Mechanisms of Neurosteroid Regulation of Migraine

描述（由申请人提供）：偏头痛是最常见的神经系统疾病之一，超过2900万美国人患有伴随偏头痛发作的衰弱性头痛和感觉障碍。偏头痛无法治愈，目前的治疗方案往往无效，或使患者遭受严重的不良副作用。虽然偏头痛的根本原因仍然未知，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）的神经学现象可能导致偏头痛先兆，从而导致偏头痛的发展。偏头痛患者通常会识别特定的偏头痛触发因素，包括压力，酒精，饮食，月经周期和怀孕。这些触发因素也被认为会增加大脑中神经类固醇的水平。神经类固醇可以直接在脑中合成，也可以由外周产生的性类固醇合成，并可以通过调节抑制性GABA能功能来影响神经元的兴奋性。偏头痛患者的神经元兴奋性增加，可以降低发展CSD的阈值。虽然性类固醇在偏头痛中的作用已被广泛研究，但在脑源性神经类固醇如何直接影响偏头痛的理解方面存在重大差距。该建议的重点是神经类固醇诱导的兴奋性变化的作用和机制，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性的，并且通过选择性地增强皮质抑制，矛盾地降低了CSD发展的阈值。三个具体的目标测试这一假设和潜在的机制，利用尖端先进的电生理学，成像，光遗传学和LSPS电路映射技术在一个建立的动物模型CSD。首先，神经类固醇如何区别地影响兴奋性和抑制性神经元？(Aim第二，神经甾体介导的CSD增强机制是什么？(Aim第三，神经类固醇是否能解除皮质抑制并放大突触回路？(Aim 3）。我们的初步数据表明，神经甾体降低CSD的阈值可能通过选择行动的快速尖峰的中间神经元，减少抑制驱动兴奋性锥体神经元。从拟议的实验数据将提供洞察偏头痛的病理生理学，以及通过神经类固醇可能是一个共同的调解几个偏头痛触发机制。此外，我们将研究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，以及预防或减少偏头痛的治疗干预的潜在新靶点。

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.