Model matters: Differential outcomes in traumatic optic neuropathy pathophysiology between blunt and blast-wave mediated head injuries

Abstract

Over 3 million people in the United States live with long-term disability as a result of a traumatic brain injury (TBI). The purpose of this study was to characterize and compare two different animal models of TBI (blunt head trauma and blast TBI) to determine common and divergent characteristics of these models. With recent literature reviews noting the prevalence of visual system injury in animal models of TBI, coupled with clinical estimates of 50-75% of all TBI cases, we decided to assess commonalities, if they existed, through visual system injury. Blast, repeat blast, and blunt injury were induced in adult male mice to observe and quantify visual deficits. Retinal ganglion cell loss and axonal degeneration in the optic tract, superior colliculus, and lateral geniculate nuclei were examined to trace injury outcomes throughout major vision-associated areas. Optokinetic response, immunohistochemistry, and western blots were analyzed. Where a single blunt injury produces significant visual deficits a single blast injury appears to have less severe visual consequences. Visual deficits after repeat blasts are similar to a single blast. Single blast injury induces contralateral damage to right optic chiasm and tract whereas bilateral injury follows a single blunt injury. Repeat blast injuries are required to see degeneration patterns in downstream regions similar to the damage seen in a single blunt injury. This finding is further supported by Amyloid Precursor Protein (APP) staining in injured cohorts. Blunt injured groups present with staining 1.2 mm of the optic nerve, indicating axonal breakage closer to the optic chiasm. In blast groups, APP was identifiable in a bilateral pattern only in the geniculate nucleus. Evidence for unilateral neuronal degeneration in brain tissue with bilateral axonal ruptures are pivotal discoveries in this model differentiation. Analysis of the two injury models suggest there is a significant difference in the histological outcomes dependent on injury type, though visual system injury is likely present in more cases than are currently diagnosed clinically.

Brief Oxygen Exposure after Traumatic Brain Injury Hastens Recovery and Promotes Adaptive Chronic Endoplasmic Reticulum Stress Responses

“…However, how could there be increased axonal degeneration with more surviving RGCs? Previous micro-CT data [ 32 ] coupled with a lack of positive amyloid precursor staining in the brains of our mice [ 33 ] suggest that the location of axon injury in our model is likely inside, or near, the intracanicular portion of the optic canal. This means that the damage to the axons is occurring between the RGC cell bodies in the eye and their projection targets in the brain.…”

Targeting eIF2α in TBI-induced traumatic optic neuropathy: Effects of Salubrinal and the Integrated Stress Response Inhibitor.

“…While optic nerve crush, transection, and ocular blast injures optic nerve axons in or behind the eye, we injure the optic nerve in a replicable 1-1.5 mm section just proximal to the optic chiasm. (Hetzer et al, 2023) Thus, most of what we know about the proximal axon is from in vitro or ex vivo studies (Almasieh et al, 2017; Hao et al, 2016; Hao et al, 2019; Baleriola et al, 2014; Mok et al, 2009; Pathak et al, 2016). This distinction is made more important because differences between signaling in distal and proximal axon segments have been unearthed including retrograde phosphatidyl serine externalization (Almasieh et al, 2017), upregulation of the DLK-cJUN pathway (Asghari Adib et al, 2018; Kievit, 2019; Ugbode et al, 2019; Larhammar et al, 2017), local calcium signaling (Frati et al, 2017; Calixto et al, 2012), and more.…”

“…Nevertheless, TON remains understudied in this context despite emerging evidence that it is likely a more prevalent co-morbidity of TBI than previously assumed (Evans et al, 2021; Hetzer et al, 2023). Our weight-drop TBI model provides an opportune system for exploring the effects of traumatic axonal injury to the optic nerve as we have shown that our closed-head injury produces replicable damage to the optic nerve with subsequent death of retinal ganglion cells (RGCs).…”