A non-invasive biomechanical model of mild TBI in larval zebrafish.

Abstract

A mild traumatic brain injury is a neurological dysfunction caused by biomechanical forces transmitted to the brain in physical impacts. The current understanding of the neuropathological cascade resulting in the manifested clinical signs and symptoms is limited due to the absence of sensitive brain imaging methods. Zebrafish are established models for the reproduction and study of neurobiological pathologies. However, all available models mostly recreate moderate-to-severe focal injuries in adult zebrafish. The present work has induced a mild brain trauma in larval zebrafish through a non-invasive biomechanical approach. A custom-made apparatus with a commercially available motor was employed to expose larvae to rapidly decelerating linear movements. The neurophysiological changes following concussion were assessed through behavioural quantifications of startle reflex locomotor distance and habituation metrics. Here we show that the injury was followed, within five minutes, by a transient anxiety state and CNS dysfunction manifested by increased startle responsivity with impaired startle habituation, putatively mirroring the human clinical sign of hypersensitivity to noise. Within a day after the injury, chronic effects arose, as evidenced by an overall reduced responsivity to sensory stimulation (lower amplitude and distance travelled along successive stimuli), reflecting the human post-concussive symptomatology. This study represents a step forward towards the establishment of a parsimonious (simple, less ethically concerning, yet sensitive) animal model of mild TBI. Our behavioural findings mimic aspects of acute and chronic effects of human concussion, which warrant further study at molecular, cellular and circuit levels. While our model opens wide avenues for studying the underlying cellular and molecular pathomechanisms, it also enables high-throughput testing of therapeutic interventions to accelerate post-concussive recovery.