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.
Get full access to this article
View all access options for this article.
References
1.
GardnerR.C., and YaffeK. (2015). Epidemiology of mild traumatic brain injury and neurodegenerative disease. Mol. Cell. Neurosci. 66, 75–80.
2.
McKeeA.C., CantuR.C., NowinskiC.J., Hedley-WhyteE.T., GavettB.E., BudsonA.E., SantiniV.E., LeeH.S., KubilusC.A., and SternR.A. (2009). Chronic traumatic encephalopathy in athletes: progressive tauopathy after repetitive head injury. J. Neuropathol. Exp. Neurol. 68, 709–735.
3.
WilkJ.E., HerrellR.K., WynnG.H., RiviereL.A., and HogeC.W. (2012). Mild traumatic brain injury (concussion), posttraumatic stress disorder, and depression in U.S. soldiers involved in combat deployments: association with postdeployment symptoms. Psychosom. Med. 74, 249–257.
4.
LaurerH.L., BareyreF.M., LeeV.M., TrojanowskiJ.Q., LonghiL., HooverR., SaatmanK.E., RaghupathiR., HoshinoS., GradyM.S., and McIntoshT.K. (2001). Mild head injury increasing the brain's vulnerability to a second concussive impact. J. Neurosurg. 95, 859–870.
5.
LonghiL., SaatmanK.E., FujimotoS., RaghupathiR., MeaneyD.F., DavisJ., McMillanB.S.A., ConteV., LaurerH.L., SteinS., StocchettiN., and McIntoshT.K. (2005). Temporal window of vulnerability to repetitive experimental concussive brain injury. Neurosurgery, 56, 364–374.
6.
MouzonB., ChaytowH., CrynenG., BachmeierC., StewartJ., MullanM., StewartW., and CrawfordF. (2012). Repetitive mild traumatic brain injury in a mouse model produces learning and memory deficits accompanied by histological changes. J. Neurotrauma, 29, 2761–2773.
7.
ChenH., DesaiA., and KimH.Y. (2017). Repetitive closed-head impact model of engineered rotational acceleration induces long-term cognitive impairments with persistent astrogliosis and microgliosis in mice. J. Neurotrauma, 34, 2291–2302.
8.
BlennowK., HardyJ., and ZetterbergH. (2012). The neuropathology and neurobiology of traumatic brain injury. Neuron, 76, 886–899.
9.
JohnsonV.E., StewartW., and SmithD.H. (2013). Axonal pathology in traumatic brain injury. Exp. Neurol. 246, 35–43.
10.
KinnunenK.M., GreenwoodR., PowellJ.H., LeechR., HawkinsP.C., BonnelleV., PatelM.C., CounsellS.J., and SharpD.J. (2011). White matter damage and cognitive impairment after traumatic brain injury. Brain, 134, 449–463.
11.
KrausM.F., SusmarasT., CaughlinB.P., WalkerC.J., SweeneyJ.A., and LittleD.M. (2007). White matter integrity and cognition in chronic traumatic brain injury: a diffusion tensor imaging study. Brain, 130, 2508–2519.
12.
BazarianJ.J., ZhongJ., BlythB., ZhuT., KavcicV., and PetersonD. (2007). Diffusion tensor imaging detects clinically important axonal damage after mild traumatic brain injury: a pilot study. J. Neurotrauma, 24, 1447–1459.
13.
LiptonM.L., GellellaE., LoC., GoldT., ArdekaniB.A., ShiftehK., BelloJ.A., and BranchC.A. (2008). Multifocal white matter ultrastructural abnormalities in mild traumatic brain injury with cognitive disability: a voxel-wise analysis of diffusion tensor imaging. J. Neurotrauma, 25, 1335–1342.
14.
