The hippocampus, prefrontal cortex, and perirhinal cortex are critical to incidental order memory

Abstract

Considerable research in rodents and humans indicates the hippocampus and prefrontal cortex are essential for remembering temporal relationships among stimuli, and accumulating evidence suggests the perirhinal cortex may also be involved. However, experimental parameters differ substantially across studies, which limits our ability to fully understand the fundamental contributions of these structures. In fact, previous studies vary in the type of temporal memory they emphasize (e.g., order, sequence, or separation in time), the stimuli and responses they use (e.g., trial-unique or repeated sequences, and incidental or rewarded behavior), and the degree to which they control for potential confounding factors (e.g., primary and recency effects, or order memory deficits secondary to item memory impairments). To help integrate these findings, we developed a new paradigm testing incidental memory for trial-unique series of events, and concurrently assessed order and item memory in animals with damage to the hippocampus, prefrontal cortex, or perirhinal cortex. We found that this new approach led to robust order and item memory, and that hippocampal, prefrontal and perirhinal damage selectively impaired order memory. These findings suggest the hippocampus, prefrontal cortex and perirhinal cortex are part of a broad network of structures essential for incidentally learning the order of events in episodic memory.

Keywords: Episodic memory; Memory for time; Recognition memory; Sequence memory; Temporal context; Temporal processing.

Figure 1.. Incidental order and item memory task.

A, Odors (household spices) were presented one at a time on wooden beads in front of the cage and centered. The time spent exploring the first odor (during a 30 s exposure) set the criterion exploration time for the remaining odors in the sequence. After a 60 min retention interval, subjects were given an order probe in which two odors from the sequence were presented (B vs. D) separated by ~6 cm. Preferential exploration on the odor that came earlier (B) indicated memory for order. Twenty minutes later, an item probe was presented in the same way except that it involved a comparison between another odor from the sequence and a novel odor (C vs. X). Preferential exploration toward the novel odor (X) indicated memory for the items presented in the sequence. B, All behavior was performed within each individual rat’s home cage, and active investigation time (sniffing and whisking within 1 cm of bead) was scored for each odor. Each bead was only used once to eliminate the possibility of contamination and/or change in odor strength. Therefore, when a sample odor was presented in the order or item probe, it was on a different bead (which was incubated in the same container for the same period of time).

Figure 2.. HC, PFC, or PER lesions impair order memory.

A, Lesions to HC, PFC, or PER significantly impaired order memory compared to controls. B, No significant differences were found following HC, PFC, or PER lesions on item memory. C, Difference scores (order DI minus item DI) were significantly lower than chance (difference score = 0) following HC, PFC, or PER lesions. Controls were not different from chance. Note that each animal was tested three times on each task (using different sets of odors) and the mean score of each rat was used for data analysis. Data shows group means ± SEM.

Figure 3.. HC, PFC, and PER lesions.

Neurotoxic lesions were made using multiple localized injections of NMDA, which resulted in selective cell loss and atrophy. Slices were stained for NeuN and the percent lesion area was calculated for each region of interest. A, Sample slices from a representative HC lesioned subject (top), and mean lesion area percentage across subjects (bottom; n = 11). B, Sample slices from PFC lesioned subject including all subregions analyzed (AC, PL, and IL), and the mean lesion area percentage across subjects (n = 12). C, Sample slices from a PER lesioned subject and lesion area percentage across subjects (n = 12) in PER (A/P −4.0 to −7.2), and dorsal lateral entorhinal cortex (dLEC).