Response Properties of Meningeal Afferents in Health and Migraine

脑膜提供了保护大脑的物理和免疫屏障，它是 由三叉神经初级传入感觉神经元网络支配。大量间接证据 指出脑膜传入参与了偏头痛的发生。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形成 患有偏头痛。我们目前对脑膜传入反应特性的了解 几乎完全来自于硬脑膜传入的单个单位记录，来自他们的三叉神经节 麻醉大鼠，手术暴露并减压脑膜。然而，这些录音只有 粗略地描述了脑膜传入的多样性所感受到的刺激。为了更好地 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成像方法监测其对一大组复杂生理和病理的反应 清醒小鼠完整的颅内间隙中的刺激。通过成像脑膜传入纤维的活动 在幼稚的小鼠身上，我们通过关闭的颅窗进行了令人惊讶的观察，尽管它们 假定有伤害性感受功能，一大部分传入神经在短暂的运动中被激活 对不同程度的脑膜变形进行反应并显示不同的动态变化 为了移动。我们现在建议利用我们最新开发的成像方法来推动我们的 了解脑膜传入神经的感觉功能及其反应特性 在与人类偏头痛有关的条件下调节在AIM的研究 我将研究脑膜感觉系统被调节以感知广泛的 感觉间机械刺激，包括生理性脑膜血管扩张和颅内压 立面。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 回应。目的3探讨机械敏感的Piezo2通道在心肌梗死中的相对作用。 介导传入细胞对正常脑内感觉信号的反应及其放大 在使用偏头痛触发剂之后。我们对形象提出的研究和创新方法 脑膜传入神经的活动可以极大地更好地理解 脑膜感觉系统处于动态平衡和导致偏头痛的病理生理条件下。 所取得的进展可能会加速临床前转化性头痛的研究。

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.