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1639 - Studies on environmental and cellular stress in traumatic optic neuropathy in a murine traumatic brain injury model

Thursday, February 27, 2025

5:00 PM - 6:30 PM MST

Presenting Author(s)

Nathan K. Evanson, MD, PhD

Assistant Professor
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States

Co-Author(s)

SH

Shelby Hetzer, PhD

Post-doctoral fellow
Indiana University
Indianapolis, Indiana, United States
JT

Jordyn Torrens, BS

Research Associate
University of Cincinnati
Cincinnati, Ohio, United States
MU

Macy Urig, B.S.

Research Associate
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States

Objectives: We sought to investigate the role of chronic variable stress in long-term outcomes after head trauma in a murine model, using behavioral and histological approaches. We also investigated the effects of elongation initiation factor 2alpha (eIF-2alpha) modulation on recovery after TBI and of early post-injury oxygen treatment on functional and histologic visual system recovery.

Design: Experiments were done in a murine closed head weight drop head trauma model with prominent traumatic optic neuropathy. We evaluated acute, subacute, and chronic time points (up to 28 weeks after injury). For some experiments, mice were subjected to a chronic variable stress paradigm for 2 weeks, and subacute and long-term effects on tissue measures of injury were measured. For other experiments, mice were treated with the eIF-2alpha modulators salubrinal or ISRIB after head trauma, to evaluate effects on optomotor responses and tissue measures of injury. Ongoing studies investigate effects of brief oxygen treatment after injury on long-term functional, cell stress, and histologic outcomes.

Results: Chronic variable stress after head trauma led to long-term histologic evidence of neuroprotection in the optic tracts, with evidence of altered microglial and astrocytic phagocytosis at chronic time points. Effects of eIF-2alpha modulation on functional and histologic outcomes were mixed. Post-injury oxygen treatment reduces mortality and measures of cellular stress early after injury; long-term studies are ongoing.

Conclusions: Our findings suggest that environmental stress experienced early after head trauma may be neuroprotective with respect to traumatic axonal injury in the optic nerve projections. Interventions targeting ER stress do not have unequivocal protective or maladaptive effects, suggesting that a more nuanced approach to targeting cellular stress pathways will be needed to improve outcomes after traumatic axon injury. Early results suggest oxygen treatment improves outcomes after head trauma.