The quest to model chronic traumatic encephalopathy: a multiple model and injury paradigm experience
Document Type
Article
Publication Date
2015
College/Unit
School of Medicine
Department/Program/Center
Neurosurgery
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.
Digital Commons Citation
Turner, Ryan C.; Lucke-Wold, Brandon P.; Logsdon, Aric F.; Robson, Matthew J.; Dashnaw, Matthew L.; Huang, Jason H.; Smith, Kelley E.; Huber, Jason D.; Rosen, Charles L.; and Petraglia, Anthony L., "The quest to model chronic traumatic encephalopathy: a multiple model and injury paradigm experience" (2015). Faculty & Staff Scholarship. 2153.
https://researchrepository.wvu.edu/faculty_publications/2153
Source Citation
Turner, R. C., Lucke-Wold, B. P., Logsdon, A. F., Robson, M. J., Dashnaw, M. L., Huang, J. H., Smith, K. E., Huber, J. D., Rosen, C. L., & Petraglia, A. L. (2015). The Quest to Model Chronic Traumatic Encephalopathy: A Multiple Model and Injury Paradigm Experience. Frontiers in Neurology, 6. https://doi.org/10.3389/fneur.2015.00222
Comments
© 2015 Turner, Lucke-Wold, Logsdon, Robson, Dashnaw, Huang, Smith, Huber, Rosen and Petraglia. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.