A Sequence of events model of episodic memory shows parallels in rats and humans

Abstract

A critical feature of episodic memory is the ability to remember the order of events as they occurred in time, a capacity shared across species including humans, nonhuman primates, and rodents. Accumulating evidence suggests that this capacity depends on a network of structures including the hippocampus and the prefrontal cortex, but their respective contributions remain poorly understood. As addressing this important issue will require converging evidence from complementary investigative techniques, we developed a cross-species, nonspatial sequence memory task suitable for behavioral and neurophysiological studies in rodents and in humans. The task involves the repeated presentation of sequences of items (odors in rats and images in humans) and requires subjects to make a judgment as to whether each item is presented "in sequence" or "out of sequence." To shed light on the cognitive processes and sequence representations supporting performance, different types of "out of sequence" probe trials were used including: (i) repeating an item from earlier in the sequence (Repeats; e.g., ABAD), (ii) skipping ahead in the sequence (Skips; e.g., ABD), and (iii) inserting an item from a different sequence into the same ordinal position (Ordinal Transfers; e.g., A2CD). We found a remarkable similarity in the performance of rats and humans, particularly in the pattern of results across probe trial types. Thus, the results suggest that rats and humans not only remember the sequences of events, but also use similar underlying cognitive processes and mnemonic representations. This strong cross-species correspondence validates this task for use in future basic and clinical interdisciplinary studies aimed at examining the neural mechanisms underlying episodic memory.

Keywords: hippocampus; order; prefrontal cortex; sequence memory; temporal context.

FIGURE 1.

Behavioral design of the cross-species sequence task. A: The task was designed to capture the “flow of events” aspect of episodic memory (Tulving, 1972, 1984, 2002), which conceptualizes an episode as a sequence of events segmented in time. In rats, sequences of four odors were presented through a single-odor port. In humans, sequences of six fractal images were presented in a single location on a computer monitor. Each sequence was presented multiple times within a testing session: 50% of the time the sequence was presented with all items “in sequence” (InSeq) and 50% of the time one item was presented “out of sequence” (OutSeq). Subjects were required to identify each item as InSeq (by holding a response for >1 s) or OutSeq (by holding for <1 s). Three different types of OutSeq probe trials were used during testing (Repeats, Skips, and Ordinal Transfers), which involve different cognitive processes and sequence representations. B: Repeats occurred when an earlier item was presented a second time in the sequence (e.g., ABCA). Repeats can be detected with multiple cognitive strategies and were thus used to define the upper limit of the ability to identify OutSeq items. C: Skips occurred when an item was presented too early in the sequence (e.g., ABD, which skips over item C). Detecting Skips requires accurate predictions of upcoming items and thus performance on these probe trials was used as a sensitive measure of detailed sequence memory. D: Ordinal Transfers occurred when an item from one sequence (e.g., WXYZ) was transferred to another sequence (e.g., ABCD) while retaining the item’s original ordinal position (e.g., ABYD). Ordinal Transfers were used to help identify the type of sequence representations supporting task performance (i.e., sequential item–item associations or item-in-position associations; see Fig. 3C for details).

FIGURE 2.

Sequence memory performance was remarkably similar in rats and humans. A: Performance from a representative rat. The main bar graph shows the mean RT (time the rat held in the odor port) on InSeq and OutSeq items, which indicates that rats reliably held for >1 s on InSeq items and for <1 s on OutSeq items (significant G-tests). The inset plot shows the same data sorted by ordinal position in the sequence and by item. The color of individual circles represents the correct sequence position for each odor presentation: blue represents the first sequence position (e.g., A or W), red the second position (e.g., B or X), green the third (e.g., C or Y), and purple the fourth (e.g., D or Z). Bars represent the median RT for each position (filled bar, InSeq; open bar, OutSeq). These data indicate that rats performed well at each sequence position and can identify when each odor was presented InSeq or OutSeq (significant G-tests for each sequence position and odor). It should be noted that only InSeq items are presented on the first position. B: Performance from a representative human subject. As shown in (A), the main bar graph shows the mean RT (time the person held the space bar key) on InSeq and OutSeq items, whereas the inset plot shows the same data sorted by ordinal position and by item. These data indicate that human subjects also performed well at each sequence position and could identify when each image was presented InSeq or OutSeq (significant G-tests). As with rats, the first position always featured an InSeq item. C: SMI [Eq. (1)] for the representative rat shown in (A). The SMI was used to collapse the data into a single normalized measure of sequence memory performance to directly compare the performance across species. D: SMI corresponding to the representative human subject shown in (B). E: Direct comparison of the mean SMI from all rats and humans revealed that both species performed at comparable levels on the task (nonsignificant t-test; power: [1 – β]_{d = 1} = 0.87). G*, P < 0.05 on G-test; ns, P > 0.05 on independent sample t-test.

FIGURE 3.

Performance on “out of sequence” probe trials is nearly identical between rats and humans, suggesting the use of similar cognitive processes and sequence representations across species. A: Performance on probe trials in which the OutSeq item was a repeat of an earlier item in the sequence (Repeats). The main bar graph shows accuracy for rats and humans, and the inset graph shows the same data sorted by n-back distance (how many items back did the item first occur; e.g., ABCB is a 2-back Repeat). Subjects performed at a high level on Repeats, with no significant differences observed between the groups (nonsignificant independent sample t-tests). B: Performance on probe trials in which the OutSeq item was presented earlier than its correct position (Skips). The main bar graph shows accuracy for rats and humans, and the inset graph shows the same data sorted by n-forward distance (the number of items skipped; e.g., ABD is a 1-forward Skip). Rats and humans performed similarly on Skips and both species performed significantly better on 2-forward than 1-forward Skips (significant dependent sample t-tests). C: Performance on the task can be supported by two primary representations of sequences in memory: sequential item–item associations and item-in-position associations (Kahana et al., 2010). Importantly, the two representations can be used to identify Repeats and Skips, but predict different outcomes on Ordinal Transfer trials. D: Performance on Ordinal Transfers, probe trials in which an item is presented in the correct ordinal position but in the wrong sequence (e.g., ABYD). If subjects exclusively relied on sequential item–item associations to solve the task, then Ordinal Transfer probes would be easily identified as OutSeq items (as Y should not follow B). Conversely, the same probes would be identified as InSeq items if subjects exclusively relied on item-in-position associations (as Y is in the same ordinal position as C). The main bar graph shows the rate at which subjects identified Ordinal Transfers as OutSeq, and the inset graph shows the data sorted by ordinal position of the transferred item. Rats and humans identified Ordinal Transfers as OutSeq at the same rate across positions, at levels between asymptotic performance (defined by performance on Repeats) and chance. OutSeq chance was defined as the complement to the response bias in each species for statistical tests, (Results), and plotted here as the average of the two species for simplicity. This suggests that rats and humans represent sequences using both item–item and item-in-position associations. Shaded areas in inset graphs of (A, B, and D) highlight the conditions in which data from both species were available. ns, nonsignificant on independent sample t-test; power: (1 – β)_{d = 1} = 0.87, except in the case of Ordinal Transfers where (1 – β)_{d = 1} = 0.60; *P < 0.05 on dependent sample t-test.