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

 描述（由申请人提供）：全世界近二十分之一的妇女经历严重到足以被归类为经前焦虑症（PMDD）的经前症状，然而，PMDD的神经生物学研究不足。由于PMDD患者不能通过卵巢功能的外周标志物与健康对照区分开来，因此研究重点放在神经活性类固醇与它们调节的神经递质系统之间的相互作用上至关重要。孕激素的代谢物别孕烯醇酮（allopregnanolone，ALLO）是一种强大的γ-氨基丁酸（GABAA）受体激动剂，我们和其他人提出，其通过与脑区域（例如终纹的性二形床核（BNST））的相互作用来加速PMDD症状。拟议的研究旨在研究月经周期（MC）波动的激素环境如何为PMDD女性和健康对照组之间的压力和唤醒反应差异奠定基础。感兴趣的结果包括心理生理学（声惊吓反射; ASR）和HPA轴在MC的卵泡期和黄体期对实验室应激源的反应，以及在黄体期给予舍曲林50 mg/d后的反应。探索这些主要结局与MC和SSRI治疗（仅PMDD组）的ALLO变化之间的关系，为检查SSRI治疗PMDD的作用机制提供了一种新方法。本文使用中性、可预测、不可预测（NPU）的电击声惊吓方案威胁来区分焦虑增强的ASR（由BNST调节）与恐惧增强的ASR（由杏仁核调节），这是考虑PMDD新干预措施开发时的重要区别。我们假设，与卵泡期相比，以及与黄体期女性对照组相比，PMDD女性在黄体期的基线和焦虑增强的ASR会升高，但不是恐惧增强的ASR。这些发现将与临床前研究一致，该研究表明在应激条件下共释放并通过SSRI施用增强的ALLO减少了应激激素对情境恐惧或焦虑增强的（BNST相关的）ASR的影响。我们预计组间差异或前后舍曲林对恐惧增强的ASR（杏仁核相关）没有影响。这项研究将进一步加深我们对PMDD本质的理解，并为SSRIs的治疗作用提供更多的见解，旨在促进PMDD治疗新干预措施的发展。这个补助金机制是在候选人的职业发展的关键时刻，因为她整合了她的压力生物学背景与神经类固醇和心理生理学的调查，朝着PMDD和压力反应的神经内分泌学更大的研究计划建设。拟议的研究包括来自Neill Epperson博士的专家指导和一个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。

 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.