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.

颅脑膜提供物理和免疫屏障来保护大脑， 由三叉神经初级传入感觉神经元网络支配。大量间接证据 指出脑膜传入参与偏头痛的发生。然而，我们还没有 清楚地了解脑膜传入的正常感觉功能及其如何变化 患有偏头痛。我们目前对脑膜传入反应特性的了解 几乎完全源自 TG 体细胞硬脑膜传入的单单元记录 麻醉大鼠，通过手术暴露脑膜并减压。然而，这些录音仅 提供了对脑膜传入多样性所感受到的刺激的粗略描述。为了更好 为了了解脑膜传入的功能，我们最近开发了一种基于 GCaMP 的双光子 Ca2+ 成像方法可监测其对大量复杂生理和病理的反应 清醒小鼠完整颅内空间的刺激。通过对脑膜传入纤维的活动进行成像 通过关闭颅窗，我们在幼稚小鼠中进行了令人惊讶的观察，尽管它们 假定的伤害性功能，大量传入神经在短暂运动期间被激活 发作并显示出不同程度的脑膜变形的不同动态响应 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研究 了解脑膜传入的感觉功能及其反应特性 在与人类偏头痛有关的条件下进行调节 Aim 研究 1 将研究脑膜感觉系统被调整以感知广泛的新想法 内感受机械刺激，包括生理性脑膜血管舒张和颅内压 海拔。在目标 2 中，我们将测试偏头痛触发因素放大这些正常感觉的预测 回应。目标 3 是探索机械敏感 Piezo2 通道在 介导传入神经对正常颅内内感受信号及其放大的反应 服用偏头痛触发剂后。我们提出的研究和创新的图像方法 脑膜传入神经的活动可以使人们更好地理解脑膜传入神经的作用 脑膜感觉系统处于稳态和导致偏头痛的病理生理条件下。 所取得的进展可以加速临床前转化性头痛研究。