Development of a Novel Blunt-Force TBI Model in the Adult Zebrafish to Explore TBI Sequelae and Injury-Induced Regeneration

Traumatic brain injury (TBI)-related hospitalizations, disabilities, and mortalities have continued to rise over the last two decades affecting both military and civilian populations. These injuries can result in short- and long-term consequences and have been linked to increased rates of neurodegenerative disorders. However, humans possess adult neurogenesis, albeit very restricted and limited. Nevertheless, humans therefore have the potential for regenerative recovery, although little is known about human progenitor abundance or capacity to produce a diverse neural linage. In contrast, zebrafish possess a robust regenerative capacity shown to respond to trauma across both the peripheral and central nervous systems. This novel study proposes the use of a modified blunt-force TBI in the adult zebrafish to further examine a wide range of injury-induced pathologies, as well to further elucidate the regenerative mechanisms harbored by the zebrafish towards functional recovery. This study extensively characterizes a plethora of TBI-pathologies across mild, moderate, and severe TBI. This study then describes the regenerative response temporally and spatially in response to TBI. Finally, this study describes the mechanism by which Shh signaling pathway can be leveraged as a prophylactic treatment increasing Eaat2a expression and reducing TBI-sequelae by regulating glutamate excitotoxicity. Collectively, this study provides a foundation for future studies in blunt-force TBI sequelae progression and in injury-induced neuronal regeneration in the adult zebrafish.