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

性腺激素和下丘脑在先兆偏头痛中作用的性别差异。

• 批准号: 10523716
• 负责人: Andrea M Harriott
• 金额: $ 19.56万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10523716
• 关键词: Abate; Acute; Address; Affect; Animal Model; Aptitude; Behavior; Behavioral; Brain region; Cells; Classic Migraine; Common Migraine; Craniotomy; Disease; Doctor of Philosophy; Estradiol; Estrogens; Estrus; Female; Foundations; Funding; Future; Gene Cluster; Gene Expression; General Hospitals; Genetic Transcription; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Headache; Headache Disorders; Hormonal; Hormones; Hypothalamic Hormones; Hypothalamic structure; Image; In Situ; Intervention; Knowledge; Lateral; Light; Machine Learning; Massachusetts; Measures; Menarche; Meningeal; Menopause; Menstruation; Mentors; Mentorship; Methods; Migraine; Modeling; Motor; Mus; Neurology; Neurons; Neuropeptides; Nociception; Nociceptors; Outcome Study; Pain; Patients; Pharmaceutical Preparations; Phenotype; Physicians; Play; Population; Pre-Clinical Model; Progesterone; Recurrence; Research; Research Personnel; Rodent; Role; Sensory; Severities; Sex Differences; Speech; Spreading Cortical Depression; Stress; Sumatriptan; Supervision; Testing; Testosterone; Therapeutic Intervention; Training; Training Programs; Trigeminal Nuclei; Trigeminal Pain; Trigeminal System; Visual; Woman; allodynia; behavioral study; career; career development; cell type; clinical candidate; cost; cutaneous allodynia; differential expression; disability; epidemiology study; experience; experimental study; hypocretin; in vivo; instructor; male; mechanical allodynia; medical schools; men; minimally invasive; novel; optogenetics; pain behavior; painful neuropathy; pre-clinical; preclinical study; response; sex; sex disparity; sexual dimorphism; single-cell RNA sequencing; skills; social; spreading depression; targeted treatment; transcriptomics

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.

项目摘要/摘要：这是一项为期五年的职业发展提案，探讨了性别差异 使用皮质扩散抑制作为先兆偏头痛的性腺激素和下丘脑参与 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进了这一工作。 候选人之前结合光遗传学、化学遗传学、机器学习和 该提案还提出了研究体内偏头痛机制性别差异的转录组学方法。 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 并通过强化监督培训获得尖端实验方法的离散技能 经验融合了共同导师 Cenk Ayata 教授的专业知识，他是医学博士，专门从事 抑郁症的传播以及专门研究下丘脑、性和性腺激素的医学博士 Ursula Kaiser 教授。 该培训计划将使候选人能够过渡到独立研究职业，其长期 目标是发现偏头痛的性别依赖性机制。 偏头痛在全球范围内造成了相当大的痛苦，并且对女性的影响尤为严重。 抑郁症 (SD) 是一种神经元和神经胶质去极化的慢波，是导致先兆偏头痛的原因 SD 广泛用作临床前偏头痛模型，可以激活脑膜伤害感受器并使二级敏感。 此外，微创光遗传学 SD 产生三叉神经尾核 (TNC) 中的神经元。 眶周异常性疼痛并增加小鼠的鬼脸，三叉神经伤害性激活的行为证据。 偏头痛在初潮后开始，在月经期间恶化，绝经后减轻，与性腺有关 此外，越来越多的证据支持下丘脑（下丘脑之一）的作用。 偏头痛时大脑大多数性别二态性区域的下丘脑神经元的激活，包括那些神经元的激活。 表达神经肽食欲素，可以通过下行神经肽来减轻 SD 对三叉神经疼痛的影响 然而，偏头痛相关性腺激素调节的性别差异。 具体而言，该提议尚未系统地研究下丘脑的行为或作用。 目的 (1) 研究 SD 引起的偏头痛的女性和男性性腺激素调节的性别差异 相关行为，（2）检查性别和激素对SD诱导的外侧下丘脑基因的影响 (3)检查SD诱导的三叉神经疼痛行为的食欲素能调节的性别差异。 在所提出的实验结束时，研究结果有望增强基本理解 先兆偏头痛性别差异的机制，有助于揭示先兆偏头痛的假定目标 随后对偏头痛中性别特异性下丘脑神经元参与的机制研究。