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

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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.