Retrieval-mediated learning involving episodes requires synaptic plasticity in the hippocampus

Abstract

A novel association can form between two memories even when the events to which they correspond are not physically present. For example, once an integrated memory has formed that binds the (when, where, and what) components of an event together, this memory can be triggered by one of its components, and updated with coincident information in the environment. The neural basis of this form of retrieval-mediated learning is unknown. Here, we show, for the first time, that NMDA receptors in the rat hippocampus are required for retrieval-mediated learning involving episodes, but not for the expression of such learning or for retrieval-mediated learning involving simple associations between the components of episodes. These findings provide a novel insight into learning processes that serve the desirable function of integrating stored information with new information, but whose operation might also provide a substrate for some of the cognitive symptoms of schizophrenia and Alzheimer's disease.

Figure 1.

A schematic for the behavioral procedures used in experiments 1 and 2. In experiment 1, rats received the three-stage when-where procedure outlined in the top row of the figure. During the memory formation stage, each rat received four patterns: morning + spotted + tone, morning + checked + clicks, afternoon + spotted + clicks, and afternoon + checked + tone. In the retrieval-mediated learning stage (days 5 and 6), rats received presentations of the tone which, in a third context at midday, were paired with shock. These trials should allow the evoked memories of the morning + spotted + tone and afternoon + checked + tone to become associated with shock. Presentations of clicks, and allied evoked memories, were paired with no shock. During the final expression test, the level of fear to the when-where configurations that had been paired with the tone and clicks during the memory formation stage was assessed. In the example shown here, control rats should be more likely to show fear to the when-where configurations that had been presented with the tone in the memory formation stage (i.e., morning + spotted and afternoon + checked) than to the remaining configurations. In experiment 2, rats received the three-stage when and where procedures outlined in the middle and lower rows, respectively. In the when and where subgroups, the memory formation stage involved presenting the tone or clicks with different times of day (when: morning or afternoon) or different contexts (where: spotted or checked). This retrieval-mediated learning stage should permit the time of day or context associated with the tone (or click) to become associated with shock (and no shock). During the expression test, the when or where components, which had been paired with the tone and clicks, were presented.

Figure 2.

Mean freezing ratios (+SEM) for experiment 1: retrieval-mediated learning involving episodes. Mean freezing ratios (+SEMs) in experiments 1a (left), experiment 1b (middle), and experiment 1c (right). Scores >0.50 in the morning, and scores <0.50 in the afternoon, indicate that retrieval-mediated learning has taken place and is evident at test.

Figure 3.

Histology for experiments 1 and 2. Position of the tips of the infusion cannulae, which were similarly placed in the dorsal hippocampus (specifically in CA1) in all experiments are shown (experiment 1a: closed square, aCSF; open squares, muscimol; experiment 1b: closed squares, aCSF; open squares, AP5 before; open triangles, AP5 after; experiment 1c: closed squares, aCSF on test 1; open squares, AP5 on test 1; experiment 2: closed squares,= aCSF; open squares, muscimol; open triangles, AP5).

Figure 4.

Mean freezing ratios (+SEM) in experiment 2: retrieval-mediated learning involving the components of episodes. In this case, freezing ratios >0.50 indicate that retrieval-mediated learning has taken place and is evident at test.