Neurobehavioral and inflammatory responses following traumatic brain injury in male and female mice

Abstract

Traumatic brain injury (TBI) is a leading cause of mortality and is associated with a high rate of functional comorbidities, including motor, cognitive, anxiety, depression, and emotional disorders. TBI pathophysiology and recovery are complicated and involve several mechanistic pathways that control neurobehavioral outcomes. In this study, male and female C57Bl/6 J mice were subjected to a controlled cortical impact model of TBI or sham injury and evaluated for different neurobehavioral and inflammatory outcomes over a month. We demonstrate that TBI mice have increased motor dysfunction at early and late time points following the injury as compared to the sham group. Anxiety-like symptoms were time- and task-dependent, with both sexes having increased anxiety-like behavior 2 weeks post-injury. Cognitive functions measured by T-maze presented greater deficits in TBI mice, while there was no sex or injury-related difference in depressive-like behaviors. Notably, a significant effect of sex was found in empathy-like behavior, with females showing more allogrooming and freezing behavior in the consoling and fear observational tests, respectively. Evaluating the impact of the injury-induced brain damage demonstrated a greater injury volume and neuronal degeneration in males compared to females one month after TBI. Moreover, male mice showed higher peripheral inflammatory responses, as represented by elevated serum levels of peripheral leukocytes and inflammatory markers. These results will have significant implications for understanding TBI's long-term consequences on neurobehavioral and inflammatory responses, which are sex-specific and can be considered for individualized therapeutic strategies in treating TBI.