The effect of chronic corticosterone on fear learning and memory depends on dose and the testing protocol

• Corticosterone had dose-dependent effects on the retrieval of fear memories.
• High-dose corticosterone enhanced freezing to both contextual and tone cues.
• Low-dose corticosterone enhanced freezing to tone cues only.
• Fear-induced freezing was reduced from the first to the second test session.
• Counterbalancing the order of contextual and tone testing is important.

Chronic exposure to the stress hormone corticosterone (CORT) is known to alter plasticity within hippocampal and amygdalar circuits that mediate fear learning and memory. The purpose of this experiment was to clarify the effects of chronic CORT on Pavlovian fear conditioning, which is dependent on intact hippocampal and amygdalar activity. In particular, we assessed whether the effect of chronic CORT on fear learning and memory is influenced by two factors—the dose of CORT and the order in which rats are tested for freezing to context versus tone cues. Male Long–Evans rats received low-dose CORT (5 mg/kg), high-dose CORT (40 mg/kg), or vehicle injections once daily for 21 days. On day 22, the rats were trained in a fear-conditioning paradigm. On days 23 and 24, the rats were tested for the retrieval of fear memories to context and tone cues in a counterbalanced way—half the rats received context testing on day 23 and then tone testing on day 24 and half the rats received tone testing on day 23 followed by context testing on day 24. Our results revealed dose-dependent effects of CORT on memory retrieval: Rats injected with high-dose CORT froze significantly more than control rats to both context and tone cues regardless of what testing day these cues were presented. However, rats injected with low-dose CORT froze significantly more than control rats to tone cues only. We also found an order effect in that the effects of CORT on freezing were greater on the second day of testing, regardless of whether that testing was to context or tones cues. This order effect may be due to a lack of extinction in the CORT rats. Overall, these results suggest a relationship between stress intensity and testing conditions that should be taken into account when assessing the effect of stress on fear memories.