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

 描述(由申请者提供)：全球近20名女性中有近1人出现严重的经前症状，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组区分开来，因此研究神经活性类固醇及其调节的神经递质系统之间的相互作用至关重要。孕酮的代谢物别孕酮(Allo)是一种强大的伽马氨基丁酸(GABAA)受体激动剂，我们和其他人提出，它通过与大脑区域(如性二态终纹床核(BNST))相互作用来缓解PMDD症状。这项拟议的研究旨在研究月经周期(MC)中波动的荷尔蒙环境如何为PMDD女性和健康对照组之间的压力和唤起反应的差异奠定基础。值得关注的结果包括在MC的卵泡期和黄体期以及黄体期应用舍曲林50 mg/d后，心理生理学(声学惊吓反射；ASR)和HPA轴对实验室应激源的反应。探索这些主要结果与MC和SSRI治疗(仅限PMDD组)的ALLO变化之间的关系，为研究SSRIs在治疗PMDD中的作用机制提供了一种新的方法。这里使用中性、可预测、不可预测(NPU)的冲击声惊吓威胁方案来区分焦虑增强型ASR(由BNST调节)和恐惧增强型ASR(由杏仁核调节)，这是考虑开发新的PMDD干预措施时的一个重要区别。我们假设，与卵泡期相比，患有PMDD的女性在黄体期有更高的基线和焦虑增强的ASR，但与黄体期的女性对照组相比，不会有恐惧增强的ASR。这些发现将与临床前研究相一致，该研究表明，在压力条件下共同释放并经SSRI治疗增强的Allo，减弱了应激激素对背景恐惧或焦虑增强(BNST相关)ASR的影响。我们预计两组之间没有差异，也没有舍曲林治疗前对恐惧增强的ASR(杏仁核相关)的影响。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SSRIs的治疗作用提供更多的见解，目的是促进治疗经前抑郁症的新干预措施的开发。这一资助机制出现在候选人职业发展的关键时刻，因为她将自己在压力生物学方面的背景与神经类固醇和心理生理学的研究结合在一起，朝着更大的PMDD神经内分泌学和压力响应性的研究计划迈进。拟议的研究包括尼尔·埃普森博士的专家指导和一个受人尊敬的联合导师/顾问小组的意见，并将推动候选人的职业生涯朝着女性生殖行为健康的独立方向发展。

 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.