Cortical-meningeal interactions underlying migraine headache

偏头痛背后的皮质-脑膜相互作用

• 批准号: 10319009
• 负责人: DAN LEVY
• 金额: $ 44.37万
• 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/10319009
• 关键词: Acute; Address; Adult; Afferent Neurons; Astrocytes; Attenuated; Auras; Automobile Driving; Behavior; Behavioral; Brain; Calcitonin Gene-Related Peptide; Calcium; Cephalic; Cerebral meninges; Cerebrum; Chronic; Common Migraine; Data; Development; Diffuse; Dura Mater; Electrophysiology (science); Functional disorder; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Generations; Genetic; Grant; Headache; Image; Investigation; Lead; Link; Mediating; Mediator of activation protein; 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; Receptor Signaling; Research; Research Project Grants; Role; Sensory; Signal Pathway; Signal Transduction; Spreading Cortical Depression; Subarachnoid Space; Testing; Trigeminal System; afferent nerve; allodynia; base; 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; 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.

偏头痛是全球残疾的主要原因之一。对于许多人来说，现有治疗仍然难以捉摸 由于不完全理解，患者以及新型治疗方法的发展受到限制 偏头痛发病机理。 现在，大量的工作支持偏头痛标题涉及的观念 支配大脑脑膜及其相关大容器的三叉神经感觉系统，但仍保持 不清楚该感官系统如何激活 在偏头痛攻击中。一条主要证据 指出皮质功能障碍在触发偏头痛标题中的作用，并得到了以下发现的支持。 皮质扩散抑郁症（CSD）会导致脑膜中神经元的激活和敏感性 伤害性途径。但是，CSD被认为仅在攻击的一小部分中触发标题 是由光环完成的。在没有光环的偏头痛中，还记录了感觉皮层过度兴奋性。 但是，目前尚不清楚这种皮质功能障碍（超出CSD）是否会导致脑膜 伤害感和确保头痛的产生。注意到（i）皮质过度刺激性可以驱动 皮质星形胶质细胞通过其潜水员GPCR的异常激活，（ii）这会导致过量 释放众多具有掌控性能的星形细胞因子，可以传播到脑膜中 为了假设增强的皮质星形胶质细胞GPCR连接信号与CSD无关，足以驱动 脑膜感觉途径 。为了检验我们的工作假设，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途径的激活足以驱动脑膜伤害感受器， 以及增强的星形细胞GPCRR连接 CA2+信号传导起作用（AIM 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（AIM 2）。 因为降钙素基因相关肽（CGRP）至关重要涉及偏头痛的病理生理学，但其作用是 仍然不太了解，我们将进一步测试皮质星形胶质细胞介导的脑膜伤害感受 反应和相关的偏头痛行为表型涉及颅内周围的CGRP信号传导 硬脑膜（AIM 3）。为了解决这些研究问题，我们将采用最先进的化学生成 dreadd（“设计器的设计师专门由设计师药物激活”）工具以及光遗传学 有选择地促进星形胶质细胞GPCR途径的激活。我们将将这些方法与体内结合 细胞外单单元记录，2光子钙成像，行为方法以及通用 操纵以增强感觉皮质GQ和Gi的脑膜伤害感受的后果 链接的CA2+信号。综上所述，我们提出的研究可能揭示了星形胶质细胞GPCR信号的增加 作为将感觉皮层过度刺激性和偏头痛攻击中的标题创世纪连接起来的关键机制 不涉及CSD和Aura。