Chronic functional deficits following a single closed head injury in mice are prevented by minocycline and N-acetyl cysteine.

Abstract

Traumatic brain injury (TBI) can produce chronic limb coordination and gait deficits that are associated with ongoing white matter damage. In rodent TBI models, chronic motor deficits may be obscured by aging or motor compensation. In addition, there are no treatments for TBI. The murine closed head injury (CHI) model produces diffuse, chronic white matter injury that may underlie chronic white matter dysfunction and motor deficits. Evoked compound action potentials (CAP) assess corpus callosum function from 3 to 180-days post injury (DPI). CHI acutely decreases total CAP amplitudes that recover by 90 DPI and increase further at 180 DPI. Total CAP amplitude changes are blocked by dosing of minocycline and N-acetylcysteine beginning 12 h post-injury (MN12). Injured or sham mice have similar times to traverse or number of foot faults on beam walk. DeepLabCut™ markerless limb tracking provides limb positions used to develop novel assays to assess beam walk and simple/complex wheel. Absition analysis integrates the duration and extent of foot faults during beam walk. Injured mice develop absition deficits at 90 DPI that worsen at 180 DPI suggesting a chronic and progressive decline. Chronic absition deficits are blocked by MN12 treatment. Speed typically assesses performance on simple/complex wheel. Novel limb coordination assays show that at 180 DPI, injured mice decrease coordination that significantly correlates with increased total CAP amplitude. MN12 alleviates chronic corpus callosum dysfunction and motor deficits suggesting a strong efficacy to treat TBI. DeepLabCut™ limb tracking reveals chronic deficits and motor compensation not seen with standard outcomes.