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Salvatore L Stella, Michael Anthony Grillo, Scott David Chartrand, Yunsung Kim, Mark C Stahl; Deciphering visual deficits in a larval zebrafish model of mild traumatic brain injury. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1878.
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Mild traumatic brain injury (mTBI) and concussion are somewhat interchangeable terms used to define a complex pathophysiologic process affecting the brain following trauma. Visual deficits are common in mTBI and can produce damage that can include any part of the retina, optic nerve, central visual pathways, and brain. The difference between mTBI and moderate to serve TBI can be determined using the Glasgow coma scale in humans, however, good animal models of mTBI are lacking. The aim of this study was to develop a larval zebrafish model of mTBI to assess visual deficits and underlying mechanisms involved in mTBI and its impact on vision.
The TBI blast was delivered to a chamber (containing 25 larvae 6 dpf) held by a stationary arm centered 2-4 cm above a speaker. The paradigm consisted of anesthesia for 3 minutes, followed by a short duration blast (duration: 1-5s) at 140 Hz. The larvae were allowed to recover for at least 30 min, and then tested briefly for their startle response followed by motility measurments. Visual behavior (Optomotor and optokinetic responses), immunohistochemistry, and western blotting were performed on neuronal, glial, and neurodegenerative factors on both isolated retina and whole mount brain tissue from larvae 6 to 12 dpf.
To demonstrate that zebrafish larvae only experienced mTBI, larvae lacked any visible damage to either motor axons following immunostaining with znp-1, or hair cell bundles labeled with FM 1-43 in the lateral line following acoustic trauma, indicating we are on the lower end of the Glasgow scale similar to mTBI. Larvae following TBI treatment showed less mobility at both 2 hrs and 24 hrs post-treatment than age-matched controls. Larvae also showed impaired responses to visual behavioral tests indicating that observable changes in the retina and brain contribute to mTBI. In agreement with this observation, various markers (TDP-43, APP, B-tubulin III, and caspase) all showed measurable changes in retina and brain in TBI treated larvae.
Our findings indicate this is a powerful tool to dissect the molecular and cellular basis of mTBI. In addition, this model is applicable to in vivo screening for drugs that might be used to treat mTBI lesions. Taken together, this approach has the potential to recapitulate mTBI damage observed in humans and investigate the underlying mechanism of vision loss following repetitive concussion or mTBI.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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