Background
Mild traumatic brain injury (TBI), which includes concussion, represents about 80-90% of TBI cases and causes highly variable physical, cognitive, and behavioural symptoms. While in the majority of these cases post-concussive symptoms are transient, 10-15% of patients with concussion experience persistent symptoms for at least 3 months, leading to a diagnosis of post-concussive syndrome. It is not known what differentiates those who recover quickly from symptoms from those who develop post-concussive syndrome.

Objective
The objective of this study was to describe the time course of behavioural impairment in a mouse model of mild TBI.

Methods
Mild TBI was induced in 8 weeks old C57BL/6J mice using a closed-skull Controlled Cortical Impact model, and behavioural assessments were conducted using a cross-sectional study design at 3 days, 6 weeks, 12 weeks, and 18 weeks post-injury to characterize the time course of impairment.  2-way ANOVA was used to determine the effect of group (mTBI or sham) and time on performance in each test, and t-tests were used to compare performance between groups at each time-point. A longitudinal study design was also conducted, where 8 weeks old C57BL/6J male and female mice were given a mild TBI and behaviourally assessed at 3 days, 6 weeks, and 12 weeks post-impact. Analysis was conducted using repeated measures ANOVAs and post-hoc t-tests.

Results
No differences were observed between TBI and sham mice at any of the time-points tested in the open field test, light/dark test, tail suspension test, and pre-pulse inhibition test. However, 2-way ANOVA revealed that TBI mice had significantly fewer successful arm alternations in the Y maze compared to shams animals (F(1,111)=3.79, p=0.05). Although the interaction between group and time did not reach significance (F(3,111)=1.50, p=0.22), comparing performance between groups at each time-point indicated that at 3 days post-impact mTBI mice performed worse than the sham animals (t(25.76)=-1.84, p=0.08). This deficit in the Y maze was also observed in the longitudinal study, where a 3-way repeated measures ANOVA revealed an interaction between group, sex, and time-point (F(3,105=2.46, p=0.07). Post-hoc t-tests revealed that the deficit was driven by males at the 3 days time-point (t(16.88)=-2.75,p=0.01).

Conclusions
These results demonstrate that our TBI model inflicts a mild injury, with few detectable behavioural differences compared to sham animals. However, TBI mice do appear to have a working memory deficit immediately following injury, an important cognitive symptom often associated with concussion. Future work will focus on using magnetic resonance imaging, electron microscopy, and histology to further understand the brain changes underlying the time course of behavioural impairment and recovery in mild TBI mice.

The time course of behavioural impairment in mice following mild traumatic brain injury