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Background: Experimental models are needed to better understand the pathophysiology of neurodegenerative diseases to develop novel therapeutics. The neuropathology and clinical signs of acute radiation syndrome resemble those of neurodegenerative conditions. We characterized elevated plus maze (EPM) indicators of cognitive and motor impairment in rats exposed to brain-damaging doses of gamma radiation to develop a model for neurological component of the acute radiation syndrome., Materials and Methods: Technetium 99 m was administered once through tail vein to male Wistar rats to reach an absorbed dose of Gamma radiation of 667 mGy (66.7Rad). Animal performance in the EPM was assessed every 14 days. Rats were observed for 9 weeks for the occurrence of systemic and neurological signs. Comparisons were done between irradiated and nonirradiated rats, and in each group with baseline performance., Results: EPM indicators of cognitive and motor impairment, anxiety, and depression were observed concomitantly and increased with the severity of acute radiation syndrome-like systemic and neurological signs. Alterations in EPM indicators appeared 3 weeks postirradiation and their severity increased with time. Notably, arm transitions and the distance covered in the maze were decreased (-56.71% and -73.62%, P < 0.001), as well as open arm entries and time spent in open arms (-77.78% and -76.19%, P < 0.05) and the indicator of thigmotaxis rearing (-92.45, P < 0.001)., Conclusions: Our results suggest that irradiated rat performance in the EPM paradigm reflects disease severity and could be used to perform both acute and subchronic pharmacological studies in acute radiation syndrome-like diseases in rats., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Advanced Biomedical Research.)