Mechanisms of neurovascular coupling in humans

人类神经血管耦合机制

• 批准号: RGPIN-2018-03771
• 负责人: Phillips, Aaron
• 金额: $ 1.75万
• 依托单位: University of Calgary
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=711979
• 关键词: Mechanisms; neurovascular; coupling; humans

Background: The brain requires precise control of blood flow to ensure that appropriate energy is provided and waste is removed. The need for exceptionally controlled regulation in the brain is primarily due to the limited capacity for energy storage and high metabolic demand in this tissue. Neurovascular coupling (NVC) is thought to be a key mechanism regulating this control and describes the close temporal and regional linkage between neuronal activity and cerebral blood flow (CBF) responses. The neurovascular unit is well-equipped to control blood flow precisely, which is accomplished by the close interaction of three major components: 1) Vascular contractile cells; 2) The endothelium; 3) The neuron; and 4) The astrocyte. Importance: Unraveling the mechanisms of NVC is important to understanding fundamental central nervous system processes such as thought itself and how cognition changes over the human lifespan. Rationale: Much of the research into the mechanisms of NVC has been completed using animal models with anesthesia that impacts CBF regulation, or ex vivo models where important inputs to NVC may be disconnected (e.g., central sympathetic nervous system input). Furthermore, interspecies differences, particularly in terms of brain function, have been uncovered. These issues obviate clear understanding of NVC. Nonetheless, animal work shows that important components of the NVC cascade may be: 1) Nitric oxide production (a potent vasoactive substance) through nitric oxide synthase (NOS); and 2) Specific cell receptors (alpha1 and beta). These findings in animals form the starting point for my NVC research program using an in vivo un-anesthetized human model. Overall Goals: A) To advance our knowledge of NVC using novel interventions and research approaches, B) Produce technology improving the ease/quality of NVC assessments (e.g., novel software/hardware); C) Train the next generation of natural science/engineering HQP. Discovery Themes: 1) Delineate the role of NOS in NVC; 2) Understand the impact of alpha1 adrenergic receptors inNVC; 3) Reveal the influence of beta adrenergic receptors in NVC. Nature of Work: Using pharmacological and dietary interventions we will systematically inhibit and promote the NOS, alpha1 and beta pathways in 24 humans and evaluate the impact of these pathways on NVC. This will require 15 studies (312 assessments), taking place over 5 years.

背景：大脑需要精确控制血流，以确保提供适当的能量并清除废物。大脑需要异常受控的调节主要是由于该组织的能量存储能力有限且代谢需求较高。神经血管耦合（NVC）被认为是调节这种控制的关键机制，并描述了神经元活动和脑血流（CBF）反应之间的紧密时间和区域联系。神经血管单元能够精确地控制血流，这是通过三个主要组成部分的密切相互作用来完成的：1）血管收缩细胞； 2）内皮细胞； 3）神经元； 4）星形胶质细胞。 重要性：解开 NVC 的机制对于理解基本的中枢神经系统过程（例如思想本身以及认知在人类生命周期中如何变化）非常重要。 理由：关于 NVC 机制的大部分研究都是使用影响 CBF 调节的麻醉动物模型或可能断开 NVC 重要输入（例如中枢交感神经系统输入）的离体模型来完成的。此外，还发现了物种间差异，特别是在大脑功能方面。这些问题妨碍了对雷士照明的清晰理解。尽管如此，动物研究表明，NVC 级联的重要组成部分可能是： 1) 通过一氧化氮合酶 (NOS) 产生一氧化氮（一种有效的血管活性物质）； 2) 特定细胞受体（α1 和 β）。这些在动物身上的发现构成了我的 NVC 研究项目的起点，该项目使用体内未麻醉的人体模型。 总体目标：A) 使用新颖的干预措施和研究方法增进我们对 NVC 的了解，B) 开发提高 NVC 评估的简易性/质量的技术（例如新颖的软件/硬件）； C) 培训下一代自然科学/工程高级人才。 发现主题： 1) 描述 NOS 在 NVC 中的作用； 2）了解α1肾上腺素受体对NVC的影响； 3)揭示β肾上腺素能受体对NVC的影响。 工作性质：利用药理学和饮食干预措施，我们将系统地抑制和促进 24 名人类的 NOS、α1 和 β 通路，并评估这些通路对 NVC 的影响。这需要 5 年多的时间进行 15 项研究（312 项评估）。