# Chronic and Evolving Inflammation after Traumatic Brain Injury: Microglial Priming and Neuropsychiatric Complications

> **NIH NIH R01** · OHIO STATE UNIVERSITY · 2022 · $438,366

## Abstract

PROJECT SUMMARY/ABSTRACT:
Traumatic brain injury (TBI) can lead to significant neuropsychiatric problems and neurodegenerative pathologies
that develop with time after injury. These issues may be propagated by neuroinflammatory processes that
continue well after the initial injury. Pt.3 We have reported that diffuse TBI in mice leads to “microglial priming”
within cortical and hippocampal regions, in which the microglia remain in a sensitized state and are highly
inflammatory following an immune challenge 30 days post injury (30 dpi). In this application, we show a distinct
phase transition from acute (8-24 h) to sub-acute (7 d) and then to chronic (30 d) cortical-inflammation/microglia
priming after TBI. Acutely, there was an inflammatory response after TBI that evolved into a subacute phase 7
dpi that was dominated by interferon (IFN) type I signaling. IFN responses are activated by cell distress and
damage to promote an immune response that can prime innate immune cells, including microglia. We provide
evidence of cortical neuronal damage 7 dpi with corresponding microglial activation. Pts.3&6 Single cell RNA
seq (scRNAseq) of the cortex 7 dpi shows unique clusters of microglia, trauma-associated, that are influenced
by IFNs. These microglia are involved in dendritic remodeling and suppression of neuronal homeostasis. At 30
dpi, there was cognitive impairment (associated with HPC & CTX), reduced network connectivity, and increased
immune reactivity of primed microglia. Microglia are critical in these processes because microglial elimination
(CSF1R antagonist) prevented TBI-induced neuroinflammation and IFN signaling, attenuated dendritic atrophy,
and improved network connectivity. Thus, we hypothesize that increased interferon signaling is critical in
promoting microglial priming and chronic neuroinflammation, dendritic remodeling, and cognitive decline. To
address this, three aims are proposed using a midline fluid percussion injury in mice. In Aim-1, we will eliminate
microglia to determine the influence of microglia on other CNS cells in the cortex and hippocampus acutely, sub-
acutely, and chronically after TBI. ScRNAseq will be used to determine the transcriptome signature of microglia
over time and in parallel with astrocytes, oligodendrocytes, and neurons at 3 these critical times after TBI. The
focus will be determining which cells express IFNs and IFN receptors, and how they respond to increased IFN
signaling with TBI. In Aim-2, we will determine if IFN signaling is critical in chronic neuroinflammation, pathology,
cognitive decline, and microglial priming after TBI. Here, we will attenuate IFN signaling at the levels of IFN-a/b
receptor activation (IFNαRKO, Mgl-IFNαRKO) and IFN production (STINGKO) to determine the extent to which
these interventions ameliorate neuroinflammation, pathology, and microglial priming. In Aim-3, we will determine
if TBI-induced microglial priming, chronic neuroinflammation, and cognitive decline 30 dpi ar...

## Key facts

- **NIH application ID:** 10374923
- **Project number:** 5R01NS118037-02
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Jonathan P Godbout
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $438,366
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10374923

## Citation

> US National Institutes of Health, RePORTER application 10374923, Chronic and Evolving Inflammation after Traumatic Brain Injury: Microglial Priming and Neuropsychiatric Complications (5R01NS118037-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10374923. Licensed CC0.

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