Medial entorhinal cortex plays a specialized role in learning of flexible, context-dependent interval timing behavior

In order to survive and adapt in a dynamic environment, animals must perceive and remember the temporal structure of events and actions across a wide range of timescales, