An RDoC Approach to Perinatal Affective Disorders: The Role of Neuroactive Steroids and Potential Threat

项目总结/摘要 围产期抑郁症（PND）影响6.5%-12.9%的母亲，与围产期焦虑症（PNA）共病发生在 高达50%的病例。在低收入的有色人种妇女中，这些围产期情感障碍（PNAD）的发生率 甚至更高PNAD与对孕产妇和婴儿健康的不利影响有关， 早产和低出生体重。进一步了解PNAD，对于更有效地进行PNAD的诊断和治疗具有重要意义 确定和治疗妇女，特别是高危人群中的妇女。我们还必须解决 的精神健康症状，并认识到潜在的变化，发病机制和症状概况， 病人对病人据我们所知，尽管存在这种异质性，迄今为止的研究已经调查了 PNAD几乎只与诊断有关，而与症状表型无关。研究领域 标准（RDoC）框架是一种应用新的多层次机制研究方法的工具， 心理健康，综合自我报告、行为、生理和生物措施。RDoC工具还没有 然而，已被应用于识别PNAD的转诊断表型及其神经基础。神经活性类固醇 孕激素代谢物在妊娠期间剧烈波动， 的PNAD。这些神经活性类固醇改变神经回路（即，抑制性GABAA受体）调节某些 RDoC表型，特别是潜在的威胁，或对潜在的厌恶情况的反应。初步数据 显示潜在威胁是PNAD中常见的RDoC表型，以及与PNAD相关的神经活性类固醇。 下一步是将潜在的威胁直接与神经活性类固醇联系起来，并将研究扩展到其他领域。 孕激素代谢物，特别是在怀孕早期，当PNAD率在有色人种女性中最高时。 这项研究的目的是研究神经活性类固醇合成与自我报告的关系， 低收入妇女妊娠早期潜在威胁的生理指标及PNAD症状 颜色。具体目的是（1）研究NAS合成的急性增加作为潜在的机制， 探讨NAS合成与抑郁、焦虑的关系 怀孕早期的症状，以及潜在的威胁是否介导了这些关联;（3）调查 声惊吓反应作为潜在威胁的生理指标和GABAA受体对NAS的敏感性 孕期培训目标是（1）从理论上理解RDoC框架 并将该框架应用于围产期心理健康表型的研究;（2）获得加工训练 和分析神经活性类固醇，并获得其与PNAD的关联的知识;和（3）制定一个 详细了解女性生殖生理学和内分泌学，并将其与围产期情感 紊乱最终，这种培训将使申请人朝着成为独立的目标前进 研究低收入人群围产期心理健康的发病机制和异质性的学术研究人员， 少数患者群体。

PROJECT SUMMARY / ABSTRACT Perinatal depression (PND) affects 6.5%-12.9% of mothers, with comorbid perinatal anxiety (PNA) occurring in as many as 50% of cases. In low-income women of color, rates of these perinatal affective disorders (PNAD) are even higher. PNAD are associated with adverse effects on both maternal and infant health and can contribute to pre-term birth and low birth weight. It is important to further our understanding of PNAD to more efficaciously identify and treat women, especially in at-risk populations. We must also address the considerable heterogeneity of mental health symptoms and recognize the potential variations in pathogenesis and symptom profiles from patient to patient. To our knowledge, despite this heterogeneity, studies to date have investigated biomarkers of PNAD almost exclusively in relation to diagnoses rather than symptom phenotypes. The Research Domain Criteria (RDoC) framework is a tool for applying new, multi-level mechanistic investigational approaches to mental health, integrating self-report, behavioral, physiological and biological measures. RDoC tools have not yet been applied to identify transdiagnostic phenotypes of PNAD and their neural basis. Neuroactive steroid metabolites of progesterone fluctuate drastically during pregnancy and have been implicated in the pathogenesis of PNAD. These neuroactive steroids alter the neural circuitry (i.e., inhibitory GABAA receptor) modulating certain RDoC phenotypes, particularly potential threat, or responses to potentially aversive situations. Preliminary data show potential threat to be an RDoC phenotype common in PNAD, and neuroactive steroids to relate to PNAD. The next step is to link potential threat directly to neuroactive steroids, and to extend research to other metabolites of progesterone, particularly early in pregnancy when rates of PNAD are highest in women of color. The research goal of this proposal is to examine neuroactive steroid synthesis in relation to self-report and physiological measures of potential threat as well as PNAD symptoms in early pregnancy in low-income women of color. The specific aims are to (1) investigate acute increases in NAS synthesis as a mechanism of potential threat in early pregnancy; (2) investigate the association of NAS synthesis with depression and anxiety symptoms in early pregnancy, and whether potential threat mediates these associations; and (3) investigate the acoustic startle response as a physiological index of potential threat and GABAA receptor sensitivity to NAS during pregnancy. The training goals are to (1) develop a theoretical understanding of the RDoC framework and apply the framework to the study of perinatal mental health phenotypes; (2) acquire training in processing and analysis of neuroactive steroids, and gain knowledge of their association with PNAD; and (3) develop a detailed understanding of female reproductive physiology and endocrinology, and relate this to perinatal affective disorders. Ultimately, this training will allow the applicant to advance towards a goal of becoming an independent academic researcher studying the pathogenesis and heterogeneity of perinatal mental health in low income, minority patient populations.