78 - Chronic behavioral deficits may be related to accumulation of phosphorylated tau in the piriform cortex in P301S tau transgenic rats after repeated blast exposure

Abstract Text: Traumatic Brain Injury (TBI) has been called a signature injury sustained by United States Military Service members in recent conflicts, particularly due to the increased incidence in blast exposure. While most cases are classified as mild, many service members experience repeated mild TBI (rmTBI) which has been associated with a heightened risk for early-onset dementia. The chronic neurodegenerative process after rmTBI has been attributed to the abnormal accumulation of tau, an essential microtubule-associated protein. Since tauopathies can currently only be diagnosed post-mortem, the mechanistic link between the initial injury and the ongoing degenerative process is still not well understood. There is a need to develop better preclinical models that encompass both the progression of tau pathology and wide range of behavioral impairments. Such a model would help us better evaluate treatment options, while also augmenting our understanding of causal relationships between exposure to rmTBI, tau accumulation, and eventual cognitive decline. The goal of this study is to create a valid preclinical model of a rmTBI related progressive tauopathy in male and female rats. To accomplish this, we utilized both wild type (WT) rats and rats that are heterozygous for the abnormal, mutated P301S human tau gene (htau) gene, which has an increased propensity to develop tau neuropathology. A total of sixty-nine male and female rats were exposed to five total blast rmTBIs using the Advanced Blast Simulator (ABS) or sham procedures at two-four months of age and behavioral and histological outcomes were evaluated at ten- and 18-months post injury, respectively. Behavioral measures included the Open Field Test (OFT), Novel Object Recognition Test (NOR), and Y-Maze spontaneous alteration task. We hypothesized that htau + ABS rats will present with greater behavioral abnormalities and tau accumulation compared to injured WT and sham controls. On the OFT, we found a main effect of injury, where blast injured animals displayed hyperactivity compared to sham animals. In addition, a significant interaction between genotype x sex was found, where htau females traveled more than htau males, while activity levels did not differ by genotype in males. On NOR, we found male htau + ABS rats had a significantly lower discrimination index (DI) compared to male htau + sham rats, indicating a deficit in recognition memory. No differences were seen on the Y maze, suggesting spatial working memory may remain intact. Preliminary immunohistological studies suggest greater accumulation of phosphorylated tau, particularly in the piriform cortex, in htau + ABS males compared to wild-type and sham controls. Our data suggests exposure to rmTBI early in life in rats with a predisposition to tauopathy may contribute to specific behavioral abnormalities at chronic timepoints which may differ by sex. These changes may be related to accumulation of phosphorylated tau in limbic regions, such as the piriform cortex. This is the first report of blast rmTBI in transgenic tau rats.

The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the Uniformed Services University, the Department of Defense, the U.S. government, or the Henry M. Jackson Foundation for the Advancement of Military Medicine. The study was approved by the Institutional Animal Care and Use Committee, Uniformed Services University of the Health Sciences. The authors have no financial conflicts.
Supported by the DoD Defense Health Agency 311661-2.00-66323

Keywords: blast, tau, piriform cortex, novel object recognition, open field test, tau transgenic rat