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

> **NIH NIH R37** · STANFORD UNIVERSITY · 2022 · $227,934

## Abstract

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.

## Key facts

- **NIH application ID:** 10540533
- **Project number:** 3R37MH101495-09S1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** IAN H GOTLIB
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $227,934
- **Award type:** 3
- **Project period:** 2013-09-01 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10540533

## Citation

> US National Institutes of Health, RePORTER application 10540533, Psychobiological Mechanisms Underlying the Association Between Early Life Stress and Depression Across Adolescence (3R37MH101495-09S1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10540533. Licensed CC0.

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