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

项目摘要/摘要 6.5%-12.9%的母亲会受到围产期抑郁的影响，并伴有围产期焦虑 50%的病例。在低收入有色人种中，这些围产期情感障碍(PNAD)的比例更高。 PNAD对产妇和婴儿的健康都有不利影响，并可能导致早产。 和低出生体重。进一步加深对PNAD病因的认识，以更有效地了解PNAD是很重要的 识别和治疗患者，特别是高危人群。孕酮及其代谢物水平 别孕酮(Allo)和孕酮(PA)在怀孕期间波动剧烈，一直以来 与PNAD的发病机制有关。这些神经活性类固醇(NAS)通过抑制GABAA发挥作用 受体可以改变神经回路，调节情感症状。产后从NAS中撤退引发 并改变GABAA受体亚单位的表达。我们最初发表的研究表明 NAS在怀孕早期(第一和第二个三个月)的急剧增加也与 围产期低收入有色人种。据我们所知，PNAD症状还没有研究过与 NAS的退出和激增出现在同一队列中。此外，我们的临床前工作将NAS的急性变化与 α4、γ2和δ受体亚单位组成表达的变化，但这项工作尚未完成 转化成人类的。我们已经开发了检测外周血细胞GABAA受体亚单位表达的方法 单个核血细胞(PBMC)。我们建议从Moment招募50名怀孕的参与者，这是一个长期存在的 主要由种族和少数民族组成的队列。我们将检测NAS(Allo和PA)、GABAA受体 四个时间点的亚单位表达(α4、γ2和δ)和情感症状(抑郁和焦虑)，一次 每三个月和产后。总体而言，我们假设长期应激在PNAD中很常见，特别是在 有色人种，可能导致NAS围产期变化夸大(目标1)和适应不足 GABAAR亚基(目标2)有助于PNAD的高比率。这些机制可以独立发生，也可以 在一些个体中，围产期NAS的急剧增加或退出 经期导致PNAD症状，特别是当GABAAR在功能上不适应NAS时。具体的 目的是调查(1)特定围产期NAS变化率(早孕)之间的关系 抽搐、产后戒断)和情感症状之间的关系；以及(2)动力程度之间的关联 围产期GABAA受体亚单位表达的变化与情感性症状的关系 这两个因素的交互作用。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，浪涌/戒断和GABAA受体亚单位的表达，这项研究将 对我们理解PNAD的发病机制有重要意义。这些发现最终将有助于 努力改进对PNAD症状的预测、检测和个性化治疗--特别是在低 收入较高的有色人种，他们的PNAD发病率很高，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.