Sensory plasticity in migraine

项目概要/摘要 偏头痛影响着世界人口的12%。慢性偏头痛，这完全扰乱了生活， 患者，影响接近3%，并且非常难以治疗。似乎有一种进化或'点燃' 从间歇性偏头痛转变为慢性偏头痛偏头痛是一种疼痛障碍，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的“量”增加。 我们已经确定了皮层扩散性抑制（CSD）后大脑感觉反应的变化， 大脑活动被认为是偏头痛先兆的基础。值得注意的是，这些变化与我们所看到的 在大脑的可塑性阶段，也就是学习阶段。我们的核心假设是CSD和其他与偏头痛有关的 事件会使感觉脑的正常学习机制发生变化，从而导致某种形式的功能失调的学习，或者 恶性可塑性我们怀疑急性偏头痛发作的发展， 偏头痛是由这种负可塑性过程驱动的。我们将在老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验证这一假设。我们的第一个目标是关注 由CSD引起的个体细胞功能，这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变化，每一种变化都可能 解释了我们观察到的感觉网络反应的变化。我们的第二个目标是拓宽我们的方法， 被CSD破坏的更大的神经网络。除了疼痛，偏头痛还涉及感知的变化 对光的恐惧;对光的恐惧或厌恶是非常普遍的。我们将对清醒老鼠的视觉皮层进行成像 因为他们决定在CSD之前和之后他们对光水平的偏好。我们的第三个目标将尝试应用 我们对偏头痛治疗的发展所获得的见解。感官地图锐化--其中之一 我们在CSD后发现的感觉学习的标记-可以通过功能磁共振成像在人类中识别。我们将测试 慢性CSD刺激是否会出现感觉地图的锐化，从而可能作为生物标志物 偏头痛的进展。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后过度钙活性的药物。总体而言，我们 实验应该揭示偏头痛发作的基本机制， 偏头痛的进展，并指出治疗策略，逮捕'恶性学习'，发生在 这种疾病。

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.