Long-term effects of prenatal synthetic glucocorticoid exposure on psychosocial stress reactivity and volitional control in children and adolescents

发展中的个体与他或她的发展环境之间的相互作用对于依赖经验调整行为和大脑发展至关重要。产前暴露于妊娠环境中的不利事件，如母亲应激或抑郁、糖皮质激素和药物滥用，是对发育最早的不利背景影响之一。与该项目特别相关的是产前接触合成糖皮质激素(SGC)对社会应激反应和意志控制发展的长期影响。到目前为止，对接受产前sGC治疗的人类下丘脑-垂体-肾上腺(HPA)轴功能的研究目前仅限于评估单一皮质醇基线测量和出生后不久应激诱导的皮质醇分泌，而早产是一个重要的混杂因素。此外，尽管HPA轴与大脑网络紧密相连，如前额叶电路，以削弱认知和动机调节功能，但产前sGC暴露对人类这些调节功能的长期影响一直是稀有的，而且大多限于行为评估。为了超越目前的技术水平，这项拟议的项目将使用回溯性纵向设计，评估产前sGC对心理社会应激反应、行为和意志控制的脑诱发电位测量的长期影响。拟议的项目有三个目标：首先，我们计划对儿童和青少年时期的下丘脑-垂体-肾上腺(HPA)轴功能进行全面评估，以探索(A)我们之前观察到的SGC暴露对儿童应激反应的影响是否会持续到青春期，以及(B)这些影响是否会推广到基础皮质醇分泌的长期变化。其次，通过测量脑电(EEG)，我们旨在研究产前sGC暴露对与认知监测相关的诱发脑电位的影响，众所周知，认知监测涉及与HPA轴功能密切相关的单胺能调制和脑回路。当前项目的第三个目标是研究表观遗传修饰作为一种潜在的机制来调节产前sGC对应激相关和认知措施的长期影响。除了可能获得了解与产前sGC暴露、单胺能调节和儿童青少年发育过程中的认知有关的基本机制外，鉴于sGC(欧洲和北美7%至10%的妇女)在产科护理中的广泛使用，深入了解产前sGC暴露的长期影响也具有重要的临床意义。

Interactions between the developing individual and his or her developmental contexts are crucial for experience-dependent tuning of behavioural and brain development. Prenatal exposures to unfavorable events in the gestational environment, such as maternal stress or depression, glucocorticoids and substance abuse, are among the earliest adverse contextual influences on development. Of particular relevance to this project are long-term effects of prenatal synthetic glucocorticoid (sGC) exposure on the development of social stress reactivity and volitional control. Thus far, research on hypothalamus-pituitary-adrenal (HPA) axis functioning in humans exposed to antenatal sGC treatment is currently limited to the assessment of a single cortisol baseline measure and stress-induced cortisol secretion shortly after birth with preterm birth being an important confounder. Furthermore, although the HPA-axis is tightly linked to brain networks, such as the prefrontal circuitry, that subserve cognitive and motivational regulatory functions, long-term effects of antenatal sGC exposure on these regulatory functions in humans have been sparsely addessed and are mostly limited to behavioral assessments. To go beyond the current state of the art, this proposed project will assess long-term effects of antenatal sGC on psychosocial stress reactivity, behavioral and brain evoked potential measures of volitional control, using a retrospective longitudinal design. The proposed project has three aims: First, we plan to carry out a comprehensive assessment of hypothalamus-pituitary-adrenal (HPA) axis functioning in childhood and adolescence to explore (a) whether our previously observed effects of prenatal sGC exposure on stress reactivity in children would persist into adolescence and (b) whether these effects would generalize to measures of long-term changes in basal cortisol secretion. Second, by measuring electroencephalography (EEG) we aim to investigate the effects of antenatal sGC exposure on evoked brain potentials associated with cognitive monitoring, which are known to involve monoaminergic modulations and brain circuits that are tightly linked to the HPA-axis functions. A third goal of the current project is to investigate epigenetic modifications as a potential mechanism in mediating long-term effects of antenatal sGC on stress-related and cognitive measures. Other than the potential gain of understanding basic mechanisms that relate antenatal sGC exposure, monoaminergic modulation and cognition during child and adolescent development, a deeper understanding of long-term effects of antenatal sGC exposure is also of important clinical relevance given the widespread use of sGC (7 to 10% of women in Europe and North America) in obstetric care.