Traumatic brain injury (TBI) is a leading cause of death and disability in modern societies. Diffuse axonal and vascular injury are nearly universal consequences of mechanical energy impacting the head, and are major contributors to disability throughout the spectrum of injury severity. Designing a rodent model of head injury that recapitulates the hallmarks of human TBI is important to delineate biological mechanisms of TBI, to help pinpoint targets for future therapeutic strategies.

We developed CHIMERA (Closed Head Impact Model of Engineered Rotational Acceleration), a non-surgical, impact-acceleration model of rodent TBI that reliably produces diffuse axonal injury characterized by white matter inflammation and axonal damage at 0.5J. In this thesis, we begin by investigating the behavioral and neuropathological phenotypes induced by single CHIMERA TBI up to 0.7J. We demonstrate the capability of CHIMERA to induce proportionate outcomes based on biomechanical inputs, as single CHIMERA TBI at 0.6 and 0.7J in wild-type mice induced neurological and motor deficits, and triggered white matter damage and inflammation in a dose-dependent manner. Subsequently, we expanded CHIMERA’s capacity to induce more severe injuries with evidence of vascular damage and grey matter inflammation, in the hopes that therapies can be developed for TBIs across the injury spectrum. We report that interface-assisted single CHIMERA TBI at 2.5J in wild-type mice induced neurological deficits, elevated plasma total tau and neurofilament-light levels, transiently increased proinflammatory cytokines in brain, blood-brain barrier leakage and vascular abnormalities, as well as grey matter microgliosis. Finally, we expanded the CHIMERA platform to rats, to better understand the relationship between repetitive TBI (rTBI), impulsivity and neuropathology. Compared to sham controls, rats with rTBI displayed progressive impairment in impulsive choice. In addition to histological changes sustained by the mesolimbic dopaminergic system, grey and white matter inflammation along with tau immunoreactivity were observed.

In summary, we have developed a valuable rodent model of human TBI, replicating many of the hallmarks of clinical and neuropathological TBI in both mouse and rat models. We therefore hope that this platform can be used to validate promising drug targets that may ameliorate the inflammatory and behavioral sequelae of human TBI.