The Spectrum of Neurobehavioral Sequelae after Repetitive Mild Traumatic Brain Injury: A Novel Mouse Model of Chronic Traumatic Encephalopathy

Abstract

There has been an increased focus on the neurological sequelae of repetitive mild traumatic brain injury (TBI), particularly neurodegenerative syndromes, such as chronic traumatic encephalopathy (CTE); however, no animal model exists that captures the behavioral spectrum of this phenomenon. We sought to develop an animal model of CTE. Our novel model is a modification and fusion of two of the most popular models of TBI and allows for controlled closed-head impacts to unanesthetized mice. Two-hundred and eighty 12-week-old mice were divided into control, single mild TBI (mTBI), and repetitive mTBI groups. Repetitive mTBI mice received six concussive impacts daily for 7 days. Behavior was assessed at various time points. Neurological Severity Score (NSS) was computed and vestibulomotor function tested with the wire grip test (WGT). Cognitive function was assessed with the Morris water maze (MWM), anxiety/risk-taking behavior with the elevated plus maze, and depression-like behavior with the forced swim/tail suspension tests. Sleep electroencephalogram/electromyography studies were performed at 1 month. NSS was elevated, compared to controls, in both TBI groups and improved over time. Repetitive mTBI mice demonstrated transient vestibulomotor deficits on WGT. Repetitive mTBI mice also demonstrated deficits in MWM testing. Both mTBI groups demonstrated increased anxiety at 2 weeks, but repetitive mTBI mice developed increased risk-taking behaviors at 1 month that persist at 6 months. Repetitive mTBI mice exhibit depression-like behavior at 1 month. Both groups demonstrate sleep disturbances. We describe the neurological sequelae of repetitive mTBI in a novel mouse model, which resemble several of the neuropsychiatric behaviors observed clinically in patients sustaining repetitive mild head injury.

Inhibition of Monoacylglycerol Lipase Prevents Chronic Traumatic Encephalopathy-like Neuropathology in a Mouse Model of Repetitive Mild Closed Head Injury

“…Several rodent models of rmCHI have been reported from two, three, five TBIs to 16 or 42 impacts at different intervals or frequencies. 23,24,[30][31][32][33][34][35][36][37] In the present study, we chose a mouse model of rmCHI with three impacts at an interval of 24 hours, as reported previously. 5,23,24 As shown in our results, our model displayed mild brain trauma with low NSS scores and the absence of intracranial hemorrhage and convulsions.…”

Lifelong behavioral and neuropathological consequences of repetitive mild traumatic brain injury

“…While there was no difference in the percentage of time spent in the open arms between the s‐mTBI and either of the control groups (s‐sham, 9.9 ±2.7%; r‐sham, 6.1 ± 2.1; s‐mTBI, 14.1 ± 4.3%; P  > 0.05 one‐way ANOVA followed by Tukey's post hoc test), the r‐mTBI group spent on average 30.1±8.3% of their time within the open arm (s‐sham or s‐mTBI, vs. r‐mTBI P  < 0.05; r‐sham vs. r‐mTBI, P  < 0.001; one way ANOVA followed by Tukey's post hoc test). Such an increased amount of time spent in the open arms is suggestive of disinhibition or increased risk‐taking behavior which has been previously observed in other mouse models of repetitive closed head injury 14, 24…”

Dendritic Spine Loss and Chronic White Matter Inflammation in a Mouse Model of Highly Repetitive Head Trauma

“…The issue of anesthesia and its interaction with mTBI-induced LOC will require future studies, but the introduction of rodent rmTBI models with no anesthesia will help to address these long-standing issues. 27 It is clear that exposure to previous mTBI does not increase LOC time in later mTBI exposures, and because our model is sensitive to increased impact strength, we conclude that the increased risk of developing incident concussions after prior mTBI 25 does not appear to be because of a lowering of threshold by prior mTBI.…”