# Microglia Dysregulation and Altered Responses to Stress after Traumatic Brain Injury

> **NIH NIH F31** · OHIO STATE UNIVERSITY · 2022 · $35,019

## Abstract

PROJECT SUMMARY
More than 5.3 million individuals suffer from a traumatic brain injury (TBI) related disability in the United States.
Mounting clinical and experimental evidence shows a common co-morbidity of TBI is hypothalamic-pituitary-
adrenal (HPA) axis dysfunction that results in the suppression of the stress hormone - cortisol in humans or the
equivalent corticosterone (CORT) in rodents. Suppressed CORT is associated with aberrant neuronal responses
in stress circuitry and can exacerbate post-TBI impairments, including cognitive and behavioral deficits. Sleep
fragmentation is a frequent consequence of stress, thus we predict that post-injury sleep fragmentation engages
a vulnerable biological pathway that substantially influences outcome by modulating neuroinflammation. For
example, increasing data demonstrates that microglia mediate chronic TBI-induced recovery by perpetuating
maladaptive inflammation, cytotoxicity, and altering neuronal viability and plasticity. Importantly, this microglial
response may be worsened by post-TBI stressors. For example, microglia highly express glucocorticoid receptor
(GR), which binds CORT to induce potent anti-inflammatory signaling. We hypothesize that TBI-induced
suppression of CORT may compromise the anti-inflammatory action of GR in microglia, thus CORT production
in response to stressors after TBI is vital to ensure control of inflammation. Due to the interplay of the stress and
immune axes, the effect of chronic stress on TBI outcome must be better understood. This proposal aims to
determine how neuronal activation and stress circuitry is altered in response to post-TBI sleep fragmentation,
and how microglial GR may influence inflammation, neuronal activation, and cognition with post-TBI sleep
fragmentation. Aim 1 will determine how microglia influence stress circuitry and hippocampal neuronal function
with post-TBI sleep fragmentation. To do this, Pt. 3 we will rapidly deplete microglia through CSF1R antagonism
and expose animals with and without microglia to post-TBI sleep fragmentation to define the cell specific role of
microglia on neuronal activation in stress circuitry. We will further determine the RNA profile of the hippocampus
following microglia depletion with post-TBI sleep fragmentation and perform electrophysiology to distinguish
whether differences in hippocampal activity are due to changes in neuronal function and viability or microglial
signaling. Aim 2 will test if microglial GR activation mediates inflammation, neuronal activation, and behavior
following post-TBI sleep fragmentation. To do this, we will use Pt. 3 an inducible knockout of GR in microglia
and determine differences in RNA sequencing profile, immunohistochemistry, and hippocampal-dependent
behavioral tasks with sleep fragmentation after TBI. We hypothesize that reactive microglia mediate neuronal
deficits in response to post-TBI sleep fragmentation through suppressed GR anti-inflammatory action. Ultimately,
this propo...

## Key facts

- **NIH application ID:** 10388892
- **Project number:** 1F31NS122471-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Zoe M. Tapp
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $35,019
- **Award type:** 1
- **Project period:** 2022-02-01 → 2024-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10388892

## Citation

> US National Institutes of Health, RePORTER application 10388892, Microglia Dysregulation and Altered Responses to Stress after Traumatic Brain Injury (1F31NS122471-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10388892. Licensed CC0.

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