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

项目概要/摘要 早期生活压力（ELS）是抑郁症状和严重抑郁症发展的重要危险因素。 青春期抑郁症（MDD）然而，ELS赋予这种风险的机制， 我们对此知之甚少。最近的研究表明，高水平的炎症是一种机制， ELS抑郁症外周炎症标志物升高，如C反应蛋白（CRP）， 白细胞介素-6（IL-6）和肿瘤坏死因子-α（TNF-α）与抑郁症状有关 以及青少年抑郁症的发病，可能是通过改变大脑中的功能和结构回路， 是奖励处理的基础然而，迄今为止，研究一直受到ELS概念化的限制， 尽管越来越多的证据表明，威胁、剥夺和不可预测性的经历 不同的神经后果。因此，在这份行政补充文件中，我们建议利用 母项目（R37MH101495）的基础设施，以检查不同 ELS，炎症，奖励神经回路和青春期抑郁症状的维度。在 我们招募了200多名9 - 13岁的男孩和女孩，每两年获得一次数据， 研究ELS对青春期神经轨迹的影响及其与抑郁症的关系。在 第三个时间点（T3），当参与者年龄在14 - 17岁时，我们获得了内部资金， 血液样本，并分析这些样本的一部分，以测量CRP，IL-6和TNF-α的水平;我们 当我们完成第四个时间点（T4）时，当参与者16 - 19岁时， 岁的通过利用我们现有的数据集，包括对ELS的全面评估和丰富的 通过对多个分析单元（行为、认知、神经）的奖励处理测量，我们很好地 定位于检查炎症在多大程度上在ELS与抑郁症之间起着关键作用 通过改变奖励神经回路的发展，在青春期的症状和诊断。我们特别 将能够测试：1）ELS的不同尺寸（即，剥夺、威胁和 不可预测性）与青春期后期炎症的水平和变化有关; 2） 炎症与奖赏神经回路的功能和结构的变化有关;以及3） 炎症相关的功能性和结构性奖赏回路的变化可能是改变奖赏的基础 加工介导ELS维度与抑郁症状和诊断之间的关联， 后来的青春期通过利用我们现有的数据、计划的评估和对 神经发育和抑郁症，我们将能够阐明神经免疫特征，可能是基础 青少年抑郁症的出现。

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.