TY - JOUR
T1 - Traumatic brain injury causes chronic cortical inflammation and neuronal dysfunction mediated by Microglia
AU - Witcher, Kristina G.
AU - Bray, Chelsea E.
AU - Chunchai, Titikorn
AU - Zhao, Fangli
AU - O'Neil, Shane M.
AU - Gordillo, Alan J.
AU - Campbell, Warren A.
AU - McKim, Daniel B.
AU - Liu, Xiaoyu
AU - Dziabis, Julia E.
AU - Quan, Ning
AU - Eiferman, Daniel S.
AU - Fischer, Andy J.
AU - Kokiko-Cochran, Olga N.
AU - Askwith, Candice
AU - Godbout, Jonathan P.
N1 - Funding Information:
This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) Grant R56-NS-090311 and the National Institute of Aging (NIA) Grant R01-AG-051902 (to J.P.G.). In addition, this work was supported by a P30 Core Grant (NINDS P30-NS-045758). K.G.W. and S.M.O. were supported by the National Institute of Dental and Craniofacial Research Training Grant T32-DE-014320 and K.G.W. by the Ohio State University Presidential Fellowship. T.C. was supported by the Thailand Research Fund-Royal Golden Jubilee Program Grant PHD/0146/2558 TC&SCC. We thank Plexxikon, Inc. for the use of PLX5622, Dr. Paolo Fadda at the Ohio State University Comprehensive Cancer Center Genomics Shared Resource (P30-CA-016058), and the Chronic Brain Injury Discovery Themes Initiative at Ohio State University. Our scRNA-sequencing (scRNAseq) analysis was made possible by an allotment of resources from the Ohio Supercomputing Center. The authors declare no competing financial interests. Correspondence should be addressed to Jonathan P. Godbout at jonathan.godbout@osumc.edu. https://doi.org/10.1523/JNEUROSCI.2469-20.2020 Copyright © 2021 the authors
Funding Information:
This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) Grant R56-NS-090311 and the National Institute of Aging (NIA) Grant R01-AG-051902 (to J.P.G.). In addition, this work was supported by a P30 Core Grant (NINDS P30-NS-045758). K.G.W. and S.M.O. were supported by the National Institute of Dental and Craniofacial Research Training Grant T32-DE-014320 and K.G.W. by the Ohio State University Presidential Fellowship. T.C. was supported by the Thailand Research Fund-Royal Golden Jubilee Program Grant PHD/0146/2558 TC&SCC. We thank Plexxikon, Inc. for the use of PLX5622, Dr. Paolo Fadda at the Ohio State University Comprehensive Cancer Center Genomics Shared Resource (P30-CA-016058), and the Chronic Brain Injury Discovery Themes Initiative at Ohio State University. Our scRNA-sequencing (scRNAseq) analysis was made possible by an allotment of resources from the Ohio Supercomputing Center.
Publisher Copyright:
Copyright © 2021 the authors.
PY - 2021/1/17
Y1 - 2021/1/17
N2 - 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.
AB - 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.
KW - CSF1R antagonist
KW - Microglia
KW - Neuroinflammation
KW - Neurotrauma
KW - Traumatic brain injury
UR - http://www.scopus.com/inward/record.url?scp=85102212055&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102212055&partnerID=8YFLogxK
U2 - 10.1523/JNEUROSCI.2469-20.2020
DO - 10.1523/JNEUROSCI.2469-20.2020
M3 - Article
C2 - 33452227
AN - SCOPUS:85102212055
SN - 0270-6474
VL - 41
SP - 1597
EP - 1616
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 7
ER -