Abstract
Purpose :
Most clinical cases of indirect traumatic optic neuropathy (ITON) are associated with a traumatic brain injury and are thought to be due to a brow hit. This study aims to characterize a human-relevant model of ITON for studying mechanisms and testing interventional therapies.
Methods :
ITON was induced in anesthetized tree shrew (Tupaia belangeri) by exposing the side of the head, posterior to the left eye, to 20 repeated bursts of 50psi air. Sham tree shrews were anesthetized and exposed to the sound but not the overpressure air. At baseline and over time post-injury, electroretinograms (ERGs), visual evoked potentials (VEPs), and retinal optical coherence tomography (OCT) imaging were performed. At the study endpoint, eyes and optic nerves were collected for histological assays.
Results :
Reduced total axon counts (19% below sham) increased degenerative axon profiles, and increased glial hypertrophy were detected at the proximal end of the optic nerve at 8 weeks post-injury. In this cohort, a modest reduction in amplitude for VEP N1 (5% below sham), N2 (60% below sham), and P2 (22% below sham) and a modest increase in latency for VEP N1 (9% above sham) and N2 (14% above sham) was observed while the ERG was the same as sham. Immunolabeling of glial fibrillary acid protein (GFAP) was localized primarily in the nerve fiber layer and was brighter in retinal cross-sections of injured animals compared to sham. Additional exposure – 10 blasts of 20 psi directly to the eye, coupled with 20 blasts of 50 psi to the head – resulted in similar findings, corroborating previous findings suggesting that the ON injury is mediated by hits to the head more so than direct hits to the eye.
Conclusions :
Our results highlight the tree shrew as a suitable model for studying ITON. To induce ITON in this species, repetitive exposure to focal head-directed high-pressure air blasts was required. Notably, the tree shrew showed resilience to direct ocular blasts, a characteristic likely linked to its robust ocular anatomy including a collagenous load-bearing lamina cribrosa and bony brow ridge. Coupled with the tree shrew’s greater similarity to human genetic and epigenetic variations, visual system features, and genomic and transcriptomic expression levels, this model may be useful for the clinical translation of neuroprotective and regenerative therapies.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.