Recent models of hippocampal function emphasize the potential role of this brain structure in encoding and retrieving sequences of events that compose episodic memories. Here we show that hippocampal lesions produce a severe and selective impairment in the capacity of rats to remember the sequential ordering of a series of odors, despite an intact capacity to recognize odors that recently occurred. These findings support the hypothesis that hippocampal networks mediate associations between sequential events that constitute elements of an episodic memory.In humans, hippocampal function underlies the ability to recall specific personal experiences1,2. Does this fundamental role of the hippocampus in human episodic memory extend to animals as well? Because animals cannot provide explicit reports of their experiences, this question is difficult to address experimentally. Some features of episodic memory may be assessed in animals, however, including the rich temporal, spatial and situational context of episodic memories3. In particular, recent theoretical analyses have emphasized the potential role of hippocampal circuitry in representing the sequential ordering of events that compose a unique behavioral episode4-7.Hippocampal damage impairs memory for the order of a series of recently visited spatial locations8,9. Because the hippocampus is important to spatial learning and memory in a variety of protocols10, however, there has not been conclusive evidence for a role in sequence memory specifically. It has been suggested that recognition and working memory for nonspatial stimuli also depend on associating events across time11. Selective hippocampal damage, however, has only a modest12 or no13 impairment in recognition or working memory for nonspatial cues, even when animals are required to remember long lists of single stimuli14,15. Furthermore, several recent studies have suggested a distinction between the capacity to recollect the spatial and temporal context of episodic memories, mediated by the hippocampus, and a separate capacity to remember independent events based on the familiarity of recently experienced stimuli16-20. Here, we directly compared memory for sequential order of events with memory for prior occurrence of events independent of their order.Correspondence should be addressed to H.B.E. (hbe@bu.edu). Competing interests statementThe authors declare that they have no competing financial interests. NIH Public Access Results Memory for the sequential order of eventsTo test for sequential order memory, rats were presented with a series of five randomly selected odors. Memory for each series was subsequently probed in a single-choice test in which the animal was rewarded for selecting the odor that had appeared earlier in the series (Fig. 1). Sessions included six different types of probes in a random order. Before hippocampal surgery, rats required an average of 21-38 trials to reach a criterion of 80% correct over 10 consecutive trials on each type of probe. Subjects were then divided into t...

The entorhinal cortex (EC) serves a pivotal role in corticohippocampal interactions, but a complete description of its extrinsic connections has not been presented. Here, we have summarized the cortical, subcortical, and hippocampal connections of the lateral entorhinal area (LEA) and the medial entorhinal area (MEA) in the rat. We found that the targets and relative strengths of the entorhinal connections are strikingly different for the LEA and MEA. For example, the LEA receives considerably heavier input from the piriform and insular cortices, whereas the MEA is more heavily targeted by the visual, posterior parietal, and retrosplenial cortices. Regarding subcortical connections, the LEA receives heavy input from the amygdala and olfactory structures, whereas the MEA is targeted by the dorsal thalamus, primarily the midline nuclei and also the dorsolateral and dorsoanterior thalamic nuclei. Differences in the LEA and MEA connections with hippocampal and parahippocampal structures are also described. In addition, because the EC is characterized by bands of intrinsic connectivity that span the LEA and MEA and project to different septotemporal levels of the dentate gyrus, special attention was paid to the efferents and afferents of those bands. Finally, we summarized the connections of the dorsocaudal MEA, the region in which the entorhinal "grid cells" were discovered. The subregional differences in entorhinal connectivity described here provide further evidence for functional diversity within the EC. It is hoped that these findings will inform future studies of the role of the EC in learning and memory.

The parahippocampal region in the rodent brain includes the perirhinal, postrhinal, and entorhinal cortices, the presubiculum, and the parasubiculum. In recent years, the perirhinal and postrhinal cortices have been a focus in memory research because they supply highly processed, polymodal sensory information to the hippocampus, both directly and via the entorhinal cortex. Available evidence indicates that these cortices receive different complements of cortical information, which are then forwarded to the hippocampus via parallel pathways. Here we have summarized the cortical, subcortical, and hippocampal connections of the perirhinal and postrhinal cortices in order to provide further insight into the nature of the information that is processed by these regions prior to arriving in the hippocampus. As has been previously described, the cortical afferents of the rodent postrhinal cortex are dominated by structures known to be involved in the processing of visual and spatial information, whereas the cortical afferents of the perirhinal cortex result in remarkable convergence of polymodal sensory information. The two regions are also differentiated by their cortical efferents. The perirhinal cortex projects more strongly to piriform, frontal, and insular regions, whereas the postrhinal cortex projects preferentially to visual and visuospatial regions. The subcortical connections of the two regions provide further evidence that they have different functions. For example, the perirhinal cortex has strong reciprocal connections with the amygdala, which suggest involvement in processing affective stimuli. Subcortical input to the postrhinal cortex is dominated by projections from dorsal thalamic structures, particularly the lateral posterior nucleus. Although the perirhinal and postrhinal cortices are considered to contribute to the episodic memory system, many questions remain about their particular roles. A detailed description of the anatomical connections of the perirhinal and postrhinal cortices will permit the generation of new, anatomically guided, hypotheses about their role in episodic memory and other cognitive processes.