Sex differences in the basic pathophysiology of migraine

描述(申请人提供)：在一生中，有四分之一的女性和十分之一的男性患有偏头痛。它还会造成相当大的痛苦。就像许多主要影响女性的疾病一样，人们对它知之甚少。但偏头痛在女性中更常见这一事实本身就可以为偏头痛的起源提供线索。偏头痛在生育期更为严重，但在绝经后有所改善。它在月经前后恶化，但在怀孕期间改善。这表明它的起源是荷尔蒙的作用。我们建议研究女性性激素雌激素和孕激素在皮质扩散性抑制(CSD)中的作用，这一事件被认为是某些形式的偏头痛的基础。我们的目标是了解这一过程，特别是在女性身上，因为她们受到这种疾病的影响最大。使用一种名为光学本征信号成像(OIS)的技术，我们可以直接在小鼠身上成像CSD。我们可以用这个小鼠模型来研究雌激素和孕激素在慢性阻塞性肺疾病中的作用。我们的初步数据表明孕酮对CSD有抑制作用，而雌激素对神经元准备是已知的兴奋作用，因此本研究有合理的基础。我们认为，这些激素在月经周期、妊娠和更年期的不同水平会导致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的阈值和反应来测试这一点。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慢性阻塞性肺疾病期间对大脑表面血管的影响。据认为，这些血管对CSD的反应方式是产生偏头痛患者所感受到的疼痛。在这些变化中可能有荷尔蒙的作用，因为雌激素是一种强有力的血管扩张剂。最后，我们将评估雌激素和孕激素对星形胶质细胞钙波的影响，钙波的传播方式与CSD非常相似。由于星形胶质细胞对雌激素和孕激素都有反应，它们可能参与了偏头痛的激素调节。我们将在脑片和培养中测试雌激素和黄体酮的作用。人们希望这些实验将阐明偏头痛的基本机制，特别是为什么偏头痛对女性的影响比男性大得多的问题。

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.