NamjoshiD.R., ChengW.H., McInnesK.A., MartensK.M., CarrM., WilkinsonA., FanJ., RobertJ., HayatA., CriptonP.A., and WellingtonC.L. (2014). Merging pathology with biomechanics using CHIMERA (Closed-Head Impact Model of Engineered Rotational Acceleration): a novel, surgery-free model of traumatic brain injury. Mol. Neurodegener. 9, 55.
15.
XuL., NguyenJ.V., LeharM., MenonA., RhaE., ArenaJ., RyuJ., Marsh-ArmstrongN., MarmarouC.R., and KoliatsosV.E. (2016). Repetitive mild traumatic brain injury with impact acceleration in the mouse: multifocal axonopathy, neuroinflammation, and neurodegeneration in the visual system. Exp. Neurol. 275, Pt. 3, 436–449.
16.
KapoorN., and CiuffredaK.J. (2002). Vision disturbances following traumatic brain injury. Curr. Treat. Options Neurol. 4, 271–280.
17.
BrahmK.D., WilgenburgH.M., KirbyJ., IngallaS., ChangC.Y., and GoodrichG.L. (2009). Visual impairment and dysfunction in combat-injured servicemembers with traumatic brain injury. Optom. Vis. Sci. 86, 817–825.
18.
PeskindE.R., PetrieE.C., CrossD.J., PagulayanK., McCrawK., HoffD., HartK., YuC.E., RaskindM.A., CookD.G., and MinoshimaS. (2011). Cerebrocerebellar hypometabolism associated with repetitive blast exposure mild traumatic brain injury in 12 Iraq war Veterans with persistent post-concussive symptoms. Neuroimage, 54, Suppl. 1, S76–S82.
19.
GreenwaldB.D., KapoorN., and SinghA.D. (2012). Visual impairments in the first year after traumatic brain injury. Brain Inj. 26, 1338–1359.
20.
VenturaR.E., BalcerL.J., and GalettaS.L. (2014). The neuro-ophthalmology of head trauma. Lancet Neurol. 13, 1006–1016.
21.
FoxM.W. (1965). The visual cliff test for the study of visual depth perception in the mouse. Anim. Behav. 13, 232–233.
22.
HulseP., and DudleyL.A. (2010). Visual perceptual deficiencies in the brain injury population: management from start to finish. Neurorehabilitation, 27, 269–274.
23.
YinT.C., VoorheesJ.R., GenovaR.M., DavisK.C., MadisonA.M., BrittJ.K., Cintrón-PérezC.J., McDanielL., HarperM.M., and PieperA.A. (2016). Acute axonal degeneration drives development of cognitive, motor, and visual deficits after blast-mediated traumatic brain injury in mice. eNeuro, 3. pii: ENEURO.0220-16.2016. eCollection 2016 Sep-Oct.
24.
MohanK., KecovaH., Hernandez-MerinoE., KardonR.H., and HarperM.M. (2013). Retinal ganglion cell damage in an experimental rodent model of blast-mediated traumatic brain injury. Invest. Ophthalmol. Vis. Sci. 54, 3440–3450.
25.
TzekovR., DawsonC., OrlandoM., MouzonB., ReedJ., EvansJ., CrynenG., MullanM., and CrawfordF. (2016). Sub-chronic neuropathological and biochemical changes in mouse visual system after repetitive mild traumatic brain injury. PLoS One, 11, e0153608.
26.
GuleyN.H., RogersJ.T., Del MarN.A., DengY., IslamR.M., D'SurneyL., FerrellJ., DengB., Hines-BeardJ., BuW., RenH., ElbergerA.J., MarchettaJ.G., RexT.S., HonigM.G., and ReinerA. (2016). A novel closed-head model of mild traumatic brain injury using focal primary overpressure blast to the cranium in mice. J. Neurotrauma, 33, 403–422.
27.
