Extra-cellular signal-regulated kinase 1/2 (ERK1/2) activated in the hippocampal CA1 neurons is critical for retrieval of auditory trace fear memory.

The brain regions involved with trace fear conditioning (TFC) and delayed fear conditioning (DFC) are well-characterized, but little is known about the cellular representation subsuming these types of classical conditioning. Previous evidence has shown that activation of the amygdala is required for both TFC and DFC, while TFC also involves the hippocampus for forming conditioned response to tone. Lesions of the hippocampus did not affect tone learning in DFC, but it impaired learning in TFC. Synaptic plasticity in the hippocampus, underlying a cellular representation subsuming learning and memory, is in part modulated by extra-cellular signal-regulated kinase (ERK) signaling pathway. ERK1/2 activation is required for both TFC and DFC during memory formation, but whether this pathway is involved in memory retrieval of TFC is still unknown. In the present study, we investigated changes in ERK1/2 phosphorylation after memory retrieval in groups of mice that received TFC, DFC, tone-shock un-paired conditioning, and naïve control. Our results showed that ERK1/2 phosphorylation was elevated in the hippocampal CA1 region after retrieval of all conditioned fear responses. In particular, in the TFC group, immunohistochemistry indicated higher level of ERK1/2 phosphorylation in the hippocampal pyramidal neurons 30min after tone testing. Inhibition of the ERK1/2 signaling pathway diminished fear memory elicited by a tone in TFC. Together these results suggest that the memory retrieval process in TFC is more dependent on ERK1/2 signaling pathway than that in DFC. ERK1/2 signaling is critical for retrieval associative memory of temporally noncontiguous stimuli.