AUTHOR=Turner Ryan C. , Lucke-Wold Brandon P. , Logsdon Aric F. , Robson Matthew J. , Dashnaw Matthew L. , Huang Jason H. , Smith Kelly E. , Huber Jason D. , Rosen Charles L. , Petraglia Anthony L. 

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

JOURNAL=Frontiers in Neurology

VOLUME=6

YEAR=2015

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2015.00222

DOI=10.3389/fneur.2015.00222

ISSN=1664-2295

ABSTRACT=<p>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 (<italic>q</italic> = 3.96, <italic>p</italic> &lt; 0.05). Animals exposed to repeat blast (six blasts over 2 weeks) had increased AT8 (<italic>q</italic> = 8.12, <italic>p</italic> &lt; 0.001) and AT270 (<italic>q</italic> = 4.03, <italic>p</italic> &lt; 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 (<italic>q</italic> = 4.34, <italic>p</italic> &lt; 0.05). Elevated-plus maze data revealed that rats exposed to single blast (<italic>q</italic> = 3.53, <italic>p</italic> &lt; 0.05) and repeat blast (<italic>q</italic> = 4.21, <italic>p</italic> &lt; 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 (<italic>t</italic> = 6.44, <italic>p</italic> &lt; 0.05) and repeat blast (<italic>t</italic> = 8.00, <italic>p</italic> &lt; 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.</p>