ReinerA., HeldtS.A., PresleyC.S., GuleyN.H., ElbergerA.J., DengY., D'SurneyL., RogersJ.T., FerrellJ., BuW., Del MarN., HonigM.G., GurleyS.N., and MooreB.M. II. (2014). Motor, visual and emotional deficits in mice after closed-head mild traumatic brain injury are alleviated by the novel CB2 inverse agonist SMM-189. Int. J. Mol. Sci. 16, 758–787.
28.
PhilipS.S., and DuttonG.N. (2014). Identifying and characterising cerebral visual impairment in children: a review. Clin. Exp. Optom. 97, 196–208.
29.
EvansonN.K., Guilhaume-CorreaF., HermanJ.P., and GoodmanM.D. (2018). Optic tract injury after closed head traumatic brain injury in mice: a model of indirect traumatic optic neuropathy. PLoS One, 13, e0197346.
30.
TzekovR., QuezadaA., GautierM., BigginsD., FrancesC., MouzonB., JamisonJ., MullanM., and CrawfordF. (2014). Repetitive mild traumatic brain injury causes optic nerve and retinal damage in a mouse model. J. Neuropathol. Exp. Neurol. 73, 345–361.
31.
VeloskyA.G., TuckerL.B., FuA.H., LiuJ., and McCabeJ.T. (2017). Cognitive performance of male and female C57BL/6J mice after repetitive concussive brain injuries. Behav. Brain Res. 324, 115–124.
32.
GerlaiR., AdamsB., FitchT., ChaneyS., and BaezM. (2002). Performance deficits of mGluR8 knockout mice in learning tasks: the effects of null mutation and the background genotype. Neuropharmacology, 43, 235–249.
33.
SatzJ.S., PhilpA.R., NguyenH., KusanoH., LeeJ., TurkR., RikerM.J., HernandezJ., WeissR.M., AndersonM.G., MullinsR.F., MooreS.A., StoneE.M., and CampbellK.P. (2009). Visual impairment in the absence of dystroglycan. J. Neurosci. 29, 13136–13146.
34.
Van't VeerA., BechtholtA.J., OnvaniS., PotterD., WangY., Liu-ChenL.Y., SchutzG., ChartoffE.H., RudolphU., CohenB.M., and CarlezonW.A.Jr. (2013). Ablation of kappa-opioid receptors from brain dopamine neurons has anxiolytic-like effects and enhances cocaine-induced plasticity. Neuropsychopharmacology, 38, 1585–1597.
35.
ShitakaY., TranH.T., BennettR.E., SanchezL., LevyM.A., DikranianK., and BrodyD.L. (2011). Repetitive closed-skull traumatic brain injury in mice causes persistent multifocal axonal injury and microglial reactivity. J. Neuropathol. Exp. Neurol. 70, 551–567.
36.
Vonder HaarC., MaassW.R., JacobsE.A., and HoaneM.R. (2014). Deficits in discrimination after experimental frontal brain injury are mediated by motivation and can be improved by nicotinamide administration. J. Neurotrauma, 31, 1711–1720.
37.
Vonder HaarC., MartensK.M., BashirA., McInnesK.A., ChengW.H., CheungH., StukasS., BarronC., LadnerT., WelchK.A., CriptonP.A., WinstanleyC.A., and WellingtonC.L. (2019). Repetitive closed-head impact model of engineered rotational acceleration (CHIMERA) injury in rats increases impulsivity, decreases dopaminergic innervation in the olfactory tubercle and generates white matter inflammation, tau phosphorylation and degeneration. Exp. Neurol. 317, 87–99.
38.
Lucke-WoldB.P., NaserZ.J., LogsdonA.F., TurnerR.C., SmithK.E., RobsonM.J., BailesJ.E., LeeJ.M., RosenC.L., and HuberJ.D. (2015). Amelioration of nicotinamide adenine dinucleotide phosphate-oxidase mediated stress reduces cell death after blast-induced traumatic brain injury. Transl. Res. 166, 509–528.e1.
Supplementary Material
Please find the following supplemental material available below.
For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.
For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.
