Sensory plasticity in migraine

项目摘要/摘要 偏头痛影响了世界12%的人口。慢性偏头痛，它完全扰乱了 患者，影响近3%，极难治疗。这似乎是一种进化或“点燃”。 从发作性偏头痛到慢性偏头痛。偏头痛是一种疼痛障碍，但更根本的是它是一种 大脑兴奋性紊乱，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，这是一波 大脑活动被认为是偏头痛先兆的基础。值得注意的是，这些变化类似于我们所看到的 在大脑可塑性过程中--即在学习过程中。我们的核心假设是CSD和其他与偏头痛相关的 事件替代了感官大脑的正常学习机制，导致一种形式的学习障碍-或者 恶性可塑性。我们怀疑偏头痛急性发作的发展，以及 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验证这一假说。我们的首要目标是关注 CSD引起的个体细胞功能，被认为是偏头痛先兆的基础。我们已经确定了 CSD后神经元、星形胶质细胞和血管的结构和功能变化，其中每一种都可能 解释我们观察到的感觉网络反应的变化。我们的第二个目标是拓宽我们的视野 被CSD破坏的更大的神经网络。除了疼痛，偏头痛还涉及知觉的变化 指光；畏光或厌恶光是非常普遍的。我们将成像清醒小鼠的视皮层 当他们在CSD前后决定他们对光照水平的偏好时。我们的第三个目标将尝试应用 我们对偏头痛治疗方法的发展有了深刻的认识。感觉地图锐化-其中之一 我们在CSD后识别的感觉学习标记-可能可以在人类中使用fMRI识别。我们将测试 感觉图的锐化是否发生在慢性CSD刺激下，从而可能作为一个生物标志物 偏头痛的进展。最后，根据我们的细胞发现，我们将测试两个与临床相关的 其机制可能是抑制CSD后过度钙活动的药物。总的来说，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，并指出治疗策略，以阻止发生在 这种病。

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.