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Mossy cell hypertrophy and synaptic changes in the hilus following mild diffuse traumatic brain injury in pigs

BACKGROUND: Each year in the USA, over 2.4 million people experience mild traumatic brain injury (TBI), which can induce long-term neurological deficits. The dentate gyrus of the hippocampus is notably susceptible to damage following TBI, as hilar mossy cell changes in particular may contribute to p...

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Autores principales: Grovola, Michael R., Paleologos, Nicholas, Wofford, Kathryn L., Harris, James P., Browne, Kevin D., Johnson, Victoria, Duda, John E., Wolf, John A., Cullen, D. Kacy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993507/
https://www.ncbi.nlm.nih.gov/pubmed/32005260
http://dx.doi.org/10.1186/s12974-020-1720-0
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author Grovola, Michael R.
Paleologos, Nicholas
Wofford, Kathryn L.
Harris, James P.
Browne, Kevin D.
Johnson, Victoria
Duda, John E.
Wolf, John A.
Cullen, D. Kacy
author_facet Grovola, Michael R.
Paleologos, Nicholas
Wofford, Kathryn L.
Harris, James P.
Browne, Kevin D.
Johnson, Victoria
Duda, John E.
Wolf, John A.
Cullen, D. Kacy
author_sort Grovola, Michael R.
collection PubMed
description BACKGROUND: Each year in the USA, over 2.4 million people experience mild traumatic brain injury (TBI), which can induce long-term neurological deficits. The dentate gyrus of the hippocampus is notably susceptible to damage following TBI, as hilar mossy cell changes in particular may contribute to post-TBI dysfunction. Moreover, microglial activation after TBI may play a role in hippocampal circuit and/or synaptic remodeling; however, the potential effects of chronic microglial changes are currently unknown. The objective of the current study was to assess neuropathological and neuroinflammatory changes in subregions of the dentate gyrus at acute to chronic time points following mild TBI using an established model of closed-head rotational acceleration induced TBI in pigs. METHODS: This study utilized archival tissue of pigs which were subjected to sham conditions or rapid head rotation in the coronal plane to generate mild TBI. A quantitative assessment of neuropathological changes in the hippocampus was performed via immunohistochemical labeling of whole coronal tissue sections at 3 days post-injury (DPI), 7 DPI, 30 DPI, and 1 year post-injury (YPI), with a focus on mossy cell atrophy and synaptic reorganization, in context with microglial alterations (e.g., density, proximity to mossy cells) in the dentate gyrus. RESULTS: There were no changes in mossy cell density between sham and injured animals, indicating no frank loss of mossy cells at the mild injury level evaluated. However, we found significant mossy cell hypertrophy at 7 DPI and 30 DPI in anterior (> 16% increase in mean cell area at each time; p = <  0.001 each) and 30 DPI in posterior (8.3% increase; p = <  0.0001) hippocampus. We also found dramatic increases in synapsin staining around mossy cells at 7 DPI in both anterior (74.7% increase in synapsin labeling; p = <  0.0001) and posterior (82.7% increase; p = <  0.0001) hippocampus. Interestingly, these morphological and synaptic alterations correlated with a significant change in microglia in proximity to mossy cells at 7 DPI in anterior and at 30 DPI in the posterior hippocampus. For broader context, while we found that there were significant increases in microglia density in the granule cell layer at 30 DPI (anterior and posterior) and 1 YPI (posterior only) and in the molecular layer at 1 YPI (anterior only), we found no significant changes in overall microglial density in the hilus at any of the time points evaluated post-injury. CONCLUSIONS: The alterations of mossy cell size and synaptic inputs paired with changes in microglia density around the cells demonstrate the susceptibility of hilar mossy cells after even mild TBI. This subtle hilar mossy cell pathology may play a role in aberrant hippocampal function post-TBI, although additional studies are needed to characterize potential physiological and cognitive alterations.
