Sex differences in the role of gonadal hormones and the hypothalamus in migraine with aura.

项目摘要/摘要：这是一个为期五年的职业发展建议，研究性别差异， 以皮质扩散性抑制作为先兆偏头痛的性腺激素和下丘脑受累的研究 模型候选人是哈佛医学院的讲师和马萨诸塞州总医院的医生 医院神经内科，头痛和神经性疼痛科。该提案推动了 候选人先前在光遗传学，化学遗传学，机器学习和 转录组学方法研究偏头痛机制的性别差异。该提案还 与候选人在治疗偏头痛和其他致残性头痛疾病方面的临床专业知识相结合。 培训计划的重点是增强候选人在性别差异偏头痛研究领域的能力倾向 并通过强化监督培训获得尖端实验方法的离散技能 经验结合共同导师教授的专业知识. Cenk Ayata，MD博士谁专门从事 扩散性抑郁症和Ursula Kaiser教授，医学博士，专门研究下丘脑，性和性腺激素。 该培训计划将使候选人过渡到一个独立的研究生涯，其长期 目的是发现偏头痛的性别依赖机制。 偏头痛是全球性的痛苦，对妇女的影响尤为严重。皮层扩散性 抑郁症（SD）是一种神经元和神经胶质去极化的慢波，是先兆偏头痛的原因， 广泛用作临床前偏头痛模型。SD可激活脑膜伤害性感受器并致敏二级反应 三叉神经尾侧核（TNC）。此外，微创光遗传学SD产生 眶周异常性疼痛和增加小鼠鬼脸，三叉神经伤害性激活的行为证据。的 偏头痛在初潮后开始，在月经期间停止，在绝经后减弱， 偏头痛中的激素此外，越来越多的证据支持下丘脑的作用， 偏头痛患者大脑中最具性别差异的区域下丘脑神经元的激活，包括那些 表达神经肽食欲素，可以通过降低三叉神经痛的水平来减轻SD对三叉神经痛的影响。 抑制TNC神经元。然而，性激素调节偏头痛的性别差异相关 行为或下丘脑的作用尚未得到系统的研究。具体而言，这项提案 目的：（1）探讨SD偏头痛的性激素调节的性别差异， （2）性别和激素对SD诱导的下丘脑外侧区基因表达的影响 表达和（3）检查SD诱导的三叉神经痛行为的食欲素能调节的性别差异。 在实验结束时，研究结果有望加强对基本问题的理解 先兆偏头痛的性别差异机制，并有助于揭示假定的目标， 偏头痛中性别特异性下丘脑神经元参与的后续机制研究。

Project Summary/Abstract: This is a five-year career development proposal examining sex differences in gonadal hormone and hypothalamic involvement in migraine with aura using cortical spreading depression as a model. The candidate is an Instructor at Harvard Medical School and a physician at the Massachusetts General Hospital in the Department Neurology, Division of Headache and Neuropathic Pain. This proposal advances the candidate’s prior experience with a combination of optogenetic, chemogenetic, machine learning and transcriptomic approaches to studying sex differences in migraine mechanisms in vivo. This proposal also interfaces with the candidate’s clinical expertise in treating migraine and other disabling headache disorders. The training plan focuses on enhancing the candidate’s aptitude in the field of sex differences migraine research and gaining discrete skills in cutting edge experimental methods through an intensive supervised training experience incorporating the expert knowledge of co-mentors Prof. Cenk Ayata, MD PhD who specializes in spreading depression and Prof. Ursula Kaiser, MD who specializes in hypothalamic, sex and gonadal hormones. The training program will enable the candidate’s transition to an independent research career whose long-term goal is to discover sex dependent mechanisms of migraine. Migraine accounts for considerable global suffering and disproportionately affects women. Cortical spreading depression (SD), a slow wave of neuronal and glial depolarization, is responsible for migraine with aura and is widely used as a preclinical migraine model. SD can activate meningeal nociceptors and sensitize second order neurons in the trigeminal nucleus caudalis (TNC). Furthermore, minimally invasive optogenetic SD produces periorbital allodynia and increases mouse grimace, behavioral evidence of trigeminal nociceptive activation. That migraine starts after menarche, worsens during menstruation, and abates after menopause implicates gonadal hormones in migraine. Moreover, a growing body of evidence supports a role for the hypothalamus, one of the most sexually dimorphic regions of the brain, in migraine. Activation of hypothalamic neurons, including those expressing neuropeptide orexin, could act to mitigate the impact of SD on trigeminal pain via descending inhibition of TNC neurons. However, sex differences in gonadal hormone modulation of migraine-relevant behavior or the role of the hypothalamus has not been systematically investigated. Specifically, this proposal aims to (1) investigate sex differences in female and male gonadal hormone modulation of SD-induced migraine- relevant behaviors, (2) examine sex and hormonal influences on SD-induced lateral hypothalamic gene expression and (3) examine sex differences in orexinergic modulation of SD-induced trigeminal pain behavior. At the end of the proposed experiments, study results are expected to enhance the fundamental understanding of mechanisms of sex differences in migraine with aura and contribute to uncovering putative targets for subsequent mechanistic studies of sex specific hypothalamic neuronal involvement in migraine.