# Chronic Neurobehavioral and Neuropathological Consequences of Repeated Blast Exposure in P301S Transgenic Tau Rats

## TL;DR

This study investigates the long-term effects of repeated blast exposure on brain health in rats with a genetic mutation linked to tau-related brain diseases.

## Contribution

The study introduces a novel rat model combining blast injury and P301S tau mutation to explore chronic neurobehavioral and neuropathological outcomes.

## Key findings

- Blast-injured rats showed increased activity and impaired memory, but these effects were not influenced by the P301S mutation.
- Tg12099 +/− rats had higher phosphorylated tau and astrogliosis compared to wild-type rats, independent of blast exposure.
- Sex differences were observed in microgliosis among Tg12099 +/− rats, with males showing greater IBA1 immunostaining than females.

## Abstract

Repeated blast traumatic brain injury (rbTBI) is linked to dementia risk, potentially due to abnormal tau accumulation, although a definitive causal relationship remains elusive. This study aims to develop a model of rbTBI-induced tauopathy. We utilized wild-type (WT) rats and rats that are heterozygous for the mutated P301S human tau gene (Tg12099 +/−), the presence of which increases the propensity to develop tau neuropathology. At 2–3 months of age, rats were exposed to five blasts using the Advanced Blast Simulator or sham procedures. Behavioral and histological outcomes were evaluated at 10 and 15 months post-injury, respectively. The open field test revealed increased activity in blast-injured animals compared with sham. Tg12099 +/− females exhibited greater travel distances than WT females, while male activity levels did not differ by genotype. The novel object recognition test indicated impaired recognition memory in blast-injured animals, which was unrelated to genotype. There was a greater accumulation of phosphorylated tau in several brain regions of Tg12099 +/− rats compared with WT rats, yet no observable blast injury effect. Blast did not alter astro- and microgliosis, but increased astrogliosis was observed in Tg12099 +/− rats compared with WT rats in a region-dependent manner. We observed sex-dependent changes in microgliosis within the Tg12099 +/− group, with male Tg12099 +/− rats exhibiting increased IBA1 immunostaining compared with females. No such sex difference was observed in WT rats. Our findings suggest that while rbTBI can induce persistent behavioral deficits in rats, it does not exacerbate neuropathology in Tg12099 rats.