Perinatal Affective Symptoms, Neuroactive Steroids, and GABA Receptor Plasticity in Women of Color

项目总结/摘要 围产期抑郁症影响6.5%-12.9%的母亲，共病围产期焦虑发生在多达 50%的案件。在低收入的有色人种中，这些围产期情感障碍（PNAD）的发病率甚至更高。 PNAD与对母婴健康的不良影响有关，并可能导致早产 低出生体重。因此，进一步了解PNAD的病因，对更有效地治疗PNAD具有重要意义 识别和治疗患者，尤其是高危人群。孕酮及其代谢物的水平 别孕烯醇酮（ALLO）和孕烯醇酮（PA）在怀孕期间波动剧烈， 参与PNAD的发病机制。这些神经活性类固醇（NAS）通过抑制性GABAA起作用。 受体来改变神经回路和调节情感症状。产后退出NAS引起 情感症状和修改GABAA受体亚单位的表达。我们最初发表的研究表明， 在怀孕早期（第一和第二个三个月）NAS的急性激增也与情感症状有关， 低收入围产期有色人种据我们所知，PNAD症状尚未研究与 在同一队列中NAS停药和激增。此外，我们的临床前工作将NAS的急性改变与 α4、γ2和δ GABAA受体亚基表达的组成发生变化，但这项工作尚未被证实。 翻译给人类。我们已经开发了测量外周血中GABAA受体亚单位表达的方法， 单核血细胞（PBMC）。我们建议从MoMent招募50名怀孕的参与者， 这一群体主要由少数种族和族裔组成。我们将测量NAS（ALLO和PA）、GABAA受体 亚基表达（α4，γ2和δ）和情感症状（抑郁和焦虑）在四个时间点，一次 每三个月和产后。总的来说，我们假设PNAD中常见的长期压力，特别是在 有色人种，可能会导致NAS（目标1）的围产期变化夸大和适应不足， GABAAR亚基（目的2）有助于PNAD的高发生率。这些机制可以独立发生， 交互作用，使得在一些个体中，围产期NAS的急剧增加或退出 尤其是当GABAAR不能在功能上适应NAS时。具体 目的是调查（1）特定围产期NAS变化率（早期妊娠） 情绪波动，产后戒断）和情感症状;和（2）之间的关联程度的动态 GABAA受体亚单位表达和情感症状的围产期变化，以及探讨 这两个因素的相互作用。通过研究情感症状与NAS发生率的关系， 在同一高危围产期队列中， 对我们理解PNAD的发病机制具有重要意义。这些发现最终将有助于 努力改善PNAD症状的预测，检测和个性化治疗-特别是在低- 有色人种收入人群，他们的PNAD率很高，但诊断和治疗不足。

PROJECT SUMMARY / ABSTRACT Perinatal depression affects 6.5%-12.9% of mothers, with comorbid perinatal anxiety occurring in as many as 50% of cases. In low-income people 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 preterm birth and low birth weight. It is important to further our understanding of the etiology of PNAD to more efficaciously identify and treat patients, especially in at-risk populations. Levels of progesterone, and its metabolites allopregnanolone (ALLO) and pregnanolone (PA) fluctuate drastically during pregnancy and have been implicated in the pathogenesis of PNAD. These neuroactive steroids (NAS) act via the inhibitory GABAA receptors to alter neural circuitry and modulate affective symptoms. Postpartum withdrawal from NAS provokes affective symptoms and modifies GABAA receptor subunit expression. Our initial published work suggests that acute surges in NAS early in pregnancy (1st and 2nd trimesters) are also associated with affective symptoms in low-income perinatal people of color. To our knowledge PNAD symptoms have not been studied in relation to NAS withdrawal and surges in the same cohort. Further, our preclinical work links acute alterations in NAS to changes in the composition of the α4, γ2, and δ GABAA receptor subunit expression, but this work has not been translated to humans. We have developed methods to measure GABAA receptor subunit expression in peripheral mononuclear blood cells (PBMCs). We propose to recruit 50 pregnant participants from MoMent, a longstanding cohort comprised primarily of racial and ethnic minorities. We will measure NAS (ALLO and PA), GABAA receptor subunit expression (α4, γ2, and δ) and affective symptoms (depression and anxiety) at four time points, once per trimester and postpartum. Overall, we hypothesize that protracted stress common in PNAD, particularly in people of color, may lead to exaggerated perinatal changes in NAS (Aim 1) and insufficient adaptation of GABAAR subunits (Aim 2) contributing to high rates of PNAD. These mechanisms can occur independently or interactively such that in some individuals, the dramatic increases in or withdrawal from NAS in the perinatal period contribute to PNAD symptoms, especially when GABAAR do not functionally adapt to NAS. The specific aims are to investigate (1) the association between the rate of specific perinatal NAS changes (early-pregnancy surges, postpartum withdrawal) and affective symptoms; and (2) the association between degree of dynamic perinatal changes in GABAA receptor subunit expression and affective symptoms, as well as to explore the interactive effects of these two factors. By studying affective symptoms in relation to both rate of NAS surges/withdrawal and GABAA receptor subunit expression in the same at-risk perinatal cohort, this study will have a meaningful impact on our understanding of PNAD pathogenesis. Findings will ultimately contribute to efforts to improve prediction, detection, and personalized treatment of PNAD symptoms – particularly in low- income people of color who have high rates of PNAD but are under-diagnosed and under-treated.