Animal models of sports-related head injury: bridging the gap between pre-clinical research and clinical reality

Abstract

Sports-related head impact and injury has become a very highly contentious public health and medico-legal issue. Near-daily news accounts describe the travails of concussed athletes as they struggle with depression, sleep disorders, mood swings, and cognitive problems. Some of these individuals have developed chronic traumatic encephalopathy, a progressive and debilitating neurodegenerative disorder. Animal models have always been an integral part of the study of traumatic brain injury in humans but, historically, they have concentrated on acute, severe brain injuries. This review will describe a small number of new and emerging animal models of sports-related head injury that have the potential to increase our understanding of how multiple mild head impacts, starting in adolescence, can have serious psychiatric, cognitive and histopathological outcomes much later in life. Sports-related head injury (SRHI) has emerged as a significant public health issue as athletes can develop psychiatric and neurodegenerative disorders later in life. Animal models have always been an integral part of the study of human TBI but few existing methods are valid for studying SRHI. In this review, we propose criteria for effective animal models of SRHI. Movement of the head upon impact is judged to be of primary importance in leading to concussion and persistent CNS dysfunction.

Keywords: Sports-related head injury; animal models; cognitive dysfunction; neuropathological disorders; psychiatric outcomes; repetitive mild traumatic brain injury.

Fig. 1

Repetitive mild traumatic brain injury reduces cognitive performance in adult mice. Mice were exposed to five head impacts over 3 days (1 on the first day and 2 on each of the subsequent days) using a 95 g weight dropped from a height of 1 m. Controls were treated in the same manner as experimental mice but were not exposed to head impacts. (a) Acquisition training. Fifteen days after the last head impact, mice were tested for acquisition over four training days (three trials per day) on the Barnes maze. Controls show a steady reduction in the amount of time required to find the goal box using external visual cues whereas mice exposed to five head impacts required significantly longer times. Data are presented as time required to find the goal box on each training and represent mean ± SEM (N = 6 for each group). Acquisition data were analyzed with a repeated measures one-way anova (F_7,119 = 12.12; p < 0.0001) followed by Tukey's post-hoc test (b) Memory probe test. On day 5, the goal box was removed and the time spent by mice in the quadrant of the maze where the goal box was located during acquisition training was measured as a test of memory. Mice exposed to five head impacts were significantly impaired by comparison to controls. Data represent mean ± SEM (N = 6 for each group) and were analyzed with a student's t test [t(10) = 2.432; p = 0.0353]. *p < 0.05, **p < 0.001, ***p< 0.0001.

Fig. 2

Repetitive mild head impacts alter recovery of consciousness and impair motor coordination and balance in adolescent mice. Mice (4 weeks of age) were exposed to 1, 5, or 10 head impacts (1 per day for 1, 5 or 10 days) using a 30 g weight dropped from a height of 1 m. Controls were treated in the same manner as experimental mice but were not exposed to head impacts. (a) Time required for mice to recover the righting reflex was recorded on each day that the respective groups received a head impact. Data are presented as mean ± SEM (N = 12–14 mice per group). The main effects of 1 (1X), 5 (5X), and 10 (10X) impacts (one-way anova, F_5,103 = 9.902; p < 0.0001) were only significant for 1X versus its corresponding control (Tukey's test p < 0.0001). The 5X and 10X groups were not significantly different from their controls. (b) Adolescent mice exposed to 10 head impacts were tested for motor coordination and balance on the rotarod 1 day or 30 days after the last impact. Mice exposed to repeated head impacts had a significant reduction in rotarod performance at the 1 day time point [student's t test t(21) = 2.270; p = 0.0339] and recovered by 30 days. Results are mean ± SEM (N = 12–14 mice per group). *p < 0.05, ***p < 0.0001.

Fig. 3

Effects of repeated mild head impacts on affective behavior in adolescent mice. Mice (4 weeks of age) were exposed to 5 or 10 head impacts (1 per day for 5 or 10 days) using a 30 g weight dropped from a height of 1 m. Controls were treated in the same manner as experimental mice but were not exposed to head impacts. Tests for the expression of affective-like behaviors were carried out 30 days after the last head impact. (a) Grooming time in the splash test of depression-like behavior. A 10% solution of sucrose was sprayed onto the backs of mice and the time spent self-grooming was measured. Mice exposed to 5 (Student's t test t(13) = 6.331; p < 0.0001) or 10 (Student's t test t(20) = 2.738; p = 0.0127) head impacts showed significantly less time grooming by comparison to controls, indicative of depression-like behavior. Data is presented as mean ± SEM (N = 6–12 mice for each group). ***p < 0.001, *p < 0.05. (b) Novelty suppressed feeding test of anxiety-like behavior. Mice were deprived of food for 18 h and then placed into a novel open-field environment containing a normal mouse food pellet. The time taken for mice to take the first bite from the pellet was recorded. Mice exposed to 5 [Student's t test t(16) = 2.442; p = 0.0266] or 10 (Student's t test t(18)= 2.408; p = 0.027) head impacts showed a significant increase in the amount of time to take the first bite by comparison with controls, indicative of anxiety-like behavior. Data represents mean ± SEM (N = 6–12 mice per group). *p < 0.01.