Psychobiological Mechanisms Underlying the Association Between Early Life Stress and Depression Across Adolescence

项目摘要/摘要 早期生活应激(ELS)是导致抑郁症状和严重抑郁的重要危险因素 青春期抑郁障碍(MDD)然而，ELS赋予这种风险的机制， 人们对此了解甚少。最近的研究表明，高水平的炎症可能与 患有抑郁症的ELS。炎症的外周标志物，如C-反应蛋白(CRP)， 白介素6(IL-6)和肿瘤坏死因子-α(肿瘤坏死因子-α)与抑郁症状有关 以及青少年MDD的发病，可能是通过改变大脑的功能和结构回路来实现的 这是奖励处理的基础。然而，到目前为止，研究一直受限于将ELS概念化为 单一结构，尽管越来越多的证据表明，威胁、剥夺和不可预测的经历 不同的神经后果。因此，在这份行政副刊中，我们建议利用 父项目的基础设施(R37MH101495)，以检查不同项目之间的纵向关联 青少年时期的ELS维度、炎症、奖赏神经回路和抑郁症状。在 家长资助，我们招募了200多名9-13岁的男孩和女孩，并每两年获得一次数据，以 研究ELS对青春期神经轨迹的影响及其与抑郁的关系。在 第三个时间点(T3)，当参与者14-17岁时，我们获得了内部资金来收集 并检测其中一部分样本以测量C反应蛋白、IL-6和肿瘤坏死因子-α的水平；我们正在 在我们完成第四个时间点(T4)时继续采集血液样本，届时参与者为16-19岁 几年前。通过利用我们现有的数据集，包括对ELS和RICH的全面评估 通过多个分析单元(行为、认知、神经)来衡量奖励处理，我们做得很好 定位于检查炎症在将ELS与抑郁症联系起来中起关键作用的程度 改变奖赏神经回路发育的青春期症状和诊断。具体来说，我们 将能够测试：1)ELS的不同维度(即，剥夺、威胁和 不可预测性)与青春期后期炎症水平和变化有关；2) 炎症与奖赏神经回路的功能和结构改变有关；3) 炎症相关的功能和结构奖赏回路的改变可能是奖赏改变的基础 加工在ELS维度与抑郁症状和诊断之间的关系 青春期后期。通过利用我们现有的数据、计划评估和对以下各项轨迹的分析 神经发育和抑郁，我们将能够阐明神经免疫特征可能的基础 青春期抑郁症的出现。

PROJECT SUMMARY/ABSTRACT Early life stress (ELS) is a significant risk factor for the development of depressive symptoms and of Major Depressive Disorder (MDD) in adolescence. The mechanisms through which ELS confers this risk, however, are poorly understood. Recent research implicates high levels of inflammation as a mechanism that may link ELS with depression. Elevated peripheral markers of inflammation, such as C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α), have been associated with depressive symptoms and the onset of MDD in adolescents, potentially by altering functional and structural circuits in the brain that underlie reward processing. To date, however, research has been limited by a conceptualization of ELS as a unitary construct, despite growing evidence that experiences of threat, deprivation, and unpredictability have different neural consequences. Therefore, in this administrative supplement, we are proposing to leverage the infrastructure of the parent project (R37MH101495) to examine longitudinal associations among different dimensions of ELS, inflammation, reward neurocircuitry, and depressive symptoms in adolescence. In the parent grant, we recruited over 200 boys and girls ages 9–13 years and obtained data at two-year intervals to examine the effects of ELS on neural trajectories across adolescence and their relation to depression. At the third timepoint (T3), when the participants were 14–17 years of age, we secured internal funding to collect blood samples and to assay a portion of these samples to measure levels of CRP, IL-6, and TNF-α; we are continuing to collect blood samples as we complete the fourth timepoint (T4), when participants are 16–19 years of age. By leveraging our existing data set that includes comprehensive assessments of ELS and rich measures of reward processing across multiple units of analysis (behavioral, cognitive, neural), we are well positioned to examine the extent to which inflammation plays a key role in linking ELS with depression symptoms and diagnosis in adolescence by altering the development of reward neurocircuitry. Specifically, we will be able to test whether: 1) different dimensions of ELS (i.e., experiences of deprivation, threat, and unpredictability) are associated with levels of and changes in inflammation in later adolescence; 2) changes in inflammation are associated with changes in the function and structure of reward neurocircuitry; and 3) inflammation-related changes in functional and structural reward circuitry that may underlie altered reward processing mediate the association between dimensions of ELS and depression symptoms and diagnosis in later adolescence. By leveraging our existing data, planned assessments, and analyses of trajectories of neurodevelopment and depression, we will be able to elucidate neuroimmune characteristics that may underlie the emergence of adolescent depression.