# Role of Brain-Derived Neurotrophic Factor in Regulating Neuroinflammation in Mental Health

> **NIH VA I01** · SOUTH TEXAS VETERANS HEALTH CARE SYSTEM · 2024 · —

## Abstract

Dysfunction in BDNF confers vulnerability to psychosocial stress, and myriad data generated during the initial
funding period of this project revealed that disruption of BDNF signaling also potentiated neuroinflammation and
inflammation-induced depressive-like behaviors. The US veteran population is well known to suffer high rates of
psychological stress and chronic inflammatory conditions as well as disproportionately increased risk of
depression and suicide. Understanding the contribution of neurobiological substrates that mediate this increased
risk is necessary for developing better treatment strategies to treat suffering US veterans. Unfortunately,
mechanism(s) mediating this vulnerability remain elusive. Our recent discoveries suggest that dysfunction in the
BDNF system represents a genetic vulnerability factor for the development of depression, and preliminary data
have identified therapeutically targetable neural substrates that appear to mediate this vulnerability. More
specifically, dysregulation of the kynurenine pathway in the brain has been implicated in the pathogenesis of
depressive symptomotology. Of functional significance, two metabolic branches of the kynurenine pathway are
physically compartmentalized. The neuroprotective branch that forms kynurenic acid resides in astrocytes. The
neurotoxic branch that forms 3- hydroxykynurenine and quinolinic acid resides in microglia. A large body of
evidence implicates the kynurenine pathway in depression associated with inflammation. However, a role for this
pathway in stress- or inflammation-induced depressive behavior has been largely unexplored. We have recently
reported that low-level stress, consisting of psychosocial and environmental challenges, increases
neuroprotective factors kynurenic acid and the anti-inflammatory cytokine IL-10 in the forebrain of wild-type, but
not BDNF+/- mice. In striking contrast, levels of the neurotoxic kynurenine metabolite 3-hydroxykynurenine are
markedly increased in BDNF+/- mice. These observations support our contention that protective mechanisms
present in wild-type mice are absent in BDNF deficient animals. Mice with genetic disruptions in the BDNF
system exhibit pronounced neuroinflammation, oxidative kynurenine metabolism and depressive-like behavior
relative to wild-type mice. Our overall hypothesis is that during exposure to depression risk factors (stress or
inflammation), the activity-dependent release of BDNF increases IL-10 production, which in turn modulates
kynurenine pathway metabolism resulting in increased levels of kynurenic acid. Under conditions of BDNF
deficiency or dysfunction, the absence of these neuroprotective mechanisms results in a stress-sensitive
phenotype. We will use BDNF heterozygous mice (BDNF+/- mice), which exhibit marked reductions in BDNF
expression, to mechanistically explore the aims proposed. To test our hypotheses in a translationally relevant
model, we will use transgenic mice carrying the met allele of the ...

## Key facts

- **NIH application ID:** 10911149
- **Project number:** 5I01BX003195-07
- **Recipient organization:** SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
- **Principal Investigator:** Jason C O'Connor
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2016-10-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911149

## Citation

> US National Institutes of Health, RePORTER application 10911149, Role of Brain-Derived Neurotrophic Factor in Regulating Neuroinflammation in Mental Health (5I01BX003195-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10911149. Licensed CC0.

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