Sensory plasticity in migraine

偏头痛的感觉可塑性

• 批准号: 8742020
• 负责人: Kevin Christopher Brennan
• 金额: $ 32.27万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-26 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8742020
• 关键词: Acute; Affect; Animals; Astrocytes; Attenuated; Auras; Basic Science; Behavior; Biological Markers; Biological Neural Networks; Blinking; Blood Vessels; Brain; Brain Diseases; Brain Stem; Calcium; Cell physiology; Cells; Chemosensitization; Chronic; Chronic Disease; Clinical; Coupling; Data; Decision Making; Development; Disease; Electrophysiology (science); Environment; Equilibrium; Esthesia; Event; Evolution; Familial Hemiplegic Migraine; Flunarizine; Functional Magnetic Resonance Imaging; Functional disorder; Genes; Head; Headache; Homeostasis; Human; Image; Individual; Interneurons; Kindling (Neurology); Label; Learning; Light; Lighting; Malignant - descriptor; Maps; Memantine; Metric; Microscopy; Migraine; Modeling; Modification; Mus; Neurobiology; Neurons; Neurosciences; Optics; Pain; Pain Disorder; Pathway interactions; Patients; Perception; Pharmaceutical Preparations; Photophobia; Physiological; Physiology; Population; Positioning Attribute; Preparation; Process; Publishing; Pyramidal Cells; Resolution; Role; Sensory; Sensory Disorders; Sensory Process; Signal Transduction; Spreading Cortical Depression; Structure; System; Techniques; Testing; Touch sensation; Transgenic Mice; Translating; Visual Cortex; Whole-Cell Recordings; awake; base; burden of illness; casein kinase I; clinically relevant; in vivo; insight; mutant; nervous system disorder; neurovascular unit; preference; public health relevance; release of sequestered calcium ion into cytoplasm; research study; response; sensory cortex; somatosensory; sound; spreading depression; therapeutic target; treatment strategy; two-photon

PROJECT SUMMARY/ABSTRACT Migraine affects 12% of the world population. Chronic migraine, which completely disrupts the lives of sufferers, affects close to 3%, and is extremely difficult to treat. It appears that there is an evolution or 'kindling' from an episodic to a chronic migraine state. Migraine is a pain disorder, but more fundamentally it is a disorder of brain excitability, whose fundamental manifestation is an increase in the 'volume' of sensory input. We have identified changes in brain sensory responses after cortical spreading depression (CSD), a wave of brain activity that is thought to underlie the migraine aura. Remarkably, these changes resemble what is seen in the brain during plasticity - i.e. during learning. Our core hypothesis is that CSD and other migraine-related events co-opt the normal learning machinery of the sensory brain to cause a form of dysfunctional learning - or malignant plasticity. We suspect that the development of an acute migraine attack, and the progression of migraine, is driven by this negative plasticity process. We will use imaging and electrical recordings in mice expressing genes found in migraine patients to test this hypothesis. Our first aim focuses on the changes in individual cellular function caused by CSD, which is thought to underlie the migraine aura. We have identified structural and functional changes in neurons, astrocytes, and blood vessels after CSD, each of which might explain the change in sensory network response we observed. Our second aim broadens our approach to look at larger neural networks disrupted by CSD. In addition to pain, migraine also involves changes in perception of light; photophobia or aversion to light is extremely common. We will image the visual cortex of awake mice as they decide on their preference for light levels, before and after CSD. Our third aim will try to apply the insights we have gained to the development of migraine treatments. Sensory map sharpening - one of the markers of sensory learning we identified after CSD - may be identifiable in humans using fMRI. We will test whether sharpening of sensory maps occurs on chronic CSD stimulation, and thus might serve as a biomarker of migraine progression. Finally, on the basis of our cellular findings, we will test two clinically-relevant medications whose mechanism may be suppression of excessive calcium activity after CSD. Overall, our experiments should uncover basic mechanisms underlying the development of a migraine attack and the progression of migraine, and point to treatment strategies that arrest the 'malignant learning' that takes place in this disease.

项目概要/摘要 偏头痛影响着世界 12% 的人口。慢性偏头痛，完全扰乱了人们的生活 患者的患病率接近 3%，且治疗极其困难。似乎有一种进化或“点燃” 从发作性偏头痛状态转为慢性偏头痛状态。偏头痛是一种疼痛疾病，但更根本的是，它是一种 大脑兴奋性障碍，其基本表现是感觉输入“量”的增加。 我们已经确定了皮质扩散抑制（CSD）后大脑感觉反应的变化，这是一波 被认为是偏头痛先兆的大脑活动。值得注意的是，这些变化与所看到的相似 在可塑性期间（即学习期间）在大脑中。我们的核心假设是 CSD 和其他与偏头痛相关的疾病 事件选择了感觉脑的正常学习机制，导致某种形式的功能障碍学习——或者 恶性可塑性。我们怀疑急性偏头痛的发生以及偏头痛的进展 偏头痛是由这种负可塑性过程驱动的。我们将在小鼠身上使用成像和电子记录 表达在偏头痛患者中发现的基因来检验这一假设。我们的首要目标集中在改变 由 CSD 引起的个体细胞功能被认为是偏头痛先兆的基础。我们已经确定 CSD 后神经元、星形胶质细胞和血管的结构和功能发生变化，其中每一个都可能 解释我们观察到的感觉网络反应的变化。我们的第二个目标拓宽了我们的观察方法 在被 CSD 破坏的更大的神经网络中。除了疼痛之外，偏头痛还涉及感知的改变 光的；畏光或厌恶光是非常常见的。我们将对清醒小鼠的视觉皮层进行成像 因为他们决定在 CSD 之前和之后对光照水平的偏好。我们的第三个目标将尝试应用 我们对偏头痛治疗的开发获得了见解。感官图锐化 - 其中之一 我们在 CSD 后发现的感觉学习标记 - 可以使用功能磁共振成像在人类中进行识别。我们将测试 慢性 CSD 刺激是否会导致感觉图锐化，因此可能作为生物标志物 偏头痛进展。最后，根据我们的细胞研究结果，我们将测试两个临床相关的 其机制可能是抑制 CSD 后过量钙活性的药物。总体而言，我们的 实验应该揭示偏头痛发作的基本机制以及 偏头痛的进展，并指出阻止发生在偏头痛中的“恶性学习”的治疗策略 这种病。