Sex Differences in the Role of Gonadal Hormones and the Hypothalamus in Migraine with Aura.

项目摘要/摘要：这是一份为期五年的职业发展提案，考察了 以皮质扩散性抑制为先兆的偏头痛患者性激素和下丘脑受累 模特。这位候选人是哈佛医学院的讲师和马萨诸塞州综合医院的内科医生 医院神经内科，头痛和神经病理性疼痛。这项提议推进了 应聘者在光遗传、化学遗传、机器学习和 在体内研究偏头痛机制中性别差异的转录转录方法。这项提议还包括 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。 培训计划的重点是提高候选人在性别差异偏头痛研究领域的能力 以及通过强化的监督培训获得尖端实验方法的离散技能 合作导师Cenk Ayata教授的经验，他是医学博士，专门从事 舒拉·凯泽教授，医学博士，专门研究下丘脑、性激素和性腺激素。 培训计划将使候选人能够过渡到独立的研究职业生涯，其长期 目的是发现偏头痛的性别依赖机制。 偏头痛在全球范围内造成了相当大的痛苦，对女性的影响不成比例。皮质扩散 抑郁症(SD)是一种神经元和神经胶质细胞去极化的慢波，是有先兆的偏头痛的罪魁祸首。 广泛用作临床前偏头痛模型。SD可激活脑膜伤害性感受器，敏化二阶 三叉神经尾侧核(TNC)的神经元。此外，微创的光遗传SD会产生 眼眶周围疼痛和增加小鼠的鬼脸，三叉神经伤害性激活的行为证据。那 偏头痛在月经初潮后开始，在月经期间恶化，绝经后缓解与性腺有关 偏头痛的荷尔蒙。此外，越来越多的证据支持下丘脑的作用，下丘脑是 在偏头痛中，大脑中最多的性二态区域。激活下丘脑神经元，包括 表达神经肽增食欲素可通过下行减轻SD对三叉神经痛的影响 对TNC神经元的抑制。然而，与偏头痛相关的性激素调节的性别差异 下丘脑的行为或作用还没有得到系统的研究。具体地说，这个提案 目的：(1)探讨SD诱导的偏头痛男女性腺激素调节的性别差异。 相关行为，(2)检测性别和激素对SD诱导的下丘脑外侧区基因的影响 (3)观察SD诱导的三叉神经痛行为中食欲素能调节的性别差异。 在拟议的实验结束时，研究结果有望加深对基础的理解 有先兆的偏头痛的性别差异的机制，并有助于揭示可能的靶点 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.