Mechanisms of neurovascular coupling in humans

背景：大脑需要精确控制血液流动，以确保提供适当的能量并清除废物。需要在大脑中进行特殊控制的调节主要是由于该组织的能量存储能力有限和新陈代谢需求高。神经血管偶联(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)反应之间的密切时间和区域联系。神经血管单位装备精良，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完成的：1)血管收缩细胞；2)内皮；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，如思维本身，以及认知如何在人类一生中发生变化非常重要。 理论基础：对NVC机制的大部分研究都是利用麻醉影响CBF调节的动物模型完成的，或者使用NVC的重要输入可能被断开的体外模型(例如，中枢交感神经系统输入)完成的。此外，还发现了物种间的差异，特别是在大脑功能方面。这些问题妨碍了对NVC的清晰理解。然而，动物研究表明，NVC级联反应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)；以及2)特定的细胞受体(α1和β1)。这些在动物身上的发现构成了我的NVC研究项目的起点，该项目使用的是活体未麻醉的人类模型。 总体目标：A)使用新的干预措施和研究方法提高我们对NVC的知识；B)开发技术，提高NVC评估的易用性/质量(例如，新的软件/硬件)；C)培训下一代自然科学/工程学HQP。 发现主题：1)阐明一氧化氮合酶在NVC中的作用；2)了解α1肾上腺素能受体在NVC中的作用；3)揭示β受体在NVC中的影响。 工作性质：利用药理学和饮食干预，我们将系统地抑制和促进24名人类的一氧化氮合酶、α1和β途径，并评估这些途径对NVC的影响。这将需要进行15项研究(312项评估)，历时5年。

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.