Sensory plasticity in migraine

偏头痛的感觉可塑性

• 批准号: 8914056
• 负责人: Kevin Christopher Brennan
• 金额: $ 32.59万
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8914056
• 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; Health; Homeostasis; Human; Image; Individual; Interneurons; Kindling (Neurology); Label; Learning; Light; Lighting; Malignant - descriptor; Maps; Memantine; 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; release of sequestered calcium ion into cytoplasm; research study; response; sensory cortex; sensory input; somatosensory; sound; spreading depression; therapeutic target; treatment strategy; two-photon

DESCRIPTION (provided by applicant): 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 chronc 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 insighs 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.

描述（由申请人提供）：偏头痛影响世界人口的12％。慢性偏头痛完全破坏了患者的生活，影响了近3％，并且很难治疗。看来从情节到偏头痛状态的演变或“点燃”。偏头痛是一种疼痛障碍，但从根本上讲，它是一种大脑兴奋性的障碍，其基本表现是感觉输入的“体积”的增加。我们已经确定了皮质扩散抑郁症（CSD）后的大脑感觉反应的变化，这是脑活动的一波浪潮，它被认为是偏头痛的基础。值得注意的是，这些变化类似于可塑性期间大脑中看到的内容 - 即学习过程中。我们的核心假设是 CSD和其他与偏头痛有关的事件选择了感觉大脑的正常学习机制，导致一种功能失调的学习形式或恶性可塑性。我们怀疑急性偏头痛攻击的发展以及偏头痛的进展是由这种负面的可塑性过程驱动的。我们将使用在偏头痛患者中发现基因的小鼠中使用成像和电记录来检验该假设。我们的第一个目的集中在CSD引起的单个细胞功能的变化上，这被认为是偏头痛的基础。我们已经确定了CSD后神经元，星形胶质细胞和血管的结构和功能变化，每种都可以解释我们观察到的感觉网络响应的变化。我们的第二个目标扩大了我们观察CSD中断的较大神经网络的方法。除疼痛外，偏头痛还涉及光感知的变化。恐惧症或对照明的厌恶非常普遍。我们将在CSD之前和之后决定清醒小鼠的视觉皮层。我们的第三个目标将尝试将我们获得的依据应用于偏头痛治疗的发展。感觉图锐化 - 我们在CSD之后鉴定的感觉学习的标记之一 - 在人类中使用fMRI可以识别。我们将测试在慢性CSD刺激上是否发生感觉图的锐化，因此可能是偏头痛进展的生物标志物。最后，根据我们的细胞发现，我们将测试两种与临床上相关的药物，它们的机制可能是CSD后过度钙活性的抑制。总体而言，我们的实验应揭示偏头痛发作和偏头痛进展的基本机制，并指向抑制这种疾病中“恶性学习”的治疗策略。