Chronic and progressive deficits after a single closed head injury in mice

Abstract

BackgroundAcute injury following brain trauma may evolve into a chronic and progressive disorder. Chronic consequences of TBI have been understudied, in part, due to the lack of robust behavioral changes that are delayed in onset as well as chronic and progressive. Assessment of the chronic consequences of TBI also must distinguish behavioral changes that arises due to age vs those that develop and evolve over time due to injury. MethodsC57BL/6 mice receive single closed head injury (CHI) and are analyzed at 7DPI, 14DPI or 180DPI on neurological severity score, open field, rotarod, beam walk, and simple-complex wheel. ResultsIn the center of open field, injured mice have a turn bias at 180 days post-injury (DPI) not present at 7DPI. On rotarod, injured mice have shorter latencies at 7DPI, but not at 180DPI due to a large age effect in sham-injured mice. On beam walk at 180DPI, both sham and injured groups more slowly traverse a 2cm and 1cm beam than at 7DPI. Foot-faults show no significant effects of age or injury. On simple wheel injury affects speed at 14DPI with no effect on distance travelled. The lack of injury-dependent effects on beam walk or simple-complex wheel despite visible impairment was the impetus to assess limb position using Deeplabcut markerless tracking. Custom Python scripts were then developed to compute beam walk absition or foot fault severity (integral of limb displacement over time), and step frequency and quadrupedal limb coordination in simple-complex wheel. On the 2cm beam, age increased absition in all limbs of uninjured mice and both forelimbs of injured mice. On the 1cm beam both forelimbs and the left hindlimb of injured mice at 180DPI have larger absition than uninjured mice at 180DPI or injured mice at 7DPI. On a simple wheel injury affected speed only at 14 DPI with no effect on distance travelled. In contrast, injured mice at 180DPI developed a compensatory running strategy by increasing step frequency variability. This allowed injured mice at 180 DPI to reach sham-level quadrupedal limb coordination and improve running speed as compared to 14 DPI assessment. On complex wheel, injured mice at 180DPI do not express this compensatory running strategy resulting in impaired quadrupedal limb coordination. These data suggest chronic and progressive motor deficits of injured mice at 180DPI. ConclusionsA single impact produces chronic and progressive motor deficits. Quantitative motor analysis using DeepLabCut tracking reveals deficits not seen using standard outcomes.