Research PaperEstablishing the ferret as a gyrencephalic animal model of traumatic brain injury: Optimization of controlled cortical impact procedures

- Subject-specific MRI-guided coordinates overcame anatomical variability.
- The temporalis muscle should be detached from the midline and reflected.
- The craniotomy should be closed to avoid the temporalis muscle pushing on the brain.
- This optimized surgical procedure created scaled injury in a reproducible location.
- Behavior and astrocyte/microglial responses were scaled to injury severity.

BackgroundAlthough rodent TBI studies provide valuable information regarding the effects of injury and recovery, an animal model with neuroanatomical characteristics closer to humans may provide a more meaningful basis for clinical translation. The ferret has a high white/gray matter ratio, gyrencephalic neocortex, and ventral hippocampal location. Furthermore, ferrets are amenable to behavioral training, have a body size compatible with pre-clinical MRI, and are cost-effective.New methodsWe optimized the surgical procedure for controlled cortical impact (CCI) using 9 adult male ferrets. We used subject-specific brain/skull morphometric data from anatomical MRIs to overcome across-subject variability for lesion placement. We also reflected the temporalis muscle, closed the craniotomy, and used antibiotics. We then gathered MRI, behavioral, and immunohistochemical data from 6 additional animals using the optimized surgical protocol: 1 control, 3 mild, and 1 severely injured animals (surviving one week) and 1 moderately injured animal surviving sixteen weeks.ResultsThe optimized surgical protocol resulted in consistent injury placement. Astrocytic reactivity increased with injury severity showing progressively greater numbers of astrocytes within the white matter. The density and morphological changes of microglia amplified with injury severity or time after injury. Motor and cognitive impairments scaled with injury severity.Comparison with existing method(s)The optimized surgical methods differ from those used in the rodent, and are integral to success using a ferret model.ConclusionsWe optimized ferret CCI surgery for consistent injury placement. The ferret is an excellent animal model to investigate pathophysiological and behavioral changes associated with TBI.