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Multiple Mild Traumatic Brain Injuries Lead to Visual Dysfunction in a Mouse Model.

ABSTRACT: Visual dysfunction is a common occurrence after traumatic brain injury (TBI). We investigated in this study effects of single or multiple mild TBI on visual function in mice using a closed head injury model that permits unconstrained head movement after impact. Adult mice were briefly anesthetized with isoflurane and given one or three mild TBI with the closed head injury by mechanically engineered rotational acceleration (CHIMERA) device with an interinjury interval of 24?h. Mice were then tested in the Morris water maze, visual cliff, and open field tests from day 19 to day 32 and for visual evoked potential at 5 weeks after the last injury and euthanized. Mice with multiple TBI showed impaired performance in the visible platform water maze test and had increased errors in the visual cliff test. Further, there was a graded difference in visual evoked potential, with the single injury mice showing modest reduction in N1 amplitude whereas the multiple injuries produced significant reduction compared to sham and single injury groups. The optic tract of the injured mice showed increases in glial cell immunostaining. The increase in glial fibrillary acid protein immunostaining reached statistical significance for both injured groups whereas the ionized calcium binding adaptor molecule 1 immunostaining was only significantly increased in the optic tract of repeatedly injured mice. These results indicate that multiple injuries using CHIMERA may result in visual deficits, which can affect certain behavioral performances. The change in vision may be a useful marker when monitoring repeated TBI outcome and screening for protective agents from TBI.

SUBMITTER: Desai A

PROVIDER: S-EPMC6964804 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Multiple Mild Traumatic Brain Injuries Lead to Visual Dysfunction in a Mouse Model.

Desai Abhishek A Chen Huazhen H Kim Hee-Yong HY

Journal of neurotrauma 20191108 2

Visual dysfunction is a common occurrence after traumatic brain injury (TBI). We investigated in this study effects of single or multiple mild TBI on visual function in mice using a closed head injury model that permits unconstrained head movement after impact. Adult mice were briefly anesthetized with isoflurane and given one or three mild TBI with the closed head injury by mechanically engineered rotational acceleration (CHIMERA) device with an interinjury interval of 24 h. Mice were then test ...[more]

PMID: 31530220

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Project description:Repetitive mild traumatic brain injury (r-mTBI) results in neuropathological and biochemical consequences in the human visual system. Using a recently developed mouse model of r-mTBI, with control mice receiving repetitive anesthesia alone (r-sham) we assessed the effects on the retina and optic nerve using histology, immunohistochemistry, proteomic and lipidomic analyses at 3 weeks post injury. Retina tissue was used to determine retinal ganglion cell (RGC) number, while optic nerve tissue was examined for cellularity, myelin content, protein and lipid changes. Increased cellularity and areas of demyelination were clearly detectable in optic nerves in r-mTBI, but not in r-sham. These changes were accompanied by a ~25% decrease in the total number of Brn3a-positive RGCs. Proteomic analysis of the optic nerves demonstrated various changes consistent with a negative effect of r-mTBI on major cellular processes like depolymerization of microtubules, disassembly of filaments and loss of neurons, manifested by decrease of several proteins, including neurofilaments (NEFH, NEFM, NEFL), tubulin (TUBB2A, TUBA4A), microtubule-associated proteins (MAP1A, MAP1B), collagen (COL6A1, COL6A3) and increased expression of other proteins, including heat shock proteins (HSP90B1, HSPB1), APOE and cathepsin D. Lipidomic analysis showed quantitative changes in a number of phospholipid species, including a significant increase in the total amount of lysophosphatidylcholine (LPC), including the molecular species 16:0, a known demyelinating agent. The overall amount of some ether phospholipids, like ether LPC, ether phosphatidylcholine and ether lysophosphatidylethanolamine were also increased, while the majority of individual molecular species of ester phospholipids, like phosphatidylcholine and phosphatidylethanolamine, were decreased. Results from the biochemical analysis correlate well with changes detected by histological and immunohistochemical methods and indicate the involvement of several important molecular pathways. This will allow future identification of therapeutic targets for improving the visual consequences of r-mTBI.

Project description:In the military, explosive blasts are a significant cause of mild traumatic brain injuries (mTBIs). The symptoms associated with blast mTBIs causes significant economic burdens and a diminished quality of life for many service members. At present, the distinction of the injury mechanism (blast versus non-blast) may not influence TBI diagnosis. However, using noninvasive imaging, this study reveals significant distinctions between the blast and non-blast TBI mechanisms. A cortical whole-brain thickness analysis was performed using structural high-resolution T1-weighted MRI to identify the effects of blasts in persistent mTBI (pmTBI) subjects. A total of 41 blast pmTBI subjects were individually age- and gender-matched to 41 non-blast pmTBI subjects. Using FreeSurfer, cortical thickness was quantified for the blast group, relative to the non-blast group. Cortical thinning was identified within the blast mTBI group, in two clusters bilaterally. In the left hemisphere, the cluster overlapped with the lateral orbitofrontal, rostral middle frontal, medial orbitofrontal, superior frontal, rostral anterior cingulate and frontal pole cortices (p < 0.02, two-tailed, size = 1680 mm2). In the right hemisphere, the cluster overlapped with the lateral orbitofrontal, rostral middle frontal, medial orbitofrontal, pars orbitalis, pars triangularis and insula cortices (p < 0.002, two-tailed, cluster size = 2453 mm2). Self-report assessments suggest significant differences in the Post-Traumatic Stress Disorder Checklist-Civilian Version (p < 0.05, Bonferroni-corrected) and the Neurobehavioral Symptom Inventory (p < 0.01, uncorrected) between the blast and non-blast mTBI groups. These results suggest that blast may cause a unique injury pattern related to a reduction in cortical thickness within specific brain regions which could affect symptoms. No other study has found cortical thickness difference between blast and non-blast mTBI groups and further replication is needed to confirm these initial observations.

Dataset Information

Multiple Mild Traumatic Brain Injuries Lead to Visual Dysfunction in a Mouse Model.

Publications

Multiple Mild Traumatic Brain Injuries Lead to Visual Dysfunction in a Mouse Model.

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