Elsevier

Neurobiology of Learning and Memory

Volume 116, December 2014, Pages 155-161
Neurobiology of Learning and Memory

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

https://doi.org/10.1016/j.nlm.2014.10.003Get rights and content

Highlights

  • Freezing rate minimized in the first two weeks after training when the EC inactivated.

  • Retrieval of new associative fear memory depended on the entorhinal cortex (EC).

  • Fear memory extinguished over 4–5 weeks.

  • Dependence of fear memory retrieval on the EC decreased over 4–5 weeks.

Abstract

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.

Introduction

Patients with damage to the medial temporal lobe, which includes the hippocampus and its adjacent areas, exhibit impaired memory for recent events but retain the ability to recall past memories (Scoville and Milner, 1957, Squire, 1992, Wiltgen et al., 2004). The hippocampus acquires information quickly and functions as a transient storage for recent memory. Information is processed by the hippocampus before it is sent back to the neocortex for permanent storage. A remote memory is then formed in the neocortex (Graham and Hodges, 1997, Norman and O’Reilly, 2003). The entorhinal cortex (EC) serves as the gateway between the hippocampus and neocortex by forwarding the cortical information to the hippocampus and the hippocampal information back to the neocortex (Alvarez and Squire, 1994, Wiltgen et al., 2004). The EC processes multimodal sensory information (Lavenex and Amaral, 2000, Witter et al., 2000). Patients with Alzheimer’s disease exhibit neuronal loss in layer II of the EC and patients with schizophrenia exhibit decreased volume in the EC, suggesting that the EC is related to human declarative memory deficits (Gomez-Isla et al., 1996, Baiano et al., 2008).

Fear conditioning provides a tractable behavioral paradigm to dissect the role of the medial temporal lobe (Sanders, Wiltgen, & Fanselow, 2003). In typical associative learning, a relationship is established between the conditioned stimulus (CS) and the unconditioned stimulus (US) (Sanders et al., 2003). Under normal conditions, auditory stimuli evoke responses in the visual cortex (McIntosh et al., 1998, McIntosh and Gonzalez-Lima, 1998) and visual stimuli modulate responses in the auditory cortex (Bizley et al., 2007, Kayser et al., 2008). Audiovisual interactions and representations enable the cross-modal processing of the visual modulation of neurons in the auditory cortex (Romanski, 2007, Kayser et al., 2008).

In one of our recent studies (Chen et al., 2013), we conducted an experiment with electrodes implanted in the auditory cortex and a drug cannula in the EC of behaving rats. Reversible inactivation of the EC impaired not only the encoding of an artificial associative memory between a visual stimulus and bilateral auditory cortex stimulation but also the retrieval of the memory within a week after the establishment of the memory. These results confirmed earlier reports that the retrieval of recent memory depends on the medial temporal lobe (Alvarez and Squire, 1994, Wiltgen et al., 2004). However, this study failed to examine the dependence of the retrieval of remote memory on the medial temporal lobe due to the extinction of the artificial visuoauditory associative memory. In the present study, we have designed an experiment to examine the time course of the dependence of the medial temporal lobe on the EC to retrieve associative fear memory for a time range of 5 weeks.

Section snippets

Subjects

The experiment was conducted on 22 Sprague–Dawley rats. Each rat was approximately 2 months old at the start of the experiment and weighed between 280 and 350 g. The rats were housed under a 12:12 light/dark cycle, kept in individual plastic cages and allowed free access to water and food. All experimental protocols were approved by the Animal Subjects Ethics Sub-Committees of City University of Hong Kong and The Hong Kong Polytechnic University.

Atropine sulfate (0.05 mg/kg) was administered

Results

In experiment 1, the data from 11 of the original 12 rats were analyzed. One rat was excluded from the analysis because we could obtain only 1 week of data. In experiment 2, the data from 9 of 10 rats were analyzed. One rat was excluded as it showed no freezing during the test even after conditioning for 8 days.

Discussion

The results of the current experiment demonstrate that the EC is involved in the early stage of the retrieval of cross-modal associative memories. In the first three weeks following the fear conditioning, the freezing percentage in response to a light stimulus remained high in the EC intact condition compared with the EC inactivated condition. These results suggest that the EC is involved in the retrieval of associative memory. These results are in agreement with the results of a previous study

Acknowledgments

This work was supported by the Hong Kong Research Grants Council and Ministry of Science and Technology of China (GRF561410, 2012CB966300, 2013CB530900, GRF561111, 561212, 561009, CRF09/PolyU09, T3-607/12R). We also thank the donations from Charlie Lee Charitable Foundation, Fong Shu Fook Tong Foundation, and Mr. & Mrs. P. K. Yu Memorial Scholarship.

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    1

    Current address: Department of Research & Development, BGI-Shenzhen, Shenzhen, China.

    2

    These authors contributed equally to this work.

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