Memory for the Order of Events in Specific Sequences: Contributions of the Hippocampus and Medial Prefrontal Cortex

Episodic memory involves remembering the incidental order of a series of events that comprise a specific experience. Current models of temporal organization in episodic memory have demonstrated that animals can make memory judgments about the order of serially presented events; however, in these protocols, the animals can judge items based on their relative recency. Thus, it remains unclear as to whether animals use the specific order of items in forming memories of distinct sequences. To resolve this important issue in memory representation, we presented mice repeatedly with two widely separated odor sequences and then tested their natural exploratory preference between pairs of odors selected from within or between sequences. Intact animals preferred to investigate odors that occurred earlier within each sequence, indicating they did remember the order of events within each distinct sequence. In contrast, intact animals did not discriminate between pairs of odors from different sequences. These findings indicate that preferences were not guided by relative recency, which would be expected to support graded discrimination between widely separated events. Furthermore, damage to either the hippocampus or the medial prefrontal cortex eliminated order preference within sequences. Despite the deficit in order memory, control recognition tests showed that normal mice and mice with hippocampal or medial prefrontal damage could correctly identify previously experienced odors compared with novel odors. These findings provide strong evidence that animals form representations of the order of events within specific experiences and that the hippocampus and prefrontal cortex are essential to order memory.