Evolution of Axonal Injury in the Closed Head Impact Model of Engineered Rotational Acceleration in Adult Ferrets

Concussion-related symptoms, such as impaired balance, slower processing speed, attention deficits, memory dysfunction, and irritability, are thought to result from diffuse axonal injury (DAI), characterized by selective damage to white matter axons. Axons subjected to this mechanical stretch injury exhibit diverse pathological changes, including disruption of axonal transport, neurofilament compaction and degradation, myelin sheath disruption, and loss of sodium channels required for action potential generation and propagation. These distinct forms of axonal pathology may evolve differentially over time and preferentially localize to specific white matter tracts. In this study, we employed the clinically relevant ferret model of concussion using the closed head impact model of engineered rotational acceleration (CHIMERA). 55 male ferrets were randomly allocated to sham or injury groups and then to either 24 h, 72 h, or 14d survival time points. We confirmed that axonal transport disruption and neurofilament pathology represent independent processes, with minimal colocalization but a shared peak of around 72 h following injury. Furthermore, we observed a persistent loss of ankyrin-G, a critical anchoring protein for sodium channels at the node of Ranvier, up to 14d postinjury, suggesting that the resultant impairment in axonal transmission may underlie many concussion symptoms. Indeed, injured ferrets displayed significant deficits in balance, working memory, spatial memory, and recognition memory. These findings demonstrate that the CHIMERA model in ferrets recapitulates key axonal pathologies and their associated clinical manifestations following concussion. This model offers a valuable platform for investigating the temporal evolution of axonal injury and developing targeted therapeutic interventions to mitigate concussion-related deficits.