title: A Novel Model of Traumatic Brain Injury in Adult Zebrafish Demonstrates Response to Injury and Treatment Comparable with Mammalian Models.
abstract: Traumatic brain injury (TBI) is a leading cause of death and morbidity in industrialized countries with considerable associated health care costs. The cost and time associated with pre-clinical development of TBI therapeutics is lengthy and expensive with a poor track record of successful translation to the clinic. The zebrafish is an emerging model organism in research with unique technical and genomic strengths in the study of disease and development. Its high degree of genetic homology and cell signaling pathways relative to mammalian species and amenability to high and medium throughput assays has potential to accelerate the rate of therapeutic drug identification. Accordingly, we developed a novel closed-head model of TBI in adult zebrafish using a targeted, pulsed, high-intensity focused ultrasound (pHIFU) to induce mechanical injury of the brain. Western blot results indicated altered microtubule and neurofilament expression as well as increased expression of cleaved caspase-3 and beta APP (β-APP; p < 0.05). We used automated behavioral tracking software to evaluate locomotor deficits 24 and 48 h post-injury. Significant behavioral impairment included decreased swim distance and velocity (p < 0.05), as well as heightened anxiety and altered group social dynamics. Responses to injury were pHIFU dose-dependent and modifiable with MK-801, MDL-28170, or temperature modulation. Together, results indicate that the zebrafish exhibits responses to injury and intervention similar to mammalian TBI pathophysiology and suggest the potential for use to rapidly evaluate therapeutic compounds with high efficiency.
authors.affiliation: 1 Institute of Medical Sciences, University of Toronto , Ontario, Canada .
authors.forename: Victoria
authors.initials: V
authors.lastname: McCutcheon
authors.affiliation: 2 Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital , Toronto, Ontario, Canada .
authors.forename: Eugene
authors.initials: E
authors.lastname: Park
authors.affiliation: 2 Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital , Toronto, Ontario, Canada .
authors.forename: Elaine
authors.initials: E
authors.lastname: Liu
authors.affiliation: 3 Department of Physics, Ryerson University , Toronto, Ontario, Canada .
authors.forename: Pooya
authors.initials: P
authors.lastname: Sobhebidari
authors.affiliation: 2 Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital , Toronto, Ontario, Canada .|3 Department of Physics, Ryerson University , Toronto, Ontario, Canada .
authors.forename: Jahan
authors.initials: J
authors.lastname: Tavakkoli
authors.affiliation: 2 Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital , Toronto, Ontario, Canada .|4 Departments of Medicine and Physiology, University of Toronto , Ontario, Canada .
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Wen
authors.affiliation: 1 Institute of Medical Sciences, University of Toronto , Ontario, Canada .|2 Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital , Toronto, Ontario, Canada .|5 Departments of Anesthesia and Surgery, University of Toronto , Ontario, Canada .
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Baker
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology*; D000070642:Brain Injuries, Traumatic / Q000188:drug therapy / Q000503:physiopathology* / Q000628:therapy*; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004151:Dipeptides / Q000494:pharmacology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005260:Female; D007036:Hypothermia, Induced / Q000379:methods*; D008297:Male; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000069453:Ultrasonic Waves; D015027:Zebrafish
chemical_list: D015853:Cysteine Proteinase Inhibitors; D004151:Dipeptides; D018696:Neuroprotective Agents; D016291:Dizocilpine Maleate; C058076:calpain inhibitor III
keywords: animal model; behavior; concussion; high intensity ultrasound; traumatic brain injury; zebrafish