Distinct contributions of hippocampal NMDA and AMPA receptors to encoding and retrieval of one-trial place memory

Abstract

Allocentric place memory may serve to specify the context of events stored in human episodic memory. Recently, our laboratory demonstrated that, analogous to event-place associations in episodic memory, rats could associate, within one trial, a specific food flavor with an allocentrically defined place in an open arena. Encoding, but not retrieval, of such flavor-place associations required hippocampal NMDA receptors; retrieval depended on hippocampal AMPA receptors. This might have partly reflected the contributions of these receptors to encoding and retrieval of one-trial place, rather than flavor-place, memory. Therefore, the present study developed a food-reinforced arena paradigm to study encoding and retrieval of one-trial allocentric place memory in rats; memory relied on visuospatial information and declined with increasing retention delay, still being significant after 6 h, the longest delay tested (experiments 1 and 2). Hippocampal infusion of the NMDA receptor antagonist d-AP-5 blocked encoding without affecting retrieval; hippocampal infusion of the AMPA receptor antagonist CNQX impaired retrieval (experiment 3). Finally, we confirmed that the d-AP-5 infusions selectively blocked induction of long-term potentiation, a form of synaptic plasticity, whereas CNQX impaired fast excitatory transmission, at perforant-path dentate gyrus synapses in the dorsal hippocampus in vivo (experiment 4). Our results support that encoding, but not retrieval, of one-trial allocentric place memory requires the NMDA receptor-dependent induction of hippocampal synaptic plasticity, whereas retrieval depends on AMPA receptor-mediated fast excitatory hippocampal transmission. The contributions of hippocampal NMDA and AMPA receptors to one-trial allocentric place memory may be central to episodic memory and related episodic-like forms of memory in rats.

Figure 1.

The one-trial place memory task. A, Open arena (event arena) used for the task. The arena floor has a 7 × 7 grid of circular holes covered by lids that can be removed to insert sandwells. B, A trial comprises an encoding and a retrieval phase. In the encoding phase, the rat must search for food reward (white dot) buried in a sandwell (filled circle) in a trial-specific place; all other possible sandwell locations (stippled circles) are closed and covered by sawdust. In the retrieval phase, beginning after a delay during which the rat is returned to its home cage, food is buried in a sandwell in the same place as in the encoding phase, and sandwells without food are open in four novel places; to find food efficiently in the retrieval phase, the rat must use one-trial place memory according to a win-stay rule. Start positions for encoding and retrieval phases are different requiring allocentric place memory.

Figure 2.

Development and characterization of the novel one-trial place memory task (experiments 1 and 2). Stippled horizontal lines indicate chance values of performance measures. The rats in experiment 1 (gray symbols; n = 15) were previously trained on a flavor-place memory task, whereas the rats in experiment 2 (black symbols; n = 16) were only shaped to dig in sandwells and habituated to the arena before training on the place memory task. A, Task acquisition (experiments 1 and 2a). The percentage of correct first choices (percentage of rats digging first in the correct sandwell; left) and errors (number of novel wells in which rats dug before digging in the correct one; mean ± 1 SEM; middle) for the initial training trials conducted with a 5 min delay. Trial 17 was a probe trial, in which food was omitted during the retrieval phase and the rats' dig time was measured for 60 s to calculate the percentage of dig time at the correct sandwell and the average percentage of dig time at novel sandwells (mean ± 1 SEM; right). B, Delay dependence of one-trial place memory (experiment 2b). The rats were trained with 5, 20, 60, 180, and 360 min delays (six trials at each delay: four standard training trials and two probe trials). The dig-time measures for the probe trials at the four different delays are depicted (average of two probe trials; mean ± 1 SEM). C, Arena rotation between encoding and retrieval (experiment 2c). To demonstrate that performance did not rely on cryptic odor cues, rats were tested with a 20 and a 360 min delay, with the symmetric arena being rotated by 90 or 180° between encoding and retrieval while the configuration of the intra-arena landmarks and the extra-arena room cues was kept constant (six trials at each delay: four standard training trials and two probe trials). The dig-time measures for the probe trials at the two different delays are shown (average of two probe trials; mean ± 1 SEM). D, Darkness during retrieval (experiment 2d). To demonstrate the requirement of visuospatial cues, retrieval in darkness was compared with retrieval in light (one probe trial for each condition) at a 20 min delay. The dig-time measure (mean ± 1 SEM) is shown for both conditions. Only 12 rats dug under both conditions (main graph), whereas four rats did not dig in any sandwell during darkness but performed normally in light (inset). That the average percentage of dig time in the dark condition (right; 32.3 ± 10.1%) is numerically higher than chance is essentially attributable to a single rat that dug briefly (1.0 s) in the correct well, without touching the novel wells.

Figure 3.

Effects of hippocampal AP-5 and CNQX infusions on encoding and retrieval of one-trial place memory (experiment 3, n = 14 rats). The percentage dig time at correct and novel sandwells (mean ± 1 SEM) in probe trials is presented as a performance measure; stippled horizontal lines indicate chance. A, Performance when the NMDA receptor antagonist d-AP-5 (30 mm, 1 μl) or ACSF (1 μl) was infused into the hippocampus 15 min before the encoding or retrieval phase. B, Performance when the AMPA receptor antagonist CNQX (3 mm, 1 μl) or ACSF (1 μl) was infused 15 min before the retrieval phase.

Figure 4.

Infusion sites and electrode placements in the hippocampus. A, Experiment 3: approximate locations of infusion cannula tips (black dots) in both hemispheres; experiments 4a and 4b: approximate locations of the tips of infusion cannulas (dots), stimulation electrodes (squares), and recording electrodes (stars) in the left hemisphere, depicted for the different groups (gray-scale coding). Coronal sections are adapted from Paxinos and Watson (1998); the numbers indicate the distance from bregma in millimeters. B, Photographs of cresyl violet-stained sections showing, from left to right, representative recording, infusion, and stimulation sites. Recording and stimulation sites were marked by an electrolytic lesion. White arrowheads indicate the approximate locations of the tips of the infusion cannula and the electrodes (note: bipolar stimulating electrode).

Figure 5.

Effects of hippocampal AP-5 and CNQX infusions on synaptic transmission and plasticity (experiment 4, n = 6-7 rats per group). EPSPs in the dentate gyrus evoked by low-frequency stimulation of the perforant path were recorded in anesthetized rats. Data are presented in 5 min blocks as a percentage of the average EPSP slope during the 20 min baseline recordings preceding the first infusion (percentage of baseline EPSP slope; mean ± 1 SEM). ACSF (1 μl), d-AP-5 (30 mm, 1 μl), or CNQX (3 mm, 1 μl) were infused at the times indicated by the arrows. A, Effects of hippocampal ACSF, d-AP-5, or CNQX infusions on basal (low-frequency) synaptic transmission. The vertical gray bar indicates 15-20 min after infusion, corresponding to the time during which the encoding or retrieval phase took place after the hippocampal infusions in experiment 3. B, Effects of hippocampal ACSF or AP-5 infusions on induction or maintenance of LTP. The gray bar indicates 20-25 min after tetanization, corresponding to the delay between encoding and retrieval in experiment 3.