ENRICH-2: Stress-Reactivity and Self-Regulation in Infants with Prenatal Alcohol Exposure

总结/摘要 诊断胎儿酒精谱系障碍（FASD）的新临床指南将自我调节列为其中之一 受产前酒精暴露（PAE）影响的儿童的关键行为缺陷。有一个根本 对生命早期这种缺陷的潜在机制、频谱和严重程度的认识存在差距， 最好的分析方法来识别它们。此外，产前压力和产后压力的影响 环境对PAE诱导的改变的影响知之甚少。在乙醇的更新申请中， 神经发育，婴儿和儿童健康（ENRICH）研究，我们寻求持续的支持， 招聘/保留管道，并提出新的高度创新的研究压力反应/调节， 婴儿PAE长期目标是尽早确定PAE后非典型脑发育的指标， 尽可能地进行早期干预。本申请的目的是继续关注温和的 PAE，并评价PAE对婴儿应激反应/调节的影响及其机制 改变下丘脑-垂体-肾上腺（HPA）轴和自主神经系统（ANS）功能。我们将 评价PAE（感兴趣的暴露）、产前应激（调节剂）、生物学指标之间的关系 HPA轴（介质），以及婴儿应激反应/调节的生理和行为测量 （成果）。这一建议的理由是由这样一种信念驱动的，即HPA和ANS失调导致 PAE儿童的应激反应/调节改变可能是PAE诱导的一些关键性的基础。 行为缺陷，并增加继发性残疾的脆弱性。核心假设是，PAE将 与婴儿应激反应增强和自我调节较差有关（超出产前的影响） 压力）通过胎儿编程的HPA轴。这一假设是根据以下事实提出的： UNM的临床前数据和ENRICH-1当前资助周期的临床数据，将由 追求三个具体目标，评估PAE对1）胎儿编程的贡献作用 HPA轴，评估为HPA轴的关键胎盘和脐带标志物的表达; 2）婴儿 基础-应激-恢复期的生理反应性（心率变异性[HRV]）动态变化 在新生儿期和6个月大时进行评估; 3）婴儿行为反应和调节 在新生儿期和6个月大时进行评估。全面的多系统办法 这项研究中使用的是高度创新的，以前没有使用过。创新的进一步驱动力来自于 我们专注于中度PAE和评估受损应激反应/调节轨迹的能力 （新生儿，6个月评价）。这项研究意义重大，因为它 涉及神经内分泌、电生理和 受损的应激反应/调节的行为指标，这将导致分析技术的完善 在高级行为缺陷出现之前，准确识别婴儿期PAE缺陷。

SUMMARY/ABSTRACT The new clinical guidelines for diagnosing Fetal Alcohol Spectrum Disorders (FASD) list self-regulation as one of the key behavioral deficits in children affected by prenatal alcohol exposure (PAE). There is a fundamental gap in knowledge about the underlying mechanisms, spectrum, and severity of such deficits early in life and the best analytical approaches to identify them. In addition, the effect of prenatal stress and postnatal environment on PAE-induced alterations is poorly understood. In this renewal application of the Ethanol, Neurodevelopment, Infant, and Child Health (ENRICH) study, we seek continuous support for our established recruitment/retention pipeline, and propose new highly innovative studies of stress reactivity/regulation in infants with PAE. The long-term goal is to identify indices of atypical brain development following PAE as early as possible to enable early interventions. The objective of this application is to continue our focus on moderate PAE and to evaluate PAE effects on infant stress reactivity/regulation and the mechanisms underpinning altered hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) functioning. We will evaluate the relationship between PAE (exposure of interest), prenatal stress (moderator), biological measures of HPA axis (mediators), and physiological and behavioral measures of stress reactivity/regulation in infants (outcomes). The rationale for this proposal is driven by the conviction that HPA and ANS dysregulation leading to altered stress reactivity/regulation in children with PAE might be the basis for some of the key PAE-induced behavioral deficits, and increased vulnerability to secondary disabilities. The central hypothesis is that PAE will be associated with heightened infant stress reactivity and poorer self-regulation (beyond the effect of prenatal stress) through fetal programming of the HPA axis. This hypothesis has been formulated on the basis of preclinical data at UNM and clinical data from the current funding cycle of ENRICH-1 and will be tested by pursuing three specific aims, which evaluate the contributing effects of PAE on 1) Programming of the fetal HPA axis, assessed as expression of key placental and umbilical cord markers of HPA axis; 2) Infant physiological reactivity (heart rate variability [HRV]) dynamic changes during basal-stressor-recovery periods assessed in the newborn period and at 6-months of age; 3) Infant behavioral reactivity and regulation assessed in the newborn period and at 6-months of age. The comprehensive multi-systemic approach employed in this study is highly innovative and has not previously been used. Innovation is further driven by our focus on moderate PAE and ability to assess the trajectory of impaired stress reactivity/regulation (newborn, 6-months evaluations) in a large prospective cohort study. This research is significant because it involves comprehensive repeated-measures assessment of neuroendocrine, electrophysiological, and behavioral indices of impaired stress reactivity/regulation, which will lead to refinement of analytical techniques for accurate identification of PAE deficits in infancy before higher-order behavioral deficits manifest.