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Research Articles, Neurobiology of Disease

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

Kristina G. Witcher, Chelsea E. Bray, Titikorn Chunchai, Fangli Zhao, Shane M. O'Neil, Alan J. Gordillo, Warren A. Campbell, Daniel B. McKim, Xiaoyu Liu, Julia E. Dziabis, Ning Quan, Daniel S. Eiferman, Andy J. Fischer, Olga N. Kokiko-Cochran, Candice Askwith and Jonathan P. Godbout
Journal of Neuroscience 17 February 2021, 41 (7) 1597-1616; DOI: https://doi.org/10.1523/JNEUROSCI.2469-20.2020
Kristina G. Witcher
1Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210
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Chelsea E. Bray
1Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210
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Titikorn Chunchai
1Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210
2Neurophysiology unit, Cardiac Electrophysiology Research and Training Center, Faculty of Medicine, Chiang Mai University, Chiang Mai 50200, Thailand
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Fangli Zhao
1Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210
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Shane M. O'Neil
1Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210
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Alan J. Gordillo
1Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210
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Warren A. Campbell
1Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210
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Daniel B. McKim
1Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210
3Department of Animal Sciences, University of Illinois Urbana-Champaign, Urbana, Illinois 61801
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Xiaoyu Liu
4Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, Florida 33458
5Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio 43210
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Julia E. Dziabis
1Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210
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Ning Quan
4Charles E. Schmidt College of Medicine and Brain Institute, Florida Atlantic University, Jupiter, Florida 33458
5Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio 43210
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Daniel S. Eiferman
6Department of Surgery, The Ohio State University, Columbus, Ohio 43210
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Andy J. Fischer
1Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210
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Olga N. Kokiko-Cochran
1Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210
5Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio 43210
7Chronic Brain Injury Discovery Themes Initiative, The Ohio State University, Columbus, Ohio 43210
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Candice Askwith
1Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210
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Jonathan P. Godbout
1Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210
5Institute for Behavioral Medicine Research, The Ohio State University, Columbus, Ohio 43210
7Chronic Brain Injury Discovery Themes Initiative, The Ohio State University, Columbus, Ohio 43210
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Abstract

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.

  • CSF1R antagonist
  • microglia
  • neuroinflammation
  • neurotrauma
  • traumatic brain injury

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The Journal of Neuroscience: 41 (7)
Journal of Neuroscience
Vol. 41, Issue 7
17 Feb 2021
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Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia
Kristina G. Witcher, Chelsea E. Bray, Titikorn Chunchai, Fangli Zhao, Shane M. O'Neil, Alan J. Gordillo, Warren A. Campbell, Daniel B. McKim, Xiaoyu Liu, Julia E. Dziabis, Ning Quan, Daniel S. Eiferman, Andy J. Fischer, Olga N. Kokiko-Cochran, Candice Askwith, Jonathan P. Godbout
Journal of Neuroscience 17 February 2021, 41 (7) 1597-1616; DOI: 10.1523/JNEUROSCI.2469-20.2020

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Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia
Kristina G. Witcher, Chelsea E. Bray, Titikorn Chunchai, Fangli Zhao, Shane M. O'Neil, Alan J. Gordillo, Warren A. Campbell, Daniel B. McKim, Xiaoyu Liu, Julia E. Dziabis, Ning Quan, Daniel S. Eiferman, Andy J. Fischer, Olga N. Kokiko-Cochran, Candice Askwith, Jonathan P. Godbout
Journal of Neuroscience 17 February 2021, 41 (7) 1597-1616; DOI: 10.1523/JNEUROSCI.2469-20.2020
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Keywords

  • CSF1R antagonist
  • microglia
  • neuroinflammation
  • neurotrauma
  • traumatic brain injury

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