Cortical-meningeal interactions underlying migraine headache

偏头痛是全世界导致残疾的主要原因之一。对许多人来说，现有的治疗方法仍然难以捉摸 由于认识的不完全，新的治疗方法的发展受到了限制 偏头痛的发病机制。 现在有大量的工作支持偏头痛与 三叉神经感觉系统，支配脑膜及其相关的大血管，但它仍然 不清楚这种感觉系统是如何被激活的 在偏头痛发作期间。一条领先的证据 指出了皮质功能障碍在引发偏头痛中的作用，并得到了以下发现的支持 皮质扩散性抑制(CSD)可引起脑膜神经元的激活和敏感化 伤害性通路。然而，CSD被认为只在一小部分攻击中触发令人头疼的攻击 都伴随着气场。感觉皮层过度兴奋也被记录在没有先兆的偏头痛中。 然而，除了慢性阻塞性肺疾病之外，目前尚不清楚这种皮质功能障碍是否以及如何导致脑膜。 伤害性感觉和随之而来的头痛。认为(I)大脑皮层过度兴奋性可以驱动 皮质星形胶质细胞通过其不同的GPCR异常激活，以及(Ii)这将导致过度 大量具有疼痛特性的星形细胞因子的释放可以传播到脑膜，使我们 假设与CSD无关的皮质星形胶质细胞GPCR连接信号的增强足以驱动 脑膜感觉通路 。为了测试我们的工作假设，我们将首先确定是否有选择性 感觉皮质星形胶质细胞GQ-和GI-GPCR通路的激活足以驱动脑膜伤害性感受器， 以及增强的星形细胞GPCRR是否与 Ca~(2+)信号起作用(目标1)。然后我们将检查 这种增强的皮质星形胶质细胞信号是否也可以促进偏头痛样疼痛行为(目标2)。 因为降钙素基因相关肽(CGRP)与偏头痛的病理生理学密切相关，但其作用是 目前还不清楚，我们将进一步测试皮质星形胶质细胞是否介导脑膜伤害性反应 反应和相关的偏头痛行为表型涉及颅内内的外周CGRP信号 硬脑膜(目标3)。为了解决这些研究问题，我们将采用最先进的化学遗传学 DREADD(“专门由设计师药物激活的设计师受体”)工具，以及光遗传学，以 选择性地促进星形胶质细胞GPCR通路的激活。我们将把这些方法与体内实验结合起来 细胞外单单位记录、双光子钙成像、行为方法以及遗传学 询问感觉皮质GQ和GI增强的脑膜伤害性后果的手法 链接的钙信号。综上所述，我们提议的研究可能会揭示星形胶质细胞GPCR信号的增加 在偏头痛发作中，作为连接感觉皮层过度兴奋和头痛发生的关键机制， 不涉及CSD和AURA。

Migraine is one of the top leading causes of disability worldwide. Existing treatments remain elusive for many patients, and development of novel treatments approaches has been limited due to the incomplete understanding of migraine pathogenesis. A large body of work now supports the notion that migraine headache involves the trigeminal sensory system that innervates the cerebral meninges and their related large vessels, but it remains unclear how this sensory system becomes activated during a migraine attack. One leading line of evidence points to the role of cortical dysfunction in triggering migraine headache, and is supported by the findings that cortical spreading depression (CSD) can cause the activation and sensitization of neurons in the meningeal nociceptive pathway. However, CSD is thought to trigger the headache in only the small subset of attacks that are accompanied by aura. Sensory cortex hyperexcitability has also been documented in migraine without aura. However, it is unclear whether and how such cortical dysfunction, beyond CSD, might lead to meningeal nociception and the ensuing generation of headache. The notions that (i) cortical hyperexcitability can drive abnormal activation of cortical astrocytes via their diverse GPCRs, and (ii) that this would result in excessive release of numerous astrocytic factors with algesic properties that can propagate into the meninges, has led us to hypothesize that heightened cortical astrocyte GPCR-linked signaling, unrelated to CSD, is sufficient to drive the meningeal sensory pathway . To test our working hypothesis, we will first determine whether selective activation of sensory cortical astrocyte Gq- and Gi-GPCR pathways are sufficient to drive meningeal nociceptors, and whether enhanced astrocytic GPCRR-linked Ca2+ signaling plays a role (Aim 1). We will then examine whether such enhanced cortical astrocyte signaling can also promote migraine-like pain behaviors (Aim 2). Because calcitonin gene-related peptide (CGRP) is critically involved migraine pathophysiology, but its role is still not well understood, we will further test whether the cortical astrocyte mediated meningeal nociceptive responses and related migraine behavioral phenotype involve peripheral CGRP signaling within the intracranial dura mater (Aim 3). To address these research questions, we will employ a state-of-the-art chemogenetic DREADD (“designer receptors exclusively activated by designer drugs”) tools, as well as optogenetics, to selectively promote activation of astrocyte GPCR pathways. We will combine these approaches with in vivo extracellular single-unit recording , 2-photon calcium imaging, behavioral approaches, as well as genetic manipulations to interrogate the meningeal nociceptive consequences of enhanced sensory cortical Gq- and Gi- linked Ca2+ signaling. Taken together, our proposed research could reveal increased astrocyte GPCR signaling as a key mechanism that links sensory cortex hyperexcitability and headache genesis in in migraine attacks that do not involve CSD and aura.