Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia
Open accessAbstract
Traumatic brain injury (TBI) can lead to significant neuropsychiatric problems and neurodegenerative pathologies, which develop and persist years after injury. Neuroinflammatory processes evolve over this same period. Therefore, we aimed to determine the contribution of microglia to neuropathology at acute [1 d postinjury (dpi)], subacute (7 dpi), and chronic (30 dpi) time points. Microglia were depleted with PLX5622, a CSF1R antagonist, before midline fluid percussion injury (FPI) in male mice and cortical neuropathology/inflammation was assessed using a neuropathology mRNA panel. Gene expression associated with inflammation and neuropathology were robustly increased acutely after injury (1 dpi) and the majority of this expression was microglia independent. At 7 and 30 dpi, however, microglial depletion reversed TBI-related expression of genes associated with inflammation, interferon signaling, and neuropathology. Myriad suppressed genes at subacute and chronic endpoints were attributed to neurons. To understand the relationship between microglia, neurons, and other glia, single-cell RNA sequencing was completed 7 dpi, a critical time point in the evolution from acute to chronic pathogenesis. Cortical microglia exhibited distinct TBI-associated clustering with increased type-1 interferon and neurodegenerative/damage-related genes. In cortical neurons, genes associated with dopamine signaling, long-term potentiation, calcium signaling, and synaptogenesis were suppressed. Microglial depletion reversed the majority of these neuronal alterations. Furthermore, there was reduced cortical dendritic complexity 7 dpi, reduced neuronal connectively 30 dpi, and cognitive impairment 30 dpi. All of these TBI-associated functional and behavioral impairments were prevented by microglial depletion. Collectively, these studies indicate that microglia promote persistent neuropathology and long-term functional impairments in neuronal homeostasis after TBI. SIGNIFICANCE STATEMENT Millions of traumatic brain injuries (TBIs) occur in the United States alone each year. Survivors face elevated rates of cognitive and psychiatric complications long after the inciting injury. Recent studies of human brain injury link chronic neuroinflammation to adverse neurologic outcomes, suggesting that evolving inflammatory processes may be an opportunity for intervention. Here, we eliminate microglia to compare the effects of diffuse TBI on neurons in the presence and absence of microglia and microglia-mediated inflammation. In the absence of microglia, neurons do not undergo TBI-induced changes in gene transcription or structure. Microglial elimination prevented TBI-induced cognitive changes 30 d postinjury (dpi). Therefore, microglia have a critical role in disrupting neuronal homeostasis after TBI, particularly at subacute and chronic timepoints.
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As time passes following primary injury, neuroprotective functions are lost, and microglia become the prime motivators of neuroinflammatory gene expression in the post-TBI brain.
“However, as time passes following the primary injury the neuroprotective functions are lost, and microglia become the prime motivators of neuroinflammatory gene expression in the post-TBI brain [112].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [112]
Microglia associated with the long-term inflammatory phenotype following TBI are commonly defined as MHC-II/CD86/Cd11b positive, with upregulated expression of NOX24, Tlr4, Trem2, CD68, Clec7a, and Stat1, and higher expression of interferon- and immune-associated signaling genes.
“Microglia associated with the long-term inflammatory phenotype following TBI are commonly defined as MHC-II/CD86/Cd11b positive, with upregulated expression of NOX24, Tlr4, Trem2, CD68, Clec7a, and Stat1, and higher expression of interferon- and immune-associated signaling genes [100,112,115,116].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [112]
Pharmacological clearance of microglia post-injury in mice is neuroprotective and reduces cognitive impairment.
“Importantly, a recent study in mice demonstrated pharmacological clearance of microglia post-injury is neuroprotective and reduces cognitive impairment [112].”
From Untangling senescent and damage‐associated microglia in the aging and diseased brain (2023) · cites this paper as [112]
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- Authors
- Witcher, K. G., Bray, C. E., Chunchai, T., Zhao, F., O'Neil, S. M., Gordillo, A. J., Campbell, W. A., McKim, D. B., Liu, X., Dziabis, J. E., Quan, N., Eiferman, D. S., Fischer, A. J., Kokiko-Cochran, O. N., Askwith, C., & Godbout, J. P.
- Affiliations
- The Ohio State University (US)
- Chiang Mai University (TH)
- University of Illinois Urbana-Champaign (US)
- ORCID
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2021-01-15
- Volume
- 41
- Issue
- 7
- Pages
- 1597-1616
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC7896020
- OpenAlex
- W3122084099
- Semantic Scholar
- 208acaf468f5f7c686e0993b06307c428b26a1dd
- Cited by
- 387
- References
- 69
- Citations by year
- 2026: 62 · 2025: 79 · 2024: 98 · 2023: 62 · 2022: 71 · 2021: 14
- FWCI
- 29.90
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Neurological Disorders and Stroke (R56-NS-090311, P30-NS-045758)
- HHS | NIH | National Institute on Aging (R01-AG-051902)
- HHS | NIH | National Institute of Dental and Craniofacial Research (T32-DE-014320)
- Thailand Research Fund-Royal Golden Jubilee Program (PHD/0146/2558)
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Keywords
- traumatic brain injury, microglia, neuroinflammation, chronic neuroinflammation, microglial depletion, PLX5622, fluid percussion injury, neuronal dysfunction, interferon signaling, type I interferon, dendritic complexity, cognitive impairment, single-cell RNA sequencing, long-term potentiation, dopamine signaling
- MeSH terms
- Brain Injuries, Traumatic, Animals, Cerebral Cortex, Encephalitis, Interferons, Male, Mice, Inbred C57BL, Motor Activity, Neurons, Organic Chemicals, Psychomotor Performance, Suppression, Genetic, Gene Expression, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Microglia, Long-Term Potentiation, Calcium Signaling, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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