Cortical-Meningeal Interactions Underlying Migraine Headache

偏头痛背后的皮质-脑膜相互作用

• 批准号: 10534662
• 负责人: DAN LEVY
• 金额: $ 49.8万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10534662
• 关键词: Acute; Address; Adult; Afferent Neurons; Anesthesia procedures; Astrocytes; Attenuated; Auras; Automobile Driving; Behavior; Behavioral; Brain; Calcitonin Gene-Related Peptide; Calcium; Cephalic; Cerebral meninges; Chronic; Common Migraine; Data; Development; Dura Mater; Electrophysiology (science); Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Generations; Genetic; Grant; Headache; ITPR1 gene; Image; Investigation; Leptomeninges; Link; Mediating; Mediator; Meningeal; Meninges; Methods; Migraine; Monitor; Monoclonal Antibodies; Mus; Nerve Endings; Neurons; Nitroglycerin; Nociception; Nociceptors; Pathogenesis; Pathway interactions; Patients; Peptide Signal Sequences; Peripheral; Play; Population; Process; Property; Rattus; Research; Research Project Grants; Role; Sensory; Signal Pathway; Signal Transduction; Spreading Cortical Depression; Subarachnoid Space; Testing; Trigeminal System; afferent nerve; allodynia; behavioral phenotyping; cell type; designer receptors exclusively activated by designer drugs; disability; extracellular; genetic approach; genetic manipulation; imaging approach; imaging modality; in vivo; inhibiting antibody; nociceptive response; novel; optogenetics; pain behavior; pain sensitivity; receptor; response; sensory cortex; sensory system; tool; two-photon

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.

偏头痛是全球导致残疾的首要原因之一。现有的治疗方法对许多人来说仍然难以捉摸 由于了解不完全，新治疗方法的开发受到限制 偏头痛的发病机制。 现在大量的研究工作支持这样的观点：偏头痛与 三叉神经感觉系统，支配脑膜及其相关大血管，但它仍然存在 不清楚这个感觉系统是如何被激活的 偏头痛发作期间。一条主要证据 指出皮质功能障碍在引发偏头痛中的作用，并得到以下研究结果的支持 皮质扩散抑制（CSD）可引起脑膜神经元的激活和敏化 伤害感受途径。然而，CSD 被认为只会在一小部分攻击中引发头痛。 都伴随着灵气。感觉皮层过度兴奋也被记录在无先兆偏头痛中。 然而，目前尚不清楚除了 CSD 之外，这种皮质功能障碍是否以及如何导致脑膜损伤 伤害感受和随之而来的头痛。 (i) 皮质过度兴奋可以驱动的概念 皮质星形胶质细胞通过其不同的 GPCR 异常激活，并且 (ii) 这会导致过度的 释放大量具有镇痛特性的星形细胞因子，可以传播到脑膜中，使我们 假设与 CSD 无关的皮质星形胶质细胞 GPCR 相关信号增强足以驱动 脑膜感觉通路 。为了检验我们的工作假设，我们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感受器， 以及是否增强星形胶质细胞 GPCRR 相关 Ca2+ 信号传导发挥了作用（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传导是否也会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 目前还不是很清楚，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感受 反应和相关偏头痛行为表型涉及颅内外周 CGRP 信号传导 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技术 DREADD（“专门由设计药物激活的设计受体”）工具以及光遗传学， 选择性促进星形胶质细胞 GPCR 通路的激活。我们将把这些方法与体内 细胞外单单位记录、2光子钙成像、行为方法以及遗传 询问增强感觉皮层 Gq- 和 Gi- 的脑膜伤害性后果的操作 相关的 Ca2+ 信号传导。综上所述，我们提出的研究可能揭示星形胶质细胞 GPCR 信号传导增强 作为连接感觉皮层过度兴奋和偏头痛发作中头痛发生的关键机制 不涉及CSD和光环。