PT - JOURNAL ARTICLE AU - Sai Ambika Tadepalli AU - Zsolt Kristóf Bali AU - Nóra Bruszt AU - Lili Veronika Nagy AU - Krisztina Amrein AU - Bálint Fazekas AU - András Büki AU - Endre Czeiter AU - István Hernádi TI - Long-term cognitive impairment without diffuse axonal injury following repetitive mild traumatic brain injury in rats AID - 10.1101/695718 DP - 2019 Jan 01 TA - bioRxiv PG - 695718 4099 - http://biorxiv.org/content/early/2019/07/20/695718.short 4100 - http://biorxiv.org/content/early/2019/07/20/695718.full AB - Repetitive mild traumatic brain injuries (TBI) impair cognitive abilities and increase risk of neurodegenerative disorders in humans. We developed two repetitive mild TBI models in rats with different time intervals between successive weight-drop injuries, and assessed cognitive performance and biomarker profiles. Rats were subjected to repetitive Sham (no injury), single mild (mTBI), repetitive mild (rmTBI – 5 hits, 24 h apart), rapid repetitive mild (rapTBI – 5 hits, 5 min apart) and single severe (sTBI) TBI. We assessed cognitive performance 2 and 8 weeks after TBI in the novel object recognition test (NOR), and 6-7 weeks after TBI in the water maze (MWM). Acute immunohistochemical markers were checked 24 h after TBI, and blood biomarkers were measured with ELISA 8 weeks after TBI. In the NOR, both rmTBI and rapTBI showed poor performance at 2 weeks post-injury. At 8 weeks post-injury, the rmTBI group still performed worse than the Sham and mTBI groups, while the rapTBI group recovered. In the MWM, the rapTBI group performed worse than Sham and mTBI. Acute APP and RMO-14 immunohistochemistry showed axonal injury at the pontomedullary junction in the sTBI, but not in other groups. ELISA showed increased serum GFAP levels 8 weeks after sTBI, while no differences were found between the injury groups in the levels of phosphorylated-tau and S100β. Results suggest that the rmTBI protocol is the most suitable model for testing cognitive impairment after mild repetitive head injuries. The lack of common biomarkers suggests novel unknown underlying mechanisms of rmTBI.ANOVAAnalysis of varianceAPPAmyloid precursor proteinBBBBlood-brain barrierCSFCerebrospinal fluidDAIDiffuse axonal injuryELISAEnzyme-linked immunosorbent assayFGAPGlial fibrillary acidic proteinMWMMorris water mazeNORNovel object recognitionOFTOpen field testpTauPhosphorylated-tauRMO-14Neurofilament medium chainTBITraumatic brain injury