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

有色人种女性的围产期情感症状、神经活性类固醇和 GABA 受体可塑性

• 批准号: 10572847
• 负责人: Tory Anne Eisenlohr-Moul
• 金额: $ 23.99万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572847
• 关键词: Acute; Adverse effects; Affect; Affective Symptoms; Allopregnanolone; Anxiety; Anxiety Disorders; Behavior; Biological Factors; Blood; Color; Data; Detection; Diagnosis; Estradiol; Etiology; FDA approved; Failure; Female; First Pregnancy Trimester; GABA Receptor; Hormonal; Hormones; Human; Impairment; Individual; Infant; Infant Health; Isomerism; Latina; Link; Longitudinal Studies; Low Birth Weight Infant; Low Income Population; Low income; Maternal Health; Measures; Mental Depression; Mental Health; Methods; Mood Disorders; Moods; Mothers; Participant; Pathogenesis; Patients; Pattern; Perinatal; Peripheral Blood Mononuclear Cell; Play; Population; Populations at Risk; Postpartum Depression; Postpartum Period; Postpartum Women; Pre-Clinical Model; Predisposition; Pregnancy; Pregnanolone; Pregnant Women; Premature Birth; Progesterone; Publishing; Regulation; Risk; Rodent Model; Role; Sample Size; Second Pregnancy Trimester; Steroid Receptors; Stress; Symptoms; Testing; Third Pregnancy Trimester; Time; Translating; Trauma; Visit; Withdrawal; Withdrawal Symptom; Work; antenatal; anxiety symptoms; cohort; comorbidity; depressive symptoms; early pregnancy; emotional symptom; ethnic minority; experimental study; improved; intravenous injection; male; mood symptom; neural circuit; neurosteroids; people of color; perinatal period; peripartum depression; personalized medicine; positive allosteric modulator; pre-clinical; pregnant; prevent; racial minority; receptor; recruit; women of color; Acute; Adverse effects; Affect; Affective Symptoms; Allopregnanolone; Anxiety; Anxiety Disorders; Behavior; Biological Factors; Blood; Color; Data; Detection; Diagnosis; Estradiol; Etiology; FDA approved; Failure; Female; First Pregnancy Trimester; GABA Receptor; Hormonal; Hormones; Human; Impairment; Individual; Infant; Infant Health; Isomerism; Latina; Link; Longitudinal Studies; Low Birth Weight Infant; Low Income Population; Low income; Maternal Health; Measures; Mental Depression; Mental Health; Methods; Mood Disorders; Moods; Mothers; Participant; Pathogenesis; Patients; Pattern; Perinatal; Peripheral Blood Mononuclear Cell; Play; Population; Populations at Risk; Postpartum Depression; Postpartum Period; Postpartum Women; Pre-Clinical Model; Predisposition; Pregnancy; Pregnanolone; Pregnant Women; Premature Birth; Progesterone; Publishing; Regulation; Risk; Rodent Model; Role; Sample Size; Second Pregnancy Trimester; Steroid Receptors; Stress; Symptoms; Testing; Third Pregnancy Trimester; Time; Translating; Trauma; Visit; Withdrawal; Withdrawal Symptom; Work; antenatal; anxiety symptoms; cohort; comorbidity; depressive symptoms; early pregnancy; emotional symptom; ethnic minority; experimental study; improved; intravenous injection; male; mood symptom; neural circuit; neurosteroids; people of color; perinatal period; peripartum depression; personalized medicine; positive allosteric modulator; pre-clinical; pregnant; prevent; racial minority; receptor; recruit; women of color

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.

项目摘要 /摘要 围产期抑郁影响6.5％-12.9％的母亲，合并症的围产期焦虑发生在多数 50％的病例。在有色人种的低收入人群中，这些围产期情感障碍（PNAD）的比率更高。 PNAD与对母校和婴儿健康的不利影响有关，可以促成早产 和低出生体重。重要的是要进一步了解PNAD的病因，以更有效地 识别和治疗患者，尤其是在高危人群中。孕酮及其代谢物的水平 allopregnanolone（allo）和untixtolone（pa）在怀孕期间急剧波动，一直在 在PNAD的发病机理中实施。这些神经活性类固醇（NAS）通过抑制性GABAA作用 受体改变神经回路并调节情感症状。产后从NAS挑衅中提取 情感症状并修饰GABAA受体亚基表达。我们最初发表的工作表明 怀孕初期NAS的急性激增（第一和第二三个）也与情感症状有关 低收入有色人种。据我们所知，PNAD症状尚未研究 NAS退出并在同一队列中涌现。此外，我们的临床前工作将NAS的急性改变与 α4，γ2和δGABAA受体亚基表达的组成的变化，但是这项工作并非 翻译成人类。我们已经开发了测量外周中GABAA受体亚基表达的方法 单核血细胞（PBMC）。我们提议从一瞬间招募50名怀孕参与者，这是一个长期的 队列主要包括种族和少数民族。我们将测量NAS（Allo和PA），Gabaa接收器 亚基表达（α4，γ2和δ）和情感症状（抑郁和动画）在四个时间点，一次 每妊娠和产后。总体而言，我们假设PNAD中常见的持久压力，特别是在 有色人种，可能导致NAS的围产期变化（AIM 1），并且适应不足 Gabaar亚基（AIM 2）促成高率的PNAD。这些机制可以独立发生或 在某些人中，互动上的戏剧性增加或从围产期中的NAS提取 周期会导致PNAD症状，尤其是当Gabaar在功能上不适合NAS时。具体 目的是调查（1）特定围产期NAS变化的速率（早年怀孕）之间的关联 潮流，产后戒断）和情感症状； （2）动态程度之间的关联 GABAA受体亚基表达和情感症状的围产期变化，并探索 这两个因素的互动效应。通过研究与NAS的两个率有关的情感症状 在同一危险的围产期队列中的浪费/戒断和GABAA受体亚基表达，这项研究将 对我们对PNAD发病机理的理解产生有意义的影响。调查结果最终将有助于 改善PNAD症状的预测，检测和个性化治疗的努力，尤其是在低 - 有色人种的收入人士的PNAD率很高，但诊断不足和治疗不足。