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.

为保护大脑提供物理和免疫障碍的颅脑介质是 由三叉神经传入感官神经元网络支配。大量间接证据 指出了脑膜传入者参与偏头痛标题创世纪。但是，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为 从事偏头痛。我们当前对脑膜传入的响应属性的了解 几乎完全来自其TG Somata的硬脑膜传入的单单元录音 麻醉大鼠，外科手术暴露和抑制脑膜。但是，这些录音只有 提供了对脑膜传入的多样性所感受到的刺激的粗略描述。更好 了解脑膜传入的功能，我们最近开发了一个基于GCAMP的两光子 CA2+成像方法来监视其对大量复杂生理和病理的反应 在清醒小鼠完整的颅内空间中刺激。通过成像脑膜传入纤维的活性 在幼稚的老鼠通过封闭的颅窗中，我们做出了令人惊讶的观察，使他们的 假定的伤害性函数，在短暂的运动中激活了大量传统 回合并显示出不同级别的脑膜变形的不同动态 运动。现在，我们建议利用我们新开发的成像方法来促进我们的 了解脑膜传入的感觉功能以及它们的响应特性如何 在人类研究中偏头痛标题中暗示的条件下进行调节。 1将调查脑膜感觉系统的新颖想法，以感知各种各样的想法 感知性的机械刺激，包括物理脑膜衰减和颅内压 海拔。在AIM 2中，我们将测试偏头痛触发者扩大这些正常感觉的预测 回答。 AIM 3是探索机械敏感压电通道的相对贡献 介导传入者对正常颅内互感信号的反应及其扩增 偏头痛触发器后。我们提出的研究和创新的图像方法 脑膜传入的活动可以在动态上更好地理解 体内稳态的脑膜感觉系统以及导致偏头痛的病理生理状况。 取得的进步可以加速临床前翻译标题研究。