The Quest to Model Chronic Traumatic Encephalopathy: A Multiple Model and Injury Paradigm Experience

Authors

Ryan C. Turner, Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, USA; Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA.
Brandon P. Lucke-Wold, Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, USA; Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA.
Aric F. Logsdon, 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.
Matthew J. Robson, Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
Matthew L. Dashnaw, Department of Neurosurgery, University of Rochester School of Medicine and Dentistry, Rochester, NY, USA.
Jason H. Huang, Department of Neurosurgery, Baylor Scott and White Health System, Temple, TX, USA.
Kelly E. Smith, Department of Basic Pharmaceutical Sciences, West Virginia University School of Pharmacy, Morgantown, WV, USA.
Jason D. Huber, 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.
Charles L. Rosen, Department of Neurosurgery, West Virginia University School of Medicine, Morgantown, WV, USA; Center for Neuroscience, West Virginia University School of Medicine, Morgantown, WV, USA.
Anthony L. Petraglia, Rochester Regional HealthFollow

Department

Neurosurgery

Document Type

Article

Publication Title

Frontiers in neurology

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.

First Page

222

DOI

10.3389/fneur.2015.00222

Volume

6

Publication Date

11-6-2015

PubMed ID

26539159

Recommended 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, 222. https://doi.org/10.3389/fneur.2015.00222