Fragmented early-life experiences, aberrant circuit maturation, emotional vulnerabilities

破碎的早期生活经历、异常的电路成熟、情感脆弱

• 批准号: 10595596
• 负责人: CURT ALAN SANDMAN
• 金额: $ 49.78万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-17 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595596
• 关键词: 1 year old; 6 year old; Address; Adolescence; Adolescent and Young Adult; Age; Age of Onset; Anhedonia; Animal Experiments; Anxiety; Assessment tool; Attention; Award; Behavior; Biological; Biological Markers; Birth; Brain; Child; Child Mental Health; Childhood; Cognition; Cognitive; Collaborations; Data; Detection; Development; Diagnostic; Dimensions; Early identification; Emotional; Emotions; Epigenetic Process; Exposure to; Functional Magnetic Resonance Imaging; Home; Home environment; Household; Image; Impaired cognition; Individual; Infant; Intervention; Life; Life Experience; Link; Magnetic Resonance Imaging; Measures; Mental Health; Mental disorders; Methylation; Moods; Outcome; Pattern; Poverty; Probability; Prospective cohort; Psychopathology; Recording of previous events; Reporting; Research Domain Criteria; Rewards; Risk; Risk Factors; Risk Marker; Sampling; Sensory; Signal Transduction; Specificity; Stimulus; Suggestion; Symptoms; System; Testing; behavioral outcome; boys; cognitive development; cohort; early childhood; early life exposure; experimental study; fetal; girls; infancy; maternal depression; methylome; methylomics; neuroimaging; novel; novel strategies; pleasure; postnatal; predictive marker; predictive signature; prenatal; prenatal exposure; prospective; recruit; response; sex; young adult

This trans-disciplinary Center renewal proposal addresses early environmental signals that influence cognitive and emotional outcomes and the mechanisms by which these signals modulate the development of brain circuits underlying emotion and cognition. We have identified that patterns of maternal signals profoundly influence cognitive and emotional development: Specifically, unpredictable and fragmented patterns of maternal mood and behavior (FRAG) beginning in the fetal period increase the risk for internalizing symptoms that presage anhedonia and cognitive impairments in infancy through adolescence. Importantly, the effects of FRAG are additional to those of previously identified influences (e.g. maternal depression, anxiety, sensitivity). In this revised renewal application we benefit from Reviewer suggestions and capitalize on a cohort of children developed during the original award period for whom we have an unprecedented pre and postnatal exposure history, to test the hypothesis that FRAG is a novel form of adversity that influences mental health outcomes via aberrant maturation of brain circuits. Extending our existing cognitive and emotional assessments and considering sex and ages at exposure and assessment as important variables, we will emphasize anhedonia, a novel FRAG outcome identified across species with emerging significance as an important transdiagnostic dimensional entity in mental illness. We will examine the early manifestation of anhedonia in 3-6 year old children using a dimensional RDoC approach, determine novel maternal signals that increase risk for its expression, and identify mechanisms and biomarkers focusing, respectively, on disruption of normal brain circuit development and epigenetic signatures. Thus, we shall capitalize on our cutting edge neuroimaging, intra-individual methylomics and novel assessment tools to test the following hypotheses: (1) that early life exposure to fragmented and unpredictable maternal signals increases risk for anhedonia in 3 to 6-year-old children. (2) that exposure to a fragmented and unpredictable early life home environment increases the risk of anhedonia in 3 to 6-year-old children. (3) that early life exposure to fragmented and unpredictable maternal and environmental signals increases risk for anhedonia in early childhood through the disruption of pleasure/reward brain circuits and that methylome changes (signatures) in two paired samples from the same infant will provide predictive biomarkers of this risk.

这个跨学科中心更新提案涉及影响认知的早期环境信号 以及情感结果以及这些信号调节大脑发展的机制 电路的基础情感和认知。我们已经确定了产妇信号的模式 影响认知和情感发展：特别是，不可预测和分散的模式 从胎儿时期开始的母性情绪和行为（碎片）增加了内在症状的风险 通过青春期婴儿期的狂热和认知障碍。重要的是， 碎片还与先前确定的影响（例如母体抑郁，焦虑，敏感性）相比。 在此修订后的续签申请中，我们受益于审稿人的建议，并利用了一群儿童 在原始奖励期间开发的，我们有前所未有的前后暴露 历史，以检验以下假设，即碎片是一种新的逆境形式，会影响心理健康结果 通过脑电路的异常成熟。扩展我们现有的认知和情感评估以及 将暴露和评估时的性别和年龄视为重要变量，我们将强调Anhedonia， 一种新型的碎片结果，在具有重要意义的物种中确定为重要的转诊 精神疾病中的维度实体。我们将研究3-6岁的Anhedonia的早期表现 使用维度RDOC方法的儿童，确定新颖的母体信号，以增加其风险 表达，分别识别聚焦于正常大脑的机制和生物标志物 电路发展和表观遗传签名。因此，我们将利用我们的前沿神经影像学， 个体内部甲基甲基学和新的评估工具，以检验以下假设：（1）早期生命 暴露于零散且不可预测的产妇信号会增加3至6岁的Anhedonia的风险 孩子们。 （2）暴露于零散且不可预测的早期生活环境的环境增加了 3至6岁的孩子的Anhedonia。 （3）早期寿命暴露于零散和不可预测的母亲 环境信号通过中断而增加了童年时期的阿尼多尼亚的风险 愉悦/奖励脑电路和两个配对样品中的甲基团变化（签名） 婴儿将提供这种风险的预测生物标志物。