Sensory plasticity in migraine

描述（由申请人提供）：偏头痛影响世界人口的12%。慢性偏头痛完全扰乱了患者的生活，影响接近3%，并且非常难以治疗。似乎有一个从发作性偏头痛到慢性偏头痛状态的演变或“点燃”。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“体积”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，这是一种被认为是偏头痛先兆的大脑活动波。值得注意的是，这些变化类似于大脑在可塑性过程中所看到的变化-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会影响大脑感觉系统的正常学习机制，从而导致学习功能障碍或恶性可塑性。我们怀疑急性偏头痛发作的发展和偏头痛的进展是由这种负可塑性过程驱动的。我们将在表达偏头痛患者基因的小鼠中使用成像和电子记录来验证这一假设。我们的第一个目标集中在CSD引起的个体细胞功能的变化，这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，每一个都可以解释我们观察到的感觉网络反应的变化。我们的第二个目标扩展了我们的方法，以研究被CSD破坏的更大的神经网络。除了疼痛之外，偏头痛还涉及对光的感知的变化;对光的恐惧或厌恶是非常常见的。我们将对清醒小鼠的视觉皮层进行成像，因为它们在CSD之前和之后决定了它们对光照水平的偏好。我们的第三个目标是尝试将我们已经获得的见解应用于偏头痛治疗的发展。感觉地图的锐化--我们在CSD之后发现的感觉学习的标志之一--可能在人类中使用功能磁共振成像来识别。我们将测试是否锐化感觉地图发生慢性CSD刺激，从而可能作为偏头痛进展的生物标志物。最后，根据我们的细胞研究结果，我们将测试两种临床相关的药物，其机制可能是抑制CSD后过度的钙活性。总的来说，我们的实验应该揭示偏头痛发作和偏头痛进展的基本机制，并指出阻止这种疾病发生的“恶性学习”的治疗策略。

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.