Mechanisms of Neurosteroid Regulation of Migraine

神经类固醇调节偏头痛的机制

• 批准号: 8672480
• 负责人: Trent Anderson
• 金额: $ 33.14万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8672480
• 关键词: Address; Adverse effects; Affect; Alcohols; Allopregnanolone; American; Animal Model; Auras; Brain; Cells; Classic Migraine; Data; Development; Diet; Equilibrium; Finasteride; Functional disorder; Glutamates; Goals; Gonadal Steroid Hormones; Halorhodopsins; Headache; Image; Interneurons; Lasers; Lead; Left; Maps; Mediating; Mediator of activation protein; Menstrual cycle; Metabolism; Migraine; Neurologic; Neurons; Output; Oxidoreductase; Pain; Pathogenesis; Pathway interactions; Patients; Population; Pregnancy; Progesterone; Recurrence; Regulation; Reporting; Retinal blind spot; Risk; Role; Scanning; Sensory; Severities; Spreading Cortical Depression; Steroids; Stress; Symptoms; Synapses; Techniques; Testing; Therapeutic Intervention; Visual; base; cell type; disorder prevention; excitatory neuron; gain of function; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; inhibitor/antagonist; inhibitory neuron; insight; nervous system disorder; neural circuit; neuronal excitability; neurosteroids; neurotransmission; new therapeutic target; novel; optogenetics; prevent; public health relevance; research study; synaptic function

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.

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令人衰弱的头痛和感觉障碍。偏头痛无法治愈，目前的治疗方案通常无效或让患者遭受严重的副作用。虽然偏头痛的根本原因仍不清楚，但许多患者报告称有一种先兆，通常被认为是闪烁灯光或盲点的视觉障碍。一种被称为皮质扩散抑制（CSD）的神经现象可能会导致偏头痛先兆，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。神经类固醇可以直接在大脑中合成，也可以从外周产生的性类固醇中合成，并且可以通过调节抑制性 GABA 功能来影响神经元兴奋性。据报道，偏头痛患者的神经元兴奋性增加，可以降低发生 CSD 的阈值。虽然性类固醇对偏头痛的影响已被广泛研究，但对于脑源性神经类固醇如何直接影响偏头痛的理解仍存在重大差距。该提案重点关注神经类固醇引起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，并且通过选择性增强皮质抑制反而降低了 CSD 发生的阈值。三个具体目标利用尖端先进的电生理学、成像、光遗传学和 LSPS 电路映射技术在已建立的 CSD 动物模型中测试这一假设及其潜在机制。首先，神经类固醇如何不同地影响兴奋性和抑制性神经元？ （目标 1）；其次，神经类固醇介导的CSD增强机制是什么？ （目标 2）；第三，神经类固醇是否会抑制皮质并放大突触回路？ （目标 3）。我们的初步数据表明，神经类固醇可能通过对快速尖峰中间神经元的选择性作用来降低 CSD 的阈值，从而减少对兴奋性锥体神经元的抑制驱动。拟议实验的数据将提供对偏头痛病理生理学的见解，以及神经类固醇可能成为几种偏头痛触发因素的常见介质的机制。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目标。