Time course of the dependence of associative memory retrieval on the entorhinal cortex

As the gateway between the hippocampal system and the neocortex, the entorhinal cortex (EC) is hypothesized to be the hub in which the transformation of recent memory to remote memory is processed. We explored the role of the EC on the retrieval of recent and remote associative fear memory. A within-subject approach was adopted to compare the freezing rates of rats in EC intact and EC inactivated conditions following trace fear conditioning. The EC was inactivated by infusing an AMPA antagonist. The fear conditioning used a combined visual and auditory conditioned stimulus with a foot shock. On week 1 following the conditioning, the rats in the EC intact condition exhibited a freezing rate of 92.4 ± 9.5% in response to the light stimulus compared with a 6.3 ± 7.9% freezing rate in the EC inactivated condition. The freezing rates were 87.0 ± 17.8% and 4.7 ± 6.5% on week 2 in the EC intact and inactivated conditions, respectively. These results indicate that the EC participates in the retrieval of associative memory. Extinction of the fear memory was observed in the EC intact condition, as the mean freezing rate decreased to 62.7 ± 23.0% on week 4 and 41.2 ± 26.4% on week 5. However, the freezing rate increased to 26.8 ± 14.2% on week 4 and 22.3 ± 14.4% on week 5 in the EC inactivated condition. The normalized dependence of fear memory retrieval on the EC was 93.2 ± 8.3% on week 1, and significantly decreased on weeks 4 and 5. In summary, the retrieval of associative memory depends on the EC, but this dependence decreases over time.