Sex differences in persistent decline in neurological function after modeling repetitive sport-related mild head injuries in young mice.

Repetitive mild traumatic brain injury (rmTBI) may lead to neurological deficits long after the last injury. However, few studies have examined the persistence of deficits in both sexes. Although women tend to have poorer outcomes than men after concussion, little is known about the cumulative effects of rmTBI during chronic recovery periods. We hypothesized that female mice would display more severe and longer lasting neurological deficits than males following 25 rmTBI over 30 days. Anesthetized mice were subjected to rmTBI using a weight drop model over a trapdoor to provide impact and rotational acceleration. rmTBI was performed 5 days a week for 5 weeks. Mice were assessed starting 5 and 15 weeks following the final injury. A separate pilot study followed male mice for 12 months. Both sexes showed motor deficits 5- and 15-weeks following injury, but only male mice developed affective and cognitive deficits by 15 weeks post injury. These deficits became more pronounced 12 months after injury, supporting a persistent decline long after rmTBI. Sex differences were not readily explained by changes in inflammation in the brain (GFAP, Iba1) that were transient in both sexes and resolved by 15 weeks except for in the optic tract. Diffusion tensor imaging analysis suggests that rmTBI induces disruptions in brain microstructure in several white matter tracts and thalamus that persist for at least 6 months. In contrast to findings in human TBI, female mice appeared to experience better outcomes from rmTBI than males, but the underlying mechanisms remain to be elucidated.