Time-dependent fear memory generalization triggered by phosphodiesterase 5 inhibition during reconsolidation

Fear generalization, a lack of discrimination between safe and unsafe cues, is a hallmark of posttraumatic stress disorder. The phosphodiesterase 5 (PDE5) regulates the cyclic guanosine monophosphate (cGMP) pathway, which has been proposed to be involved in fear memory generalization. However, whether PDE5 activity underlies fear memory generalization remains unexplored. Considering the importance of retrieval-induced reconsolidation in memory maintenance, we aimed to investigate whether PDE5 inhibition during reconsolidation of recent fear memory affects generalization over time in adult male Wistar rats submitted to contextual fear conditioning. The PDE5 inhibition with vardenafil (VAR) 1 mg/kg i.p. during reconsolidation triggered a time-dependent fear generalization without affecting fear memory in the paired context. Fear generalization and impaired pattern separation appear to be interlinked. Likewise, an impairment of object pattern separation was observed in the VAR-treated group at the remote time point. These effects depended on memory retrieval and were restricted to the reconsolidation time window. A chemogenetic inhibition of the anterior cingulate cortex (ACC), a region involved in allocating remote memories and generalization, prevented the effects of VAR. Moreover, VAR infusion into the ACC (6 μg/0.2 μL) after retrieval also promoted fear generalization and impaired OPS in remote time point, suggesting that ACC underlies the behavioral outcomes of the treatment with VAR. In conclusion, our results suggest that inhibiting PDE5 during the reconsolidation of a recent fear memory recruits the activity of the ACC, triggering fear memory generalization and impairing object pattern separation over time.