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spelling pubmed-69935072020-02-04 Mossy cell hypertrophy and synaptic changes in the hilus following mild diffuse traumatic brain injury in pigs Grovola, Michael R. Paleologos, Nicholas Wofford, Kathryn L. Harris, James P. Browne, Kevin D. Johnson, Victoria Duda, John E. Wolf, John A. Cullen, D. Kacy J Neuroinflammation Research BACKGROUND: Each year in the USA, over 2.4 million people experience mild traumatic brain injury (TBI), which can induce long-term neurological deficits. The dentate gyrus of the hippocampus is notably susceptible to damage following TBI, as hilar mossy cell changes in particular may contribute to post-TBI dysfunction. Moreover, microglial activation after TBI may play a role in hippocampal circuit and/or synaptic remodeling; however, the potential effects of chronic microglial changes are currently unknown. The objective of the current study was to assess neuropathological and neuroinflammatory changes in subregions of the dentate gyrus at acute to chronic time points following mild TBI using an established model of closed-head rotational acceleration induced TBI in pigs. METHODS: This study utilized archival tissue of pigs which were subjected to sham conditions or rapid head rotation in the coronal plane to generate mild TBI. A quantitative assessment of neuropathological changes in the hippocampus was performed via immunohistochemical labeling of whole coronal tissue sections at 3 days post-injury (DPI), 7 DPI, 30 DPI, and 1 year post-injury (YPI), with a focus on mossy cell atrophy and synaptic reorganization, in context with microglial alterations (e.g., density, proximity to mossy cells) in the dentate gyrus. RESULTS: There were no changes in mossy cell density between sham and injured animals, indicating no frank loss of mossy cells at the mild injury level evaluated. However, we found significant mossy cell hypertrophy at 7 DPI and 30 DPI in anterior (> 16% increase in mean cell area at each time; p = <  0.001 each) and 30 DPI in posterior (8.3% increase; p = <  0.0001) hippocampus. We also found dramatic increases in synapsin staining around mossy cells at 7 DPI in both anterior (74.7% increase in synapsin labeling; p = <  0.0001) and posterior (82.7% increase; p = <  0.0001) hippocampus. Interestingly, these morphological and synaptic alterations correlated with a significant change in microglia in proximity to mossy cells at 7 DPI in anterior and at 30 DPI in the posterior hippocampus. For broader context, while we found that there were significant increases in microglia density in the granule cell layer at 30 DPI (anterior and posterior) and 1 YPI (posterior only) and in the molecular layer at 1 YPI (anterior only), we found no significant changes in overall microglial density in the hilus at any of the time points evaluated post-injury. CONCLUSIONS: The alterations of mossy cell size and synaptic inputs paired with changes in microglia density around the cells demonstrate the susceptibility of hilar mossy cells after even mild TBI. This subtle hilar mossy cell pathology may play a role in aberrant hippocampal function post-TBI, although additional studies are needed to characterize potential physiological and cognitive alterations. BioMed Central 2020-01-31 /pmc/articles/PMC6993507/ /pubmed/32005260 http://dx.doi.org/10.1186/s12974-020-1720-0 Text en © The Author(s). 2020 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Grovola, Michael R.
Paleologos, Nicholas
Wofford, Kathryn L.
Harris, James P.
Browne, Kevin D.
Johnson, Victoria
Duda, John E.
Wolf, John A.
Cullen, D. Kacy
Mossy cell hypertrophy and synaptic changes in the hilus following mild diffuse traumatic brain injury in pigs
title Mossy cell hypertrophy and synaptic changes in the hilus following mild diffuse traumatic brain injury in pigs
title_full Mossy cell hypertrophy and synaptic changes in the hilus following mild diffuse traumatic brain injury in pigs
title_fullStr Mossy cell hypertrophy and synaptic changes in the hilus following mild diffuse traumatic brain injury in pigs
title_full_unstemmed Mossy cell hypertrophy and synaptic changes in the hilus following mild diffuse traumatic brain injury in pigs
title_short Mossy cell hypertrophy and synaptic changes in the hilus following mild diffuse traumatic brain injury in pigs
title_sort mossy cell hypertrophy and synaptic changes in the hilus following mild diffuse traumatic brain injury in pigs
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993507/
https://www.ncbi.nlm.nih.gov/pubmed/32005260
http://dx.doi.org/10.1186/s12974-020-1720-0
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