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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要围产期抑郁症影响着 6.5%-12.9% 的母亲，其中多达 6.5%-12.9% 的母亲患有围产期焦虑症在低收入有色人种中，50% 的围产期情感障碍 (PNAD) 发病率更高。 PNAD 对孕产妇和婴儿健康产生不利影响，并可能导致早产进一步有效地了解 PNAD 的病因学非常重要。识别和治疗患者，尤其是高危人群的黄体酮及其代谢物水平。四氢孕酮 (ALLO) 和孕酮 (PA) 在怀孕期间波动剧烈，并且已被这些神经活性类固醇 (NAS) 通过抑制性 GABAA 发挥作用。受体改变神经回路并调节产后 NAS 戒断症状。我们最初发表的工作表明，情感症状并改变 GABAA 受体亚基的表达。妊娠早期（妊娠第一和第二个月）NAS 的急性激增也与情感症状相关据我们所知，尚未对低收入围产期有色人种的 PNAD 症状进行研究。此外，我们的临床前工作将 NAS 的急性改变与同一队列中的 NAS 退出和激增联系起来。 α4、γ2和δ GABAA受体亚基表达的组成发生变化，但这项工作尚未得到证实我们已经开发出测量外周 GABAA 受体亚基表达的方法。我们建议从长期存在的 MoMent 招募 50 名怀孕参与者。我们将测量 NAS（ALLO 和 PA）、GABAA 受体。四个时间点的亚基表达（α4、γ2 和 δ）和情感症状（抑郁和焦虑），一次总体而言，我们在 PNAD 中面临着常见的长期压力，尤其是在妊娠期和产后。有色人种，可能会导致围产期 NAS 变化过大（目标 1）和适应不足 GABAAR 亚基（目标 2）导致高 PNAD 发生率。这些机制可以独立发生，也可以发生。交互作用，使得某些个体在围产期 NAS 急剧增加或退出期会导致 PNAD 症状，特别是当 GABAAR 不能在功能上适应 NAS 时。目的是调查 (1) 特定围产期 NAS 变化率（妊娠早期 (2) 动态程度之间的关联；围产期 GABAA 受体亚基表达和情感症状的变化，以及探索通过研究与 NAS 发生率相关的情感症状。同一高危围产期队列中的激增/戒断和 GABAA 受体亚基表达，本研究将对我们对 PNAD 发病机制的理解产生有意义的影响，研究结果最终将有助于我们理解 PNAD 发病机制。改善 PNAD 症状的预测、检测和个性化治疗，特别是在低危人群中 PNAD 发病率较高但诊断和治疗不足的有色人种收入人群。