Blunt-force traumatic brain injury (TBI) affects an increasing number of people worldwide as the range of injury severity and heterogeneity of injury pathologies have been recognized. Most current damage models utilize non-regenerative organisms, less common TBI mechanisms (penetrating, chemical, blast), and are limited in scalability of injury severity. We describe a scalable blunt-force TBI model that exhibits a wide range of human clinical pathologies and allows for the study of both injury pathology/progression and mechanisms of regenerative recovery. We modified the Marmarou weight drop model for adult zebrafish, which delivers a scalable injury spanning mild, moderate, and severe phenotypes. Following injury, zebrafish display a wide range of severity-dependent, injury-induced pathologies, including seizures, blood–brain barrier disruption, neuroinflammation, edema, vascular injury, decreased recovery rate, neuronal cell death, sensorimotor difficulties, and cognitive deficits. Injury-induced pathologies rapidly dissipate 4–7 days post-injury as robust cell proliferation is observed across the neuroaxis. In the cerebellum, proliferating nestin:GFP-positive cells originated from the cerebellar crest by 60 h post-injury, which then infiltrated into the granule cell layer and differentiated into neurons. Shh pathway genes increased in expression shortly following injury. Injection of the Shh agonist purmorphamine in undamaged fish induced a significant proliferative response, while the proliferative response was inhibited in injured fish treated with cyclopamine, a Shh antagonist. Collectively, these data demonstrate that a scalable blunt-force TBI to adult zebrafish results in many pathologies similar to human TBI, followed by recovery, and neuronal regeneration in a Shh-dependent manner.
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This project was funded, in part, with support from the Indiana Spinal Cord & Brain Injury Research Fund from the Indiana State Department of Health to DRH. Its contents are solely the responsibility of the providers and do not necessarily represent the official views of the Indiana State Department of Health. This work was also supported by grants from the National Science Foundation Graduate Research Fellowship Program #DGE-1841556 (JTH), LTC Neil Hyland Fellowship of Notre Dame (JTH), Sentinels of Freedom Fellowship (JTH), Pat Tillman Scholarship (JTH), the Office of The Director of the National Institutes of Health (NIH) under Award Number S10OD020067 (ACM), the Center for Zebrafish Research at the University of Notre Dame, and the Center for Stem Cells and Regenerative Medicine at the University of Notre Dame.
The following are available online at https://www.mdpi.com/article/10.3390/biomedicines9080861/s1, Figure S1: Blunt-force TBI does not induce retinal damage, Figure S2: sTBI induces increased cell proliferation across the neuroaxis, Table S1: Sensorimotor ethogram. The materials are also available for download as the additional file listed at the end of this record.
Hentig, James; Cloghessy, Kaylee; Lahne, Manuela; Jung, Yoo Jin; Petersen, Rebecca A.; Morris, Ann C.; and Hyde, David R., "Zebrafish Blunt-Force TBI Induces Heterogenous Injury Pathologies That Mimic Human TBI and Responds with Sonic Hedgehog-Dependent Cell Proliferation across the Neuroaxis" (2021). Biology Faculty Publications. 211.