Sex differences in the basic pathophysiology of migraine

描述（由申请人提供）：一生中有四分之一的女性和十分之一的男性患有偏头痛。它也会造成相当大的痛苦。像许多主要影响妇女的疾病一样，人们对它知之甚少。但偏头痛在女性中更常见的事实可以为其起源提供线索。偏头痛在生育年龄更严重，但在绝经后有所改善。月经前后会恶化，但在怀孕期间会有所改善。这表明荷尔蒙在其起源中起了作用。我们建议研究雌性激素雌激素和黄体酮在皮质扩张性抑制（CSD）中的作用，这一事件被认为是某些形式偏头痛的基础。目标是了解女性的具体过程，因为她们最容易患这种疾病。利用光学本征信号成像（OIS）技术，我们可以直接对小鼠CSD进行成像。我们可以利用该小鼠模型来研究雌激素和孕激素在CSD中的作用。我们的初步数据表明黄体酮对CSD有抑制作用，而雌激素对神经元制剂具有兴奋性，因此本研究有合理的依据。我们认为，这些激素在月经周期、妊娠期和绝经期的不同水平导致了对CSD易感性的变化。我们将通过测量雌性小鼠在这些不同阶段对CSD的阈值和反应来验证这一点。接下来，我们将评估这些激素对雄性和去卵巢雌性小鼠CSD的影响，以分离它们在不受内源性激素影响的情况下的作用。我们还将研究雌激素和黄体酮在CSD期间对脑表面血管的影响。这些血管被认为以这样一种方式对CSD作出反应，即它们产生偏头痛患者所感受到的疼痛。激素可能在这些变化中起作用，因为雌激素是一种有效的血管扩张剂。最后，我们将评估雌激素和黄体酮对星形胶质细胞钙波的影响，其传播方式与CSD非常相似。由于星形胶质细胞对雌激素和黄体酮都有反应，它们可能参与偏头痛的激素调节。我们将在脑切片和培养中测试雌激素和黄体酮的作用。人们希望这些实验能揭示偏头痛的基本机制，特别是为什么偏头痛对女性的影响比男性大得多。

DESCRIPTION (provided by applicant): Migraine affects one in four women, and one in ten men, over a lifetime. It also causes considerable suffering. Like many diseases that mainly affect women, it is poorly understood. But the very fact that migraine is more frequent in women can yield clues to its origins. Migraine is more severe during the reproductive years, but improves after menopause. It worsens around menstruation, but improves during pregnancy. This suggests a hormonal role in its origins. We propose to study the role of the female sex hormones estrogen and progesterone in cortical spreading depression (CSD), the event thought to underlie certain forms of migraine. The goal is to understand the process specifically in women, as they suffer most from this disease. Using a technique called optical intrinsic signal imaging (OIS), we can directly image CSD in mice. We can use this mouse model to study the role of estrogen and progesterone in CSD. Our preliminary data suggests an inhibitory effect of progesterone on CSD, and estrogen is known to be excitatory to neuronal preparations, thus there is a rational basis for this study. We propose that the different levels of these hormones over the menstrual cycle, pregnancy, and menopause cause changes in the susceptibility to CSD. We will test this by measuring threshold for and response to CSD at these different stages in female mice. Next, we will evaluate the effect of these hormones on CSD in male and ovariectomized female mice, in order to isolate their roles without the effect of endogenous hormones. We will also examine the effects of estrogen and progesterone on the surface vessels of the brain during CSD. These vessels are thought to respond to CSD in such a way that they generate the pain felt by the migraine sufferer. A hormonal role is possible in these changes, as estrogen is a potent vasodilator. Finally, we will evaluate the effects of estrogen and progesterone on astrocyte calcium waves, which propagate in a manner remarkably similar to CSD. As astrocytes respond to both estrogen and progesterone, it is possible that they participate in the hormonal modulation of migraine. We will test the effects of estrogen and progesterone in brain slices and in culture. It is hoped that these experiments will shed light on the basic mechanisms of migraine, in particular the question of why migraine affects women so much more than men.