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.

项目总结/摘要 偏头痛影响世界人口的12%，是导致残疾的主要原因之一。然而 令人惊讶的是，人们对这种疾病的基本特征知之甚少。偏头痛的一个主要问题是 其典型特征偏头痛发作是如何产生的。对于大约三分之一的偏头痛患者来说， 发作的疼痛之前有一种先兆，通常是一种感觉幻觉。与攻击不同的是， 在人类和动物模型系统中，它是生理学上可测量的，因为它的生理相关性是 大规模去极化称为皮层扩散性抑制（CSD）。通过了解CSD是如何生成的， 我们就能理解攻击是如何开始的我们的三个目标解决偏头痛发作的起源， 不同角度第一个目标建立在我们的工作基础上，表明CSD，就像光环一样， 感觉皮层我们问为什么这种偏好存在，并期望了解机制， 将产生关于光环以及攻击是如何产生的见解。我们结合成像， 电生理学和转运蛋白表达分析，以检查细胞外钾的再摄取， 谷氨酸，假设桶皮质可能表现出相对缺乏的再摄取相比， 其他地区。第二个目的是检验星形胶质细胞重摄取机制的失败或饱和 是CSD点火的基础我们关于CSD增殖的初步数据显示，星形胶质细胞的激活早于 波，并表明钾再摄取失败，在前进的波前。我们将从基因上消除 关键星形胶质细胞介导的钾重摄取，因为皮质在体内达到CSD阈值， 测试星形胶质细胞的作用，并确定哪种机制最重要。第三个目标是问CSD， 一个表面上完整的大脑会产生大量的去极化。这是我们关于感官的初步数据 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。 我们将系统地测试清醒行为动物的先兆触发，同时我们从感觉皮层记录 使用双光子显微镜。