Genetic Diversity Influences Response and Outcome to Blast Traumatic Brain Injury in a Murine Model

Blast-induced traumatic brain injury (bTBI) is a significant health concern for military personnel, causing potential long-term neurological consequences. Given the unique and heterogeneous genetic makeup of the human population, the acute responses and evolving sequelae from blast exposure are difficult to predict. To address these challenges, murine models are invaluable in the study of bTBI, as they allow researchers to carefully control exposure parameters while examining physiological changes across genetic, cellular, and whole-organism levels over time. In this study, we investigated the role of genetic diversity in bTBI by examining six common mouse strains-A/J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HILtJ, C57BL/6J, and CAST/EiJ-and their possible differential response to blast overpressure. We assessed immediate neurological impairment, respiratory symptoms, lethality thresholds, and gross pathological and histological changes following blast overpressure exposure across these strains. We observed significant strain-dependent differences across all the measured outcomes. In particular, C57BL/6J mice exhibited the longest normalized righting times and highest incidence of subdural hematomas. Notably, the strains used as models of type I/II diabetes (NZO/HILtJ and NOD/ShiLtJ) showed the highest resilience to blast-induced lethality. In comparison, the CAST/EiJ strain was the most susceptible to immediate apnea and had the lowest lethality threshold. The NZO/HILtJ mice showed the highest incidence of pulmonary bleeding. Our findings highlight the substantial influence of the genetic background on the bTBI outcomes in mice, even with highly controlled physical exposure conditions. This comprehensive characterization of strain-dependent responses to bTBI provides a foundation for investigating the genetic influences on blast injury outcomes and developing more targeted preventative and/or therapeutic strategies for bTBI.