Abstract
Traumatic brain injury (TBI) resulting from repeated head trauma is frequently characterized by diffuse axonal injury and long-term motor, cognitive and neuropsychiatric symptoms. Given the delay, often decades, between repeated head traumas and the presentation of symptoms in TBI patients, animal models of repeated injuries should be studied longitudinally to properly assess the longer-term effects of multiple concussive injuries on functional outcomes. In this study, male and cycling female C57BL/6J mice underwent repeated (three) concussive brain injuries (rCBI) delivered via a Leica ImpactOne cortical impact device and were assessed chronically on motor (open field and rotarod), cognitive (y-maze and active place avoidance), and neuropsychiatric (marble-burying, elevated zero maze and tail suspension) tests. Motor deficits were significant on the rotarod on the day following the injuries, and slight impairment remained for up to 6 months. All mice that sustained rCBI had significant cognitive deficits on the active place avoidance test and showed greater agitation (less immobility) in the tail suspension test. Only injured male mice were significantly hyperactive in the open field, and had increased time spent in the open quadrants of the elevated zero maze. One year after the injuries, mice of both sexes exhibited persistent pathological changes by the presence of Prussian blue staining (indication of prior microbleeds), primarily in the cortex at the site of the injury, and increased GFAP staining in the perilesional cortex and axonal tracts (corpus callosum and optic tracts). These data demonstrate that a pathological phenotype with motor, cognitive, and neuropsychiatric symptoms can be observed in an animal model of rCBI for at least one year post-injury, providing a pre-clinical setting for the study of the link between multiple brain injuries and neurodegenerative disorders. Furthermore, this is the first study to include both sexes in a pre-clinical long-term rCBI model, and female mice are less impaired functionally than males.
Highlights
The effects of traumatic brain injury (TBI) are far-reaching, with a global incidence estimated in 2007 to be ∼10 million [1]
Consistent with reports of other investigators [17,18,19], there were significant behavioral deficits concurrent with ongoing neuroinflammation in axonal tracts 1 year following the injuries, this is the first long-term rCBI study in rodents that has been inclusive of both sexes, and we have demonstrated that male mice fare worse on two behavioral tasks, despite showing a similar neuropathological profile to injured female mice
There is a need for continued development of translational models of chronic rTBI with measurable functional and pathological features that lend themselves to therapeutic intervention
Summary
The effects of traumatic brain injury (TBI) are far-reaching, with a global incidence estimated in 2007 to be ∼10 million [1]. More attention has been directed to the effects of repeated TBI, in the context of military operations and contact sports (e.g., American football, soccer, boxing). Both military personnel and contact sports participants are at greater risk for exposure to multiple concussive and sub-concussive TBIs (repeated concussive brain injuries; rCBI). In the context of sports, head injuries are associated with multiple contact sports in both men and women [5], and in the National Football League up to 30% of players sustaining a concussion go on to receive repeat TBIs [6]. Multiple TBIs are associated with delayed neurodegenerative conditions including chronic traumatic encephalopathy [7], a condition characterized by perivascular accumulation of hyperphosphorylated tau [8] and behavioral symptoms including (but not limited to) cognitive dysfunction, violence, depression, and suicidality [9, 10]
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