Cortical Spreading Depression in the Origins of the Migraine Attack

偏头痛发作起源中的皮质扩散性抑郁

• 批准号: 10187664
• 负责人: Kevin Christopher Brennan
• 金额: $ 33.14万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10187664
• 关键词: Address; Affect; Animal Model; Animals; Astrocytes; Auras; Biological Models; Brain; Brain region; Cerebral cortex; Data; Disease; Electrophysiology (science); Event; Exhibits; Failure; Familial Hemiplegic Migraine; Glutamates; Goals; Human; Image; In Vitro; Individual; Lead; Measurable; Mediator of activation protein; Migraine; Motor Cortex; Mus; Neurobiology; Neuroglia; Neurons; Neurosciences Research; Pain; Patients; Physiological; Population; Potassium; Potassium Glutamate; Predisposition; Resolution; Role; Sensory; Sensory Hallucinations; Spreading Cortical Depression; System; Techniques; Testing; Vibrissae; Visual Cortex; Work; awake; barrel cortex; base; disability; expectation; experimental study; extracellular; genetic manipulation; human model; in vivo; insight; novel; reuptake; sensory cortex; tool; two photon microscopy

PROJECT SUMMARY/ABSTRACT Migraine affects 12% of the world population, and is one of the leading causes of disability worldide. Yet surprisingly little is known about the basic features of this disease. One of the major questions in migraine is how its quintessential feature, the migraine attack, is generated. For approximately a third of migraineurs, the pain of the attack is preceded by an aura, typically a sensory hallucination. Unlike the attack, the aura is physiologially measurable, in humans and in animal model systems, because its physiological correlate is a massive depolarization called cortical spreading depression (CSD). By understanding how CSD is generated, we can understand how the attack begins. Our three aims address the origins of the migraine attack from different angles. The first aim builds on our work showing that CSD, like the aura, has a predilection for sensory cortex. We ask why this predilection exists, with the expectation that understanding the mechanisms will yield insights as to how the aura, and thus the attack, are generated. We use a combination of imaging, electrophysiology and transporter expression analysis to examine the reuptake of extracellular potassium and glutamate, with the hypothesis that barrel cortex may exhibit a relative deficiency in reuptake compared to other regions. The second aim tests the hypothesis that failure or saturation of astrocytic reuptake mechanisms underlies CSD ignition. Our preliminary data on CSD propagation shows astrocyte activation well in advance of the wave, and suggests a failure of potassium reuptake at the advancing wavefront. We will genetically ablate key astrocyte mediators of potassium reuptake as the cortex is brought to CSD threshold in vivo, in order to test the role of the astrocyte, and determine which mechanism is most important. The third aim asks how CSD, a massive depolarization, is generated in an ostensibly intact brain. Here our preliminary data on sensory cortex susceptibility is particularly important, as it allows us to constrain potentially open-ended experiments. We will systematically test triggers of aura in awake behaving animals while we record from sensory cortex using two photon microscopy.

项目摘要/摘要 偏头痛影响世界人口的12％，是世界上残疾的主要原因之一。然而 令人惊讶的是，对这种疾病的基本特征知之甚少。偏头痛的主要问题之一是 如何生成其典型功能，即偏头痛攻击。对于偏头痛的大约三分之一， 攻击的痛苦之前是光环，通常是感官幻觉。与攻击不同，光环是 在人类和动物模型系统中，在生理上可测量的是，因为它的生理相关性是一种 大量的去极化称为皮质扩散抑郁症（CSD）。通过了解如何生成CSD， 我们可以理解攻击是如何开始的。我们的三个目的解决了偏头痛攻击的起源 不同的角度。第一个目标是基于我们的工作，表明CSD像Aura一样，对 感觉皮层。我们问为什么存在这种偏见，并期望理解机制 将产生有关如何产生光环以及攻击的见解。我们使用成像的组合， 电生理学和转运蛋白表达分析，以检查细胞外钾和 谷氨酸，假设桶皮层可能表现 其他地区。第二个目的检验了星形胶质性再摄取机制失败或饱和的假设 基础CSD点火。我们关于CSD传播的初步数据表明，星形胶质细胞在 波浪，暗示在前进波前的钾再摄取失败。我们将在遗传上唤醒 钾再摄取的关键星形胶质细胞介质将皮质带到体内CSD阈值，以便为了 测试星形胶质细胞的作用，并确定哪种机制最重要。第三个目标询问CSD如何 在表面上完整的大脑中产生了大量的去极化。在这里，我们有关感官的初步数据 皮层易感性尤其重要，因为它使我们能够限制潜在的开放式实验。 我们将系统地测试Aura在醒着的动物中的触发器，而从感觉皮层记录 使用两个光子显微镜。