Abstract
Traumatic brain injury (TBI) is a leading cause of death and disability that lacks targeted therapies. Successful translation of promising neuroprotective therapies will likely require more precise identification of target populations through greater study of crucial biological factors like age and sex. A growing body of work supports the impact of these factors on response to and recovery from TBI. However, age and sex are understudied in TBI animal models. The first aim of this study was to demonstrate the feasibility of lateral fluid percussion injury (FPI) in juvenile mice as a model of pediatric TBI. Subsequently, we were interested in examining the impact of young age and sex on TBI outcome. After adapting the lateral FPI model to 21-day-old male and female mice, we characterized the molecular, histological, and functional outcomes. Whereas similar tissue injury was observed in male and female juvenile mice exposed to TBI, we observed differences in neuroinflammation and neurobehavioral function. Overall, our findings revealed less acute inflammatory cytokine expression, greater subacute microglial/macrophage accumulation, and greater neurological recovery in juvenile male mice after TBI. Given that ongoing brain development may affect progression of and recovery from TBI, juvenile models are of critical importance. The sex-dependent differences we discovered after FPI support the necessity of also including this biological variable in future TBI studies. Understanding the mechanisms underlying age- and sex-dependent differences may result in the discovery of novel therapeutic targets for TBI.
Highlights
Traumatic brain injury (TBI) is a leading cause of death and disability that affects over 2 million people per year in the United States.[1]
To determine whether lateral fluid percussion injury (FPI) could be adapted for use in juvenile mice to create a reproducible model relevant to pediatric TBI, we evaluated gene expression, neuropathology, and neurobehavioral function
Gliogenesis is still ongoing, beyond the peak period.[6,17]. These parallels in neurodeveloment make the P21 rodent an effective tool for the study of the unique pathophysiology of pediatric TBI and its impact on ongoing brain maturation
Summary
Traumatic brain injury (TBI) is a leading cause of death and disability that affects over 2 million people per year in the United States.[1]. Severe TBI can cause different pathoanatomical states, including focal contusion/hemorrhage and diffuse axonal injury, with most injuries being mixed. An animal model of mixed injury can be induced by a lateral fluid percussion injury (FPI). Lateral FPI has been adapted to juvenile rats, to our knowledge, it has not been used in juvenile mice, limiting the use of available transgenic and knockout lines in this mixed-TBI model.[6]
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