A Controlled Impact of Optic Nerve as a New Model of Traumatic Optic Neuropathy in Mouse

Abstract

PurposeTraumatic optic neuropathy (TON) is the most feared visual consequence of head and ocular trauma in both military and civilian communities, for which standard treatment does not exist. Animal models are critical for the development of novel TON therapies as well as the understanding of TON pathophysiology. However, the models currently used for TON have some limitations regarding consistency and mirroring the exact pathological progression of TON in closed ocular trauma. In this study, we modified the model of controlled cortical impact and adapted it for studying TON.MethodsWe defined new standardized procedures to induce TON in mice, wherein the optic nerve is reproducibly exposed to a graded controlled impact of known velocity to produce a graded deficit in retinal ganglion cell (RGC) electrophysiological functions.ResultsThe key results of validating this newly modified model, “controlled orbital impact (COI),” included (1) the injury parameters (velocity as well as contusion depth and time), which were quantifiable and manageable to generate a wide range of TON severities; (2) a reproducible endpoint of diminished positive scotopic threshold response (pSTR) has been achieved without the interference of surgical variability and destruction of surrounding tissues; (3) the contralateral eyes showed no significant difference to the eyes of naïve mice, allowing them to be used as an internal control to minimize interindividual variability among mice; and (4) the occurrence of injury-associated mortality and/or ocular comorbidity was rare.ConclusionsTaken together, this model overcomes some limitations of prior TON mouse models and provides an innovative platform to identify therapeutic targets for neuroprotection and/or neurorestoration following traumatic ocular injury.

RGC and Vision Loss From Traumatic Optic Neuropathy Induced by Repetitive Closed Head Trauma Is Dependent on Timing and Force of Impact

“…15 , 16 Difficulty quantifying the mechanical force applied to induce the crush injury and difficulty in entering the mouse orbit without disrupting the blood plexus surrounding the globe and thus causing severe ischemia are major drawbacks of this model, 17 and the mechanism of injury does not represent the typical shearing injury most patients experience with blunt head trauma. 4 Recent studies have focused on creating models that simulate indirect trauma to the optic nerve caused by ocular or head injury, including ocular blasts of compressed air directed against the eye, 18 sonication-induced TON by delivery of ultrasonic pulses, 19 exposure of the optic nerve to a graded controlled impact of known velocity, 20 and mild repetitive controlled blunt trauma to the head. 21 Each model has advantages and disadvantages related to reproducibility, mortality rate, undesirable ocular injuries, and mirroring the exact pathological progression in TON.…”

“… 21 Each model has advantages and disadvantages related to reproducibility, mortality rate, undesirable ocular injuries, and mirroring the exact pathological progression in TON. 19 , 20 …”

Models and treatments for traumatic optic neuropathy and demyelinating optic neuritis

“…Recently, 2 novel models were developed, namely the sonication‐induced TON model (SI‐TON, Figure c) (Tao et al, ) and controlled orbital impact (COI, Figure a3) model (Ibrahim et al, ). SI‐TON is a noninvasive model that uses ultrasonic pulses to create the injury.…”

<p>The role of long noncoding RNA in traumatic brain injury</p>

“…Traumatic optic neuropathy is one of the most feared and common complications of head and ocular trauma, for which a standard treatment has yet to be established 42. Yao et al43 investigated the role of MALAT1 in the retinal neurodegeneration of optic nerve transection models of rats and mice.…”