Potentiating hemorrhage in a periadolescent rat model of closed-head traumatic brain injury worsens hyperexcitability but not behavioral deficits
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Abstract
Post-traumatic epilepsy (PTE) and neurocognitive deficits are devastating sequelae of head injuries that are common in adolescents. Investigating desperately needed treatments is hindered by the difficulties in inducing PTE in rodents and the lack of established immature rat models of pediatric PTE. Hemorrhage is a significant risk factor for PTE, but compared to humans, rats are less prone to bleeding because of their rapid blood coagulation system. In this study, we promoted bleeding in the controlled cortical impact (CCI) closed-head injury model with a 20 min pre-impact 600 IU/kg intraperitoneal heparin injection in postnatal day 35 (P35) periadolescent rats, given the preponderance of such injuries in this age group. Temporo-parietal CCI was performed post-heparin (HTBI group) or post-saline (TBI group). Controls were subjected to sham procedures following heparin or saline administration. Continuous long-term EEG monitoring was performed for 3 months post-CCI. Sensorimotor testing, the Morris water maze, and a modified active avoidance test were conducted between P80 and P100. Glial fibrillary acidic protein (GFAP) levels and neuronal damage were also assessed. Compared to TBI rats, HTBI rats had persistently higher EEG spiking and increased hippocampal GFAP levels (p < 0.05). No sensorimotor deficits were detected in any group. Compared to controls, both HTBI and TBI groups had a long-term hippocampal neuronal loss (p < 0.05), as well as contextual and visuospatial learning deficits (p < 0.05). The hippocampal astrogliosis and EEG spiking detected in all rats subjected to our hemorrhage-promoting procedure suggest the emergence of hyperexcitable networks and pave the way to a periadolescent PTE rat model. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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Adolescent, Astrocyte, Behavior, Controlled cortical impact, Epilepsy, Hemorrhage, Hyperexcitable, Spike, Age factors, Animals, Biomarkers, Biopsy, Brain injuries, traumatic, Disease models, animal, Disease susceptibility, Electroencephalography, Glial fibrillary acidic protein, Immunohistochemistry, Maze learning, Neurons, Rats, Acepromazine, Eye ointment, Heparin, Ketamine, Paracetamol, Protein p100, Protein p80, Sodium chloride, Water, Xylazine, Biological marker, Adult, Animal experiment, Animal model, Animal tissue, Article, Astrocytosis, Avoidance behavior, Behavior disorder, Blood clotting, Brain hemorrhage, Clinical assessment, Clinical feature, Comparative study, Controlled study, Cortical excitability, Electrode implantation, Electroencephalography monitoring, Epileptogenesis, Groups by age, Hargreaves test, Head injury, Hippocampus, Hyperexcitability, Learning disorder, Long term care, Male, Morris water maze test, Nerve cell lesion, Nonhuman, Postnatal care, Rat, Rat model, Rotarod test, Seizure, Sensorimotor function, Sham procedure, Spatial memory, Spike wave, Temporoparietal junction, Traumatic brain injury, Traumatic epilepsy, Von frey test, Age, Animal, Bleeding, Complication, Disease model, Disease predisposition, Maze test, Metabolism, Nerve cell, Pathophysiology