Mechanisms of Neurosteroid Regulation of Migraine

描述(申请人提供)：偏头痛是最常见的神经疾病之一，超过2900万美国人患有伴随偏头痛发作的令人衰弱的头痛和感觉障碍。目前还没有治愈偏头痛的方法，目前的治疗方案往往无效，或者让患者遭受严重的副作用。虽然偏头痛的根本原因尚不清楚，但许多患者报告的先兆通常被认为是闪光或盲点的视觉障碍。一种被称为皮质扩散性抑制(CSD)的神经现象可能会导致偏头痛先兆，导致偏头痛的发展。偏头痛患者经常找出特定的偏头痛诱因，包括压力、酒精、饮食、月经周期和怀孕。众所周知，这些触发因素还会增加大脑中神经类固醇的水平。神经类固醇可以在大脑中直接合成，也可以从外周产生的性类固醇中合成，并可以通过调节抑制性GABA能功能来影响神经元的兴奋性。据报道，偏头痛患者的神经元兴奋性增加，可以降低发生CSD的门槛。虽然性激素在偏头痛中的作用已经得到了广泛的研究，但对脑源性神经类固醇如何直接影响偏头痛的理解存在着严重的差距。这项建议集中在神经类固醇引起的兴奋性改变的作用和机制，以及它们如何影响CSD和偏头痛。我们假设，神经类固醇的作用是细胞类型依赖的，并且通过选择性地增强皮质抑制，矛盾地降低了CSD发生的阈值。在已建立的CSD动物模型中，利用尖端先进的电生理、成像、光遗传学和LSPs电路标测技术，有三个特定的目标来测试这一假说和潜在的机制。首先，神经类固醇如何不同地影响兴奋性神经元和抑制性神经元？(目标1)；第二，神经类固醇增强CSD的机制是什么？(目标2)；第三，神经类固醇是否抑制大脑皮层并放大突触回路？(目标3)。我们的初步数据表明，神经类固醇可能通过对快速放电的中间神经元的选择性作用，减少对兴奋性锥体神经元的抑制驱动，从而降低CSD的阈值。来自拟议实验的数据将为偏头痛的病理生理学以及神经类固醇可能是几种偏头痛触发因素的共同媒介的机制提供洞察力。此外，我们将检查是否可以针对特定的神经元群体来预防或抑制CSD。这些发现将使我们能够确定可能导致偏头痛患者兴奋性增强的机制，并可能为预防或减少偏头痛的治疗干预提供新的靶点。

DESCRIPTION (provided by applicant): Migraine is one of the most common neurological disorders with over 29 million Americans suffering from the debilitating headaches and sensory disturbances that accompany a migraine attack. There is no cure for migraine and current treatment options are often ineffective or leave patients suffering from significant adverse side effects. While the underlying cause of migraine remains unknown many patients report an aura that is often perceived as a visual disturbance of flashing lights or blind spots. A neurological phenomenon known as cortical spreading depression (CSD) may cause migraine aura leading to the development of migraine pain. Migraine patients often identify specific migraine triggers including stress, alcohol, diet, the menstrual cycle and pregnancy. These triggers are also known to increase levels of neurosteroids in the brain. Neurosteroids can be synthesized directly in the brain or from peripherally produced sex steroids and can influence neuronal excitability through modulation of inhibitory GABAergic function. Increased neuronal excitability has been reported in migraine patients and can lower the threshold for developing CSD. While the effects of sex steroids in migraine have been extensively studied there is a critical gap in th understanding of how brain-derived neurosteroids may directly influence migraine. This proposal focuses on the actions and mechanism of neurosteroid induced changes to excitability and how they may impact CSD and migraine. We hypothesize that the effects of neurosteroids are cell type dependent and by selectively enhancing cortical inhibition paradoxically decrease the threshold for the development of CSD. Three specific aims test this hypothesis and the underlying mechanism utilizing cutting-edge advanced electrophysiological, imaging, optogenetic and LSPS circuit mapping techniques in an established animal model of CSD. First, how do neurosteroids differentially affect excitatory and inhibitory neurons? (Aim 1); second, what is the mechanism of neurosteroid mediated enhancement of CSD? (Aim 2); and third, do neurosteroids disinhibit the cortex and amplify synaptic circuits? (Aim 3). Our preliminary data demonstrate that neurosteroids decrease the threshold for CSD potentially through a select action on fast-spiking interneurons that reduces inhibitory drive onto excitatory pyramidal neurons. The data from the proposed experiments will provide insights into the pathophysiology of migraine as well as a mechanism through which neurosteroids may be a common mediator for several migraine triggers. Additionally, we will examine if specific neuronal populations can be targeted to prevent or inhibit CSD. These findings will allow us to identify mechanisms that may lead to enhanced excitability in migraine patients and potentially novel targets for therapeutic intervention to prevent or minimize migraine headache.