title: The Quest to Model Chronic Traumatic Encephalopathy: A Multiple Model and Injury Paradigm Experience.
abstract: Chronic neurodegeneration following a history of neurotrauma is frequently associated with neuropsychiatric and cognitive symptoms. In order to enhance understanding about the underlying pathophysiology linking neurotrauma to neurodegeneration, a multi-model preclinical approach must be established to account for the different injury paradigms and pathophysiologic mechanisms. We investigated the development of tau pathology and behavioral changes using a multi-model and multi-institutional approach, comparing the preclinical results to tauopathy patterns seen in post-mortem human samples from athletes diagnosed with chronic traumatic encephalopathy (CTE). We utilized a scaled and validated blast-induced traumatic brain injury model in rats and a modified pneumatic closed-head impact model in mice. Tau hyperphosphorylation was evaluated by western blot and immunohistochemistry. Elevated-plus maze and Morris water maze were employed to measure impulsive-like behavior and cognitive deficits respectively. Animals exposed to single blast (~50 PSI reflected peak overpressure) exhibited elevated AT8 immunoreactivity in the contralateral hippocampus at 1 month compared to controls (q = 3.96, p < 0.05). Animals exposed to repeat blast (six blasts over 2 weeks) had increased AT8 (q = 8.12, p < 0.001) and AT270 (q = 4.03, p < 0.05) in the contralateral hippocampus at 1 month post-injury compared to controls. In the modified controlled closed-head impact mouse model, no significant difference in AT8 was seen at 7 days, however a significant elevation was detected at 1 month following injury in the ipsilateral hippocampus compared to control (q = 4.34, p < 0.05). Elevated-plus maze data revealed that rats exposed to single blast (q = 3.53, p < 0.05) and repeat blast (q = 4.21, p < 0.05) spent more time in seconds exploring the open arms compared to controls. Morris water maze testing revealed a significant difference between groups in acquisition times on days 22-27. During the probe trial, single blast (t = 6.44, p < 0.05) and repeat blast (t = 8.00, p < 0.05) rats spent less time in seconds exploring where the platform had been located compared to controls. This study provides a multi-model example of replicating tau and behavioral changes in animals and provides a foundation for future investigation of CTE disease pathophysiology and therapeutic development.
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine , Morgantown, WV , USA ; Center for Neuroscience, West Virginia University School of Medicine , Morgantown, WV , USA.
authors.forename: Ryan C
authors.initials: RC
authors.lastname: Turner
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine , Morgantown, WV , USA ; Center for Neuroscience, West Virginia University School of Medicine , Morgantown, WV , USA.
authors.forename: Brandon P
authors.initials: BP
authors.lastname: Lucke-Wold
authors.affiliation: Center for Neuroscience, West Virginia University School of Medicine , Morgantown, WV , USA ; Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy , Morgantown, WV , USA.
authors.forename: Aric F
authors.initials: AF
authors.lastname: Logsdon
authors.affiliation: Department of Pharmacology, Vanderbilt University School of Medicine , Nashville, TN , USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Robson
authors.affiliation: Department of Neurosurgery, University of Rochester School of Medicine and Dentistry , Rochester, NY , USA.
authors.forename: Matthew L
authors.initials: ML
authors.lastname: Dashnaw
authors.affiliation: Department of Neurosurgery, Baylor Scott and White Health System , Temple, TX , USA.
authors.forename: Jason H
authors.initials: JH
authors.lastname: Huang
authors.affiliation: Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy , Morgantown, WV , USA.
authors.forename: Kelly E
authors.initials: KE
authors.lastname: Smith
authors.affiliation: Center for Neuroscience, West Virginia University School of Medicine , Morgantown, WV , USA ; Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy , Morgantown, WV , USA.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Huber
authors.affiliation: Department of Neurosurgery, West Virginia University School of Medicine , Morgantown, WV , USA ; Center for Neuroscience, West Virginia University School of Medicine , Morgantown, WV , USA.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Rosen
authors.affiliation: Division of Neurosurgery, Rochester Regional Health , Rochester, NY , USA.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Petraglia
keywords: animal models; chronic traumatic encephalopathy; cognitive performance; perivascular pathology; tauopathy