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Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia.

Publication ,  Journal Article
Witcher, KG; Bray, CE; Chunchai, T; Zhao, F; O'Neil, SM; Gordillo, AJ; Campbell, WA; McKim, DB; Liu, X; Dziabis, JE; Quan, N; Eiferman, DS ...
Published in: The Journal of neuroscience : the official journal of the Society for Neuroscience
February 2021

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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Published In

The Journal of neuroscience : the official journal of the Society for Neuroscience

DOI

EISSN

1529-2401

ISSN

0270-6474

Publication Date

February 2021

Volume

41

Issue

7

Start / End Page

1597 / 1616

Related Subject Headings

  • Suppression, Genetic
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Psychomotor Performance
  • Organic Chemicals
  • Neurons
  • Neurology & Neurosurgery
  • Motor Activity
  • Microglia
  • Mice, Inbred C57BL
  • Mice
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Witcher, K. G., Bray, C. E., Chunchai, T., Zhao, F., O’Neil, S. M., Gordillo, A. J., … Godbout, J. P. (2021). Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia. The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, 41(7), 1597–1616. https://doi.org/10.1523/jneurosci.2469-20.2020
Witcher, Kristina G., Chelsea E. Bray, Titikorn Chunchai, Fangli Zhao, Shane M. O’Neil, Alan J. Gordillo, Warren A. Campbell, et al. “Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 41, no. 7 (February 2021): 1597–1616. https://doi.org/10.1523/jneurosci.2469-20.2020.
Witcher KG, Bray CE, Chunchai T, Zhao F, O’Neil SM, Gordillo AJ, et al. Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2021 Feb;41(7):1597–616.
Witcher, Kristina G., et al. “Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia.The Journal of Neuroscience : The Official Journal of the Society for Neuroscience, vol. 41, no. 7, Feb. 2021, pp. 1597–616. Epmc, doi:10.1523/jneurosci.2469-20.2020.
Witcher KG, Bray CE, Chunchai T, Zhao F, O’Neil SM, Gordillo AJ, Campbell WA, McKim DB, Liu X, Dziabis JE, Quan N, Eiferman DS, Fischer AJ, Kokiko-Cochran ON, Askwith C, Godbout JP. Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2021 Feb;41(7):1597–1616.

Published In

The Journal of neuroscience : the official journal of the Society for Neuroscience

DOI

EISSN

1529-2401

ISSN

0270-6474

Publication Date

February 2021

Volume

41

Issue

7

Start / End Page

1597 / 1616

Related Subject Headings

  • Suppression, Genetic
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • Psychomotor Performance
  • Organic Chemicals
  • Neurons
  • Neurology & Neurosurgery
  • Motor Activity
  • Microglia
  • Mice, Inbred C57BL
  • Mice