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Natalie Guley, Lauren D'Surney, Joshua Rogers, Wei Bu, Nobel Del Mar, Andrea Elberger, Marcia Honig, Anton Reiner; Temporal progression of optic axon injury in a closed-skull model of TBI. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):6031.
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© ARVO (1962-2015); The Authors (2016-present)
Mild TBI is often accompanied by visual dysfunction thought to be attributable to optic nerve damage. Using a mouse model of closed-skull blast-overpressure induced mild TBI previously shown to cause replicable injury to the visual system, we sought to characterize the progression in optic nerve pathology, and its relationship to visual deficits.
Male C57BL/6 mice were subjected to closed-head overpressure blast of 0 (control) or 50-psi to the left side of the cranium, as previously described (Heldt et al., Frontiers 2014). Optomotry was used to assess visual function, while histological processing of the eye, optic nerve, and optic tract were used to evaluate the morphological consequences of blast. An EYFP reporter mouse was used to directly view axonal integrity at 1, 3, 5, and 7 days post-blast. SMI-32 and Iba-1 immunolabeling were used to further view axonal integrity, and microglial activation, respectively. Plastic-embedded, osmicated cross sections of optic nerve were used to quantify cross sectional area and count axons in blasted and sham mice.
At one day post-blast, axons in the optic tract of 50-psi mice appeared normal, as did the microglia. Beginning at 3 days, Iba-1 immunostaining revealed microglial activation that continued through 5 days, peaked at 7 days, and returned to normal by two weeks. EYFP-reporter mice and SMI-32 immunolabeling showed swollen axon bulbs (indicative of axons with disrupted microtubules) at 5 days, peaking 7 days post-blast. Axon bulbs were no longer evident in right optic tract at 16 days post-blast, but NeuroSilver staining revealed degenerating axons. Consistent with axonal injury seen in the right optic tract, many degenerating axons were seen in the left optic nerve at 3-6 weeks post-blast. Beyond 9 weeks after blast, degeneration had ceased, and left optic nerves were shrunken and contained fewer axons than control mice. Measurements of left optic nerve cross sectional area revealed that the atrophy was significantly correlated with the decrease in visual acuity and contrast sensitivity.
In the absence of direct damage to the eye, blast exposure of the cranium causes mild TBI resulting in damage to optic nerve and its central continuation as the crossed optic tract. Treatments that mitigate the progressive degeneration of optic nerve and tract during the first week after the concussive event may improve the visual outcome after mild TBI.
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