Psychophysiology, Neurosteroids, and Stress in Premenstrual Dysphoric Disorder (PMDD)

经前焦虑障碍 (PMDD) 中的心理生理学、神经类固醇和压力

• 批准号: 9252525
• 负责人: Liisa Victoria Hantsoo
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9252525
• 关键词: Acoustics; Address; Agonist; Allopregnanolone; Amygdaloid structure; Anabolism; Anxiety; Arousal; Biological; Biology; Brain; Brain Diseases; Brain region; Childhood; Clinical; Corticotropin-Releasing Hormone; Cues; DSM-V; Data; Development; Diagnosis; Disease; Event; Female; Fostering; Fright; Functional disorder; Goals; Grant; Hormonal; Hormonal Change; Hormones; Intervention; Investigation; Knowledge; Laboratories; Life; Light; Literature; Luteal Phase; Measures; Mediating; Menstrual cycle; Mental Depression; Mentors; Mentorship; Mood Disorders; Nature; Neurobiology; Neuroendocrinology; Neurosecretory Systems; Neurotransmitters; Outcome; Ovarian; Participant; Pathogenesis; Peripheral; Phase; Plasma; Pregnancy; Progesterone; Protocols documentation; Psychophysiology; Questionnaires; Recording of previous events; Reflex action; Regulation; Research; Rodent Model; Role; Sample Size; Selective Serotonin Reuptake Inhibitor; Sertraline; Severities; Shock; Stigmatization; Stress; Structure; Structure of terminal stria nuclei of preoptic region; Symptoms; System; Therapeutic; Time; Woman; Work; aged; base; behavioral health; biological adaptation to stress; career; career development; disorder risk; enhancing factor; experience; gamma-Aminobutyric Acid; habituation; hypothalamic-pituitary-adrenal axis; insight; interest; neurosteroids; novel strategies; pre-clinical; pre-clinical research; preclinical study; premenstrual dysphoric disorder; primary outcome; programs; proliferative phase Menstrual cycle; public health relevance; receptor; receptor sensitivity; reproductive; response; stressor; translational approach; treatment group

 DESCRIPTION (provided by applicant): Nearly one in twenty women worldwide experience premenstrual symptoms severe enough to be classified as premenstrual dysphoric disorder (PMDD), however, PMDD's neurobiology is understudied. As women with PMDD cannot be distinguished from healthy controls by peripheral markers of ovarian function, it is critical that research is focused on the interaction between neuroactive steroids and the neurotransmitter systems they modulate. Progesterone's metabolite allopregnanolone (ALLO) is a powerful gamma- aminobutyric acid (GABAA) receptor agonist that, we and others propose, precipitates PMDD symptoms via interaction with brain regions such as the sexually dimorphic bed nucleus of the stria terminalis (BNST). The proposed research aims to examine how the fluctuating hormonal milieu of the menstrual cycle (MC) sets the stage for differences in stress and arousal reactivity between women with PMDD and healthy controls. Outcomes of interest include psychophysiologic (acoustic startle reflex; ASR) and HPA axis response to a laboratory stressor during the follicular and luteal phases of the MC and again after luteal phase administration of sertraline 50 mg/d. Exploration of the relationship between these primary outcomes and changes in ALLO across the MC and with SSRI treatment (PMDD group only) provides a novel approach to examining mechanism of action of SSRIs in the treatment of PMDD. The Neutral, Predictable, Unpredictable (NPU) threat of shock acoustic startle protocol is used herein to differentiate between anxiety-potentiated ASR (modulated by the BNST) versus fear-potentiated ASR (modulated by the amygdala), an important distinction when considering the development of new interventions for PMDD. We hypothesize that women with PMDD will have heightened baseline and anxiety-potentiated ASR, but not fear-potentiated ASR in the luteal phase compared to the follicular phase, and compared to female controls during the luteal phase. These findings would be consistent with preclinical studies showing that ALLO, which is co-released under conditions of stress and enhanced by SSRI administration, diminishes the impact of stress hormones on contextual fear or anxiety- potentiated (BNST related) ASR. We expect no between group differences or pre-post sertraline effects on fear-potentiated ASR (amygdala related). This research will further our understanding of the nature of PMDD and provide additional insights into the therapeutic action of SSRIs with the goal of fostering development of new interventions for the treatment of PMDD. This grant mechanism comes at a critical time in the candidate's career development as she integrates her background in stress biology with investigation of neurosteroids and psychophysiology, building toward a larger research program on the neuroendocrinology of PMDD and stress responsivity. The proposed research includes expert mentorship from Dr. Neill Epperson and input from an esteemed panel of co-mentors/advisors, and will advance the candidate's career towards independence in women's reproductive behavioral health.

 描述（由申请人提供）：全世界有近二十分之一的女性经历过严重的经前症状，足以被归类为经前焦虑症 (PMDD)，然而，PMDD 的神经生物学尚未得到充分研究。由于无法通过卵巢功能的外周标志物将患有经前抑郁症的女性与健康对照者区分开来，因此研究重点关注神经活性类固醇与其调节的神经递质系统之间的相互作用至关重要。黄体酮的代谢物四氢孕酮 (ALLO) 是一种强效的 γ-氨基丁酸 (GABAA) 受体激动剂，我们和其他人认为，它通过与终纹性二态床核 (BNST) 等大脑区域相互作用，引发经前抑郁症 (PMDD) 症状。拟议的研究旨在研究月经周期（MC）中荷尔蒙环境的波动如何为患有经前抑郁症的女性和健康对照者之间的压力和性唤起反应差异奠定基础。感兴趣的结果包括在 MC 的卵泡期和黄体期以及黄体期给予舍曲林 50 mg/d 后再次对实验室应激源的心理生理学（听觉惊吓反射；ASR）和 HPA 轴反应。探索这些主要结果与整个 MC 和 SSRI 治疗（仅限 PMDD 组）的 ALLO 变化之间的关系，为检查 SSRIs 在 PMDD 治疗中的作用机制提供了一种新方法。本文使用电击声惊吓方案的中性、可预测、不可预测 (NPU) 威胁来区分焦虑增强 ASR（由 BNST 调节）与恐惧增强 ASR（由杏仁核调节），这是考虑开发 PMDD 新干预措施时的一个重要区别。我们假设，与卵泡期相比，以及与黄体期女性对照相比，患有经前抑郁症的女性在黄体期的基线和焦虑增强 ASR 会升高，但恐惧增强 ASR 不会升高。这些发现与临床前研究一致，表明 ALLO 在压力条件下共同释放并通过 SSRI 给药增强，可减少压力激素对情境恐惧或焦虑增强（BNST 相关）ASR 的影响。我们预计组间差异或舍曲林前后对恐惧增强 ASR（杏仁核相关）的影响不存在。这项研究将进一步加深我们对经前抑郁症本质的理解，并为 SSRI 的治疗作用提供更多见解，以促进开发治疗经前抑郁症的新干预措施。这一资助机制是在候选人职业发展的关键时刻推出的，因为她将压力生物学背景与神经类固醇和心理生理学研究相结合，建立了一个关于经前抑郁症和压力反应的神经内分泌学的更大的研究项目。拟议的研究包括 Neill Epperson 博士的专家指导和受人尊敬的共同导师/顾问小组的投入，并将推动候选人的职业生涯走向女性生殖行为健康的独立。