Dopamine and memory: modulation of the persistence of memory for novel hippocampal NMDA receptor-dependent paired associates

Abstract

Three experiments investigated the role in memory processing of dopamine (DA) afferents to the hippocampus (HPC) that arise from the ventral tegmental area. One hypothesis is that D(1)/D(5) receptor activation in HPC is necessary for the encoding of novel, episodic-like information; the other is that DA activation ensures the greater temporal persistence of transient hippocampal memory traces. Rats (n = 35) were trained, in separate experiments using an episodic-like memory task, to learn six paired associates (PAs) in an "event arena" involving a repeated association between specific flavors of food and locations in space. After 6 weeks of training, rats had learned a "schema" such that two new paired associates could be acquired in a single trial in one session (episodic-like memory). We show that encoding of novel PAs is sensitive to intrahippocampal microinfusion of the NMDA antagonist d-AP-5. Experiment 1 established that intrahippocampal infusion of the D(1)/D(5) dopaminergic antagonist SCH23390 [R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride] before encoding of new PAs caused impaired memory 24 h later but that SCH23390 had no effect on the later memory of previously established PAs. Experiment 2 established that SCH23390 modulated the persistence of new memories over time (30 min vs 24 h) rather than affecting initial encoding. Experiment 3 revealed that the impact of SCH23390 was not mediated by state dependence nor had an effect on memory retrieval. These findings support the second hypothesis and establish that persistent, long-term memory of rapid, hippocampal-mediated acquisition of new paired associates requires activation of D(1)/D(5) receptors in HPC at or around the time of encoding.

Figure 1.

Experimental apparatus and design. A, Layout of the event-arena apparatus (1.6 × 1.6 m) with the four start boxes and the six sand wells available to which the animals can run to collect food. B, Top, Example of an empty sand well with an inner diameter of 6 cm and a total depth of 5 cm. The sand well contains a grid 3.5 cm from the top under which 1 g of each of the six flavors pellets were placed to provide comparable olfactory cues at each sand well. B, Bottom, An example of a “full” sand well with the food pellets hidden, including any accessible reward pellets of a specific flavor. C, Schema of training and new paired associates. Timeline showing the design of experiment 1 (Fs, flavors). The syringes indicate the time of the bilateral iHPC infusions (before the beginning of the second and fifth trials on the training day of the new flavors).

Figure 2.

Acquisition of the schema, new paired associates, and NMDA dependency. A, Performance index of acquisition of the original six paired associates (sessions 1–17; white background). Single days of training of new paired associates alternated with 3 d of the original schema (sessions 18–42; gray background). Performance rose to a stable level of 80% with minimal variability. Note that performance fell to chance on session 38 when the start-box flavor cues were absent. B, Three cued-recall probe trials for the acquisition of the original schema. The graph represents percentage of dig time at the cued location (black bars) relative to that at the noncued locations (white bars). C, Hippocampal NMDA receptor dependence of the acquisition of the new paired associates. The graph represents percentage dig time at the new cued location (black bars) and the new noncued location (gray bars), as well as the average of the four original paired associates (white bars) for probe test 9 in the control (aCSF) and drug (AP-5) conditions. ns, Nonsignificant. *p < 0.05; **p < 0.01; ***p < 0.001 for t tests comparing the proportion of digging for the cued paired associates relative to chance level of 16.7%.

Figure 3.

Experiment 1: A, Dopamine dependency of encoding of new paired associates. Percentage dig time in all three conditions (NaCl, SCH23390 1 μg, and SCH23390 5 μg) across the three counterbalanced probe tests (PT4–PT6). B, SCH23390 and previously trained memories. Percentage dig time for the original paired associates in two conditions (NaCl and SCH23390 1 μg). C, The left shows plots of the locations of cannulae tips (n = 11 per HPC; experiment 1). Infusion sites are marked on the appropriate section of a stereotaxic brain atlas (Paxinos and Watson, 1998). The right shows Nissl-stained sections showing examples of representative cannulae tracks in the dorsal hippocampus in each hemisphere of the brain. ns, Nonsignificant. *p < 0.05; **p < 0.01; ***p < 0.001.

Figure 4.

Experiment 2: delay dependency. Impact of the SCH23390 on short-term (30 min) and long-term (24 h) memory. Percentage dig time at both delays (30 min or 24 h) in two drug conditions. Note good performance in the presence of the drug at 30 min but not at 24 h. ns, Nonsignificant. *p < 0.05; **p < 0.01.

Figure 5.

Experiment 3: state dependency and memory retrieval. Percentage dig time across the four counterbalanced probe tests (PT4–PT7) in all four conditions (NaCl before encoding and before retrieval, NaCl before encoding and SCH23390 before retrieval, SCH23390 before encoding and NaCl before retrieval, and SCH23390 before encoding and retrieval). Note that memory was impaired only when the drug was present at the time of encoding. ns, Nonsignificant. **p < 0.01; ***p < 0.001.