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

Abstract

Traumatic brain injury (TBI) from closed-head trauma is a leading cause of disability with limited effective interventions. Many TBI models impact brain parenchyma directly following craniotomy, and are limited by the fact that these forces do not recapitulate clinically relevant closed head injury. However, applying clinically relevant injury mechanics to an intact skull may lead to variability and as a result, modeling TBI remains a challenge. Moreover, current models often do not explore sex differences in TBI, which is critically important for translation to clinical practice. 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 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 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 injury severity cohorts with distinct behavioral recovery. Utilizing this stratification strategy, within-group rotarod variability over 6 days post-injury was reduced by 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.