The encoding of time and its binding to events are crucial for episodic memory, but how these processes are carried out in hippocampal-entorhinal circuits is unclear. Here we show in freely foraging rats that temporal information is robustly encoded across time scales from seconds to hours within the overall population state of the lateral entorhinal cortex. Similarly pronounced encoding of time was not present in the medial entorhinal cortex or in hippocampal areas CA3-CA1. When animals' experiences were constrained by behavioural tasks to become similar across repeated trials, the encoding of temporal flow across trials was reduced, whereas the encoding of time relative to the start of trials was improved. The findings suggest that populations of lateral entorhinal cortex neurons represent time inherently through the encoding of experience. This representation of episodic time may be integrated with spatial inputs from the medial entorhinal cortex in the hippocampus, allowing the hippocampus to store a unified representation of what, where and when.

To determine whether entorhinal spatial representations are continuous or fragmented, we recorded neural activity in grid cells while rats ran through a stack of interconnected, zig-zagged compartments of equal shape and orientation (a hairpin maze). The distribution of spatial firing fields was markedly similar across all compartments in which running occurred in the same direction, implying that the grid representation was fragmented into repeating submaps. Activity at neighboring positions was least correlated at the transitions between different arms, indicating that the map split regularly at the turning points. We saw similar discontinuities among place cells in the hippocampus. No fragmentation was observed when the rats followed similar trajectories in the absence of internal walls, implying that stereotypic behavior alone cannot explain the compartmentalization. These results indicate that spatial environments are represented in entorhinal cortex and hippocampus as a mosaic of discrete submaps that correspond to the geometric structure of the space.

A growing body of evidence suggests that memories are stored in the hippocampus by integrating spatial information from specialized cell types in the medial entorhinal cortex (MEC) with nonspatial information from cells in the lateral entorhinal cortex (LEC). LEC neurons show little spatial modulation when rats run in empty open-field environments but fire in the vicinity of discrete objects, suggesting that they provide information about the specific content of the spatial environment. It is unclear, however, whether firing at objects is elicited purely by stimulus properties, in a sensory-like manner, or whether any higher-order property, such as the history of experience, is also relevant. To address this question, we recorded from LEC neurons in an open field where objects were present on a subset of the trials. Whereas some neurons fired at the objects, other cells developed specific firing at places where objects had been located on previous trials, providing a readout of past experience in the environment. The latter cells generally did not respond to the object when it was present, suggesting that object cells and object-trace cells are independent cell classes. These findings identify LEC as a component of the hippocampal-cortical circuit for object-place memory.

We used a combined optogenetic-electrophysiological strategy to determine the functional identity of entorhinal cells with output to the place-cell population in the hippocampus. Channelrhodopsin-2 (ChR2) was expressed selectively in the hippocampus-targeting subset of entorhinal projection neurons by infusing retrogradely transportable ChR2-coding recombinant adeno-associated virus in the hippocampus. Virally transduced ChR2-expressing cells were identified in medial entorhinal cortex as cells that fired at fixed minimal latencies in response to local flashes of light. A large number of responsive cells were grid cells, but short-latency firing was also induced in border cells and head-direction cells, as well as cells with irregular or nonspatial firing correlates, which suggests that place fields may be generated by convergence of signals from a broad spectrum of entorhinal functional cell types.

In the hippocampus, spatial and non-spatial parameters may be represented by a dual coding scheme, in which coordinates in space are expressed by the collective firing locations of place cells and the diversity of experience at these locations is encoded by orthogonal variations in firing rates. Although the spatial signal may reflect input from medial entorhinal cortex, the sources of the variations in firing rate have not been identified. We found that rate variations in rat CA3 place cells depended on inputs from the lateral entorhinal cortex (LEC). Hippocampal rate remapping, induced by changing the shape or the color configuration of the environment, was impaired by lesions in those parts of the ipsilateral LEC that provided the densest input to the hippocampal recording position. Rate remapping was not observed in LEC itself. The findings suggest that LEC inputs are important for efficient rate coding in the hippocampus.