# The Roles of Inflammatory and Glutamatergic Processes in the Neurodevelopmental Mechanisms Underlying Adolescent Depression

> **NIH NIH K01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $132,177

## Abstract

PROJECT SUMMARY
First episodes of major depressive disorder (MDD) typically begin during adolescence. Despite the fact that
adolescent-onset MDD is associated with more severe and recurrent episodes of MDD, little work has been
done to identify mechanisms underlying depressive relapse or recurrence. Prior work by the candidate has
documented differences in functional and structural connectivity involving the anterior cingulate cortex (ACC)
between adolescents with MDD and psychiatrically healthy controls; these phenotypes are posited to reflect
altered neurodevelopment in key emotion regulation circuitry. We do not yet know, however, whether and how
MDD impacts adolescent development of ACC connectivity in a manner that contributes to an increased risk of
depressive relapse or recurrence. One mechanism may be the immune system, which activates in response to
psychosocial stressors and influences neurotransmitter systems including glutamate, the primary excitatory
neurotransmitter in the brain. Basic research indicates that higher levels of pro-inflammatory cytokines leads to
overexcitation of glutamatergic neurons to the point of neurotoxicity and, consequently, to reduced
neuroplasticity. Further, neuroimaging studies of adult MDD have reported heightened levels of inflammation
and altered levels of glutamate in the ACC. These data, combined with growing evidence that ACC
connectivity undergoes extensive maturation during adolescence, suggest that heightened inflammation and
excessive glutamate may lead to atypical development of this circuitry in adolescents with MDD. The candidate
therefore seeks to test the central hypothesis that heightened inflammation acts through glutamate
transmission to disrupt typical neurodevelopment of ACC connectivity in adolescents with MDD to increase risk
of depressive relapse or recurrence. This K01 will test this model in 60 adolescents with first episodes of MDD
assessed longitudinally over 3 time points using an innovative multimodal approach. The candidate will assay
peripheral levels of pro-inflammatory cytokines using dried blood spot technology, noninvasively image
glutamate and antioxidants in ACC using proton magnetic resonance spectroscopy, and assess
neurodevelopmental changes of ACC connectivity using functional (resting-state fMRI) and structural (diffusion
MRI) methods. This K01 fills key gaps in our understanding of whether adolescent MDD impacts development
of ACC connectivity, how inflammatory and glutamatergic mechanisms underlying MDD-related changes in
ACC connectivity contribute to subsequent relapse or recurrence in adolescents with MDD, and whether
antioxidants protect against depression recurrence by buffering the effects of inflammation on adolescent
development of ACC circuitry. Importantly, the candidate will execute this research in the context of receiving
advanced training in stress-related immune biology, causal inference modeling, and developmental
psychopathology. Results from th...

## Key facts

- **NIH application ID:** 10165829
- **Project number:** 5K01MH117442-05
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** TIFFANY CHEING HO
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $132,177
- **Award type:** 5
- **Project period:** 2018-06-01 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10165829

## Citation

> US National Institutes of Health, RePORTER application 10165829, The Roles of Inflammatory and Glutamatergic Processes in the Neurodevelopmental Mechanisms Underlying Adolescent Depression (5K01MH117442-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10165829. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*