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INTRODUCTION: Traumatic brain injury (TBI) is a debilitating neurological disorder caused by an impact to the head by an outside force. TBI results in persistent cognitive impairments, including fear generalization, the inability to distinguish between aversive and neutral stimuli. The mechanisms underlying fear generalization have not been fully elucidated, and there are no targeted therapeutics to alleviate this symptom of TBI. METHODS: To identify the neural ensembles mediating fear generalization, we utilized the ArcCreERT2 x enhanced yellow fluorescent protein (EYFP) mice, which allow for activity-dependent labeling and quantification of memory traces. Mice were administered a sham surgery or the controlled cortical impact (CCI) model of TBI. Mice were then administered a contextual fear discrimination (CFD) paradigm and memory traces were quantified in numerous brain regions. In a separate group of mice, we tested if (R,S)-ketamine could decrease fear generalization and alter the corresponding memory traces in TBI mice. RESULTS: TBI mice exhibited increased fear generalization when compared with sham mice. This behavioral phenotype was paralleled by altered memory traces in the DG, CA3, and amygdala, but not by alterations in inflammation or sleep. In TBI mice, (R,S)-ketamine facilitated fear discrimination and this behavioral improvement was reflected in DG memory trace activity. CONCLUSIONS: These data show that TBI induces fear generalization by altering fear memory traces, and that this deficit can be improved with a single injection of (R,S)-ketamine. This work enhances our understanding of the neural basis of TBI-induced fear generalization and reveals potential therapeutic avenues for alleviating this symptom.

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