-2) in shaping the spatial specificity of CBF regulation. The working hypothesis is that vasoactive substances released by strategically located cells in the parenchyma act on the cerebral vessels and regulate their tone to mediate increases in CBF. The outstanding questions are: (i) which substances are released by what cells and under which circumstances? (ii) What is the spatial specificity of with respect to the cortical architecture? (iii) What is the physiological role of vasoactive agents in the context of underlying physiological and pathophysiological processes, such as hypertension and stroke? The main research approach that we have adopted has been to combine state-of-the-art neuroimaging techniques, able to probe the brain across different spatial and temporal scales, with pharmacological manipulations aimed at determining the relative contribution, spatial specificity and cellular basis of the different pathways to the HRF. The main neuroimaging techniques to be used are anatomical and functional MRI, which are able to provide non-invasive images of the brain with sub-millimeter spatial resolution and superior soft tissue contrast. However, at its present spatial resolution, MRI can barely visualize cortical cytoarchitecture and it is certainly not yet able to resolve individual cells and capillary vessels. To understand neurovascular coupling one must be able to resolve the neurovascular unit and study its signaling mechanisms at the level of its individual cellular constituents. Two-photon microscopy is an attractive technique that allows simultaneous measurements of the activity of individual neurons and astrocytes, along with the corresponding changes in diameter and red blood cell velocities in individual vessels. However, the excellent spatial resolution of 2-photon microscopy comes at a price in 3D spatial coverage. Not only the depth of penetration is limited, but also the limitation in field-of-view prevents one from observing the feeding arteries and draining veins to the capillary network of interest, and thus the impact that the supply and drainage of blood has on the capillary response cannot be evaluated. Our lab believes that a way to get around such limitations and make forward progress is to combine the advantages of MRI and 2-photon microscopy into simultaneous or parallel multi-modal recordings, so that neurovascular coupling can be studied in all relevant spatial and temporal scales. In addition, incorporation of modern electrophysiology techniques able to probe neural activity across different cortical layers will add crucial data about the flow of information within a functional cortical column, and allow better interpretation of the temporal evolution of the hemodynamic response within that column. The integration of the above multi-modal techniques constitutes a powerful and attractive experimental approach that will shed light on the intricate mechanisms of CBF control. Current and future experiments will continue to focus on understanding the relevance of these pathways to neurovascular coupling in the presence of pathophysiological states such as hypertension and ischemic stroke.

我们感兴趣的是确定成熟的神经化学途径（例如 NO 和 COX-2）在塑造 CBF 调节的空间特异性中的生理作用。工作假设是，实质上关键位置的细胞释放的血管活性物质作用于脑血管并调节其张力以介导 CBF 的增加。悬而未决的问题是：（i）什么细胞在什么情况下释放哪些物质？ (ii) 皮质结构的空间特异性是什么？ (iii) 血管活性药物在潜在的生理和病理生理过程（例如高血压和中风）中的生理作用是什么？我们采用的主要研究方法是将最先进的神经影像技术与药理学操作相结合，这些技术能够在不同的空间和时间尺度上探测大脑，旨在确定 HRF 不同途径的相对贡献、空间特异性和细胞基础。 所使用的主要神经影像技术是解剖学和功能性 MRI，它们能够提供具有亚毫米空间分辨率和卓越软组织对比度的大脑非侵入性图像。然而，在目前的空间分辨率下，MRI 几乎无法可视化皮质细胞结构，而且它当然还无法解析单个细胞和毛细血管。为了理解神经血管耦合，我们必须能够解析神经血管单元并在其单个细胞成分水平上研究其信号传导机制。双光子显微镜是一种有吸引力的技术，可以同时测量单个神经元和星形胶质细胞的活动，以及单个血管中直径和红细胞速度的相应变化。然而，2 光子显微镜卓越的空间分辨率是以 3D 空间覆盖范围为代价的。不仅穿透深度有限，而且视野的限制也使得人们无法观察到感兴趣的毛细血管网络的供血动脉和引流静脉，因此无法评估血液的供应和引流对毛细血管反应的影响。我们实验室认为，克服这些限制并取得进展的一种方法是将 MRI 和 2 光子显微镜的优点结合到同步或并行多模态记录中，以便可以在所有相关的空间和时间尺度上研究神经血管耦合。此外，结合能够探测不同皮质层神经活动的现代电生理学技术，将添加有关功能性皮质柱内信息流的关键数据，并可以更好地解释该柱内血流动力学响应的时间演变。上述多模式技术的整合构成了一种强大且有吸引力的实验方法，它将揭示 CBF 控制的复杂机制。当前和未来的实验将继续侧重于了解在高血压和缺血性中风等病理生理状态存在下这些途径与神经血管耦合的相关性。