Development of a paediatric model of diffuse traumatic brain injury in ferrets.

Traumatic brain injury (TBI) is a leading cause of death and disability in children, especially those under five, with younger children more vulnerable to persistent cognitive and neuropsychological effects due to disrupted brain development. Paediatric brains are biomechanically more susceptible to diffuse axonal injury due to anatomical differences, with axonal injury observed in up to 80% of hospitalized children. Despite this, many preclinical TBI models focus on focal injuries, whereas to better model the evolution of axonal injury in the paediatric brain, clinically-relevant diffuse pre-clinical models are required. In this study gyrencephalic paediatric ferrets (2–3 months) equivalent to a 3–5-year-old child were injured with the Closed Head Impact Model of Engineered Rotational Acceleration (CHIMERA), and the axonal injury response and resultant motor and cognitive deficits examined to 72 h post-injury. Injury was associated with extensive axonal injury, as detected via both the amyloid precursor protein (APP) for transport disruption and neurofilament light (NFL) for neurofilament integrity, in key structures including the corpus callosum, fornix and cortical white matter. Serum GFAP was increased within 30 min of injury, returning to baseline by 72 h, with NFL elevated from 24 h to 72 h post-injury. Injured ferrets had deficits in balance, working memory and spatial memory. The adaptation of the CHIMERA model to paediatric ferrets provides the opportunity to investigate factors driving axonal pathology post-injury and how these interact with neurodevelopment.