Characterization of a Ferret Model of Traumatic Brain Injury due to Under-Vehicle Blast, Controlled Cortical Impact, or Blast Plus Impact.

Under-vehicle blast (UVB) generated from landmines is a unique traumatic brain injury (TBI) mechanism affecting warfighters. UVB hyperacceleration can result in injury independent of impact; however, a secondary impact injury can also occur. To date, translation of findings from rodent TBI models to improved patient outcomes has been unsuccessful, perhaps due to neuroanatomical differences between humans and rodents, including white-to-gray matter ratio and cortical gyrification. To address this modeling difference, a UVB model was developed in ferrets, the brains of which more closely resemble humans. Male ferrets underwent UVB-alone (Blast), controlled cortical impact (CCI)-alone, combined UVB + CCI (BCCI), or craniotomy (Sham) procedures. Neurobehavioral assays were optimized and used to assess mood, memory, and motor control. Blast and BCCI ferrets underwent neuroimaging at baseline and 7 days post-injury. All ferrets were euthanized by terminal perfusion with paraformaldehyde on day 7 for histologic analysis. Results indicate that UVB alters cortical metabolites and induces blood-brain barrier (BBB) disruption. CCI leads to BBB disruption and cortical diffuse axonal injury, but this is not exacerbated by combination with UVB. BCCI does result in several alterations in key cortical metabolites indicative of increased neuronal injury, oxidative stress, and glial activation as well as impaired neurotransmission and energy generation. Additionally, BCCI significantly increases hyperactivity and impairs spatial memory. Anxiety-like behavior, mood, and motor function approached statistical significance. Taken together, we provide a military-relevant model of UVB in a gyrencephalic animal, the ferret, that may be applied in future investigations into TBI pathophysiology and potential treatment.