Response Properties of Meningeal Afferents in Health and Migraine

健康和偏头痛中脑膜传入的反应特性

• 批准号: 10728847
• 负责人: DAN LEVY
• 金额: $ 58.56万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-18 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10728847
• 关键词: Acceleration; Afferent Neurons; Anesthesia procedures; Automobile Driving; Blood Vessels; Brain; Cephalic; Complex; Data; Development; Endowment; Exercise; Exhibits; Fiber; Genetic; Head; Headache; Health; Homeostasis; Hour; Human; Image; Immunologics; Intracranial Hypertension; Intracranial Pressure; Ion Channel; Knock-out; Knowledge; Label; Link; Locomotion; Measurement; Mechanics; Mediating; Meningeal; Meninges; Migraine; Molecular Genetics; Monitor; Mus; Nerve Endings; Neurons; Nitric Oxide Synthase; Nitroglycerin; Nociception; Operative Surgical Procedures; Pain; Pain Disorder; Pathologic; Physical activity; Physiological; Piezo 2 ion channel; Population; Process; Property; Rattus; Research; Rest; Role; Sensory; Signal Transduction; Sodium Channel; Stimulus; Stretching; Testing; Tissues; Transgenic Mice; Trigeminal System; Vasodilation; allodynia; awake; cell type; fluorescence imaging; genetic approach; imaging approach; innovation; mechanical force; mechanical stimulus; nerve supply; neural; novel; novel strategies; pain behavior; pre-clinical; response; sensory system; two-photon; vasomotion; voltage

The cranial meninges, which provide a physical and immunological barrier to protect the brain, are innervated by a network of trigeminal primary afferent sensory neurons. A large body of indirect evidence points to meningeal afferents' involvement in migraine headache genesis. However, we do not yet have a clear understanding of the normal sensory function of meningeal afferents and how they become engaged in migraine. Our current knowledge about the response properties of meningeal afferents has been almost exclusively derived from single-unit recordings of dural afferents from their TG somata in anesthetized rats with surgically exposed and depressurized meninges. Yet, these recordings have only provided a coarse description of the stimuli sensed by the diversity of meningeal afferents. To better understand the function of meningeal afferents, we recently developed a two-photon, GCaMP-based Ca2+ imaging approach to monitor their responses to a large set of complex physiological and pathological stimuli in the intact intracranial space of awake mice. By imaging the activity of meningeal afferent fibers in naïve mice via a closed cranial window, we made the surprising observations that despite their presumed nociceptive function, a large subset of afferents becomes activated during brief locomotion bouts and displays distinct dynamics to various levels of meningeal deformations that occur in response to locomotion. We now propose to leverage our newly developed imaging approach to advance our understanding of the sensory function of meningeal afferents and how their response properties are modulated under conditions that have been implicated in migraine headaches in humans Studies in Aim 1 will investigate the novel idea that the meningeal sensory system is tuned to sense a wide range of interoceptive mechanical stimuli, including physiological meningeal vasodilation and intracranial pressure elevations. In Aim 2, we will test the prediction that migraine triggers amplify these normal sensory responses. Aim 3 is to explore the relative contribution of the mechanosensitive Piezo2 channel in mediating the afferents' responses to normal intracranial interoceptive signals and their amplification following the administration of migraine triggers. Our proposed studies and innovative approach to image the activity of meningeal afferents could provide a dramatically better understanding of the role of the meningeal sensory system in homeostasis and under pathophysiological conditions that lead to migraine. Advances made could accelerate preclinical translational headache research.

脑膜是保护大脑的物理和免疫屏障， 由三叉神经初级传入感觉神经元网络支配。大量的间接证据 指出脑膜传入神经参与了偏头痛的发生。然而，我们还没有 清楚地了解脑膜传入神经的正常感觉功能以及它们如何成为 患有偏头痛我们目前对脑膜传入神经的反应特性的了解 几乎完全来自单一单位记录的硬脑膜传入从他们的TG胞体， 手术暴露并减压脑膜的麻醉大鼠。然而，这些记录只有 提供了一个粗略的描述的刺激感觉的多样性脑膜传入。更好地 为了了解脑膜传入神经的功能，我们最近开发了一种基于GCaMP的双光子 Ca2+成像方法来监测他们对一个大的复杂的生理和病理的反应， 刺激清醒小鼠的完整颅内空间。通过对脑膜传入纤维的活动进行成像 通过一个封闭的颅窗，我们在幼稚的小鼠中进行了令人惊讶的观察， 假定具有伤害性功能，在短暂的运动过程中，很大一部分传入神经被激活 对各种程度的脑膜变形， 到运动。我们现在建议利用我们新开发的成像方法来推进我们的 了解脑膜传入神经的感觉功能以及它们的反应特性如何 在与人类偏头痛有关的条件下进行调节 1将研究脑膜感觉系统被调谐以感知广泛的神经元的新想法。 内感受性机械刺激，包括生理性脑膜血管扩张和颅内压 海拔在目标2中，我们将测试偏头痛触发放大这些正常感觉的预测。 应答目的3是探索机械敏感的Piezo2通道的相对贡献， 介导传入神经对正常颅内内感受性信号的反应及其放大 偏头痛的诱因我们提出的研究和创新的方法，以形象 脑膜传入神经的活动可以更好地理解 脑膜感觉系统处于稳态和病理生理条件下，导致偏头痛。 所取得的进展可以加速临床前转化性头痛研究。