Optimization of a Translational Murine Model of Closed-head Traumatic Brain Injury

Traumatic brain injury (TBI) from closed-head trauma is a leading cause of disability with limited efficacious treatments. Modeling closed-head TBI remains challenging due to applying forces through the intact skull. We systematically investigated sources of variability in a murine model of closed-head TBI and developed a framework to reduce variability across severity and sex. We manipulated gas pressure, dwell time, and displacement to determine effects on vestibulomotor performance, spatial learning, and neuronal damage in 10-week-old male and female mice. Increasing gas pressure beyond 70psi had a ceiling effect on cellular and behavioral outcomes, while manipulating dwell time only affected behavioral performance. Increasing displacement precisely graded injury severity in both sexes across all outcomes. Physical signs of trauma occurred more frequently at higher displacements. Females performed worse than males when injured at 2.7mm displacement and had greater mortality at higher displacements. Stratifying severity based on day-1 rotarod performance retained cellular injury relationships and separated both sexes into cohorts with distinct behavioral recovery. Within-group rotarod variability over 6 days post-injury was reduced by approximately 50%. These results have important implications for translational research in TBI and provide a framework for using this clinically relevant translational injury model in both male and female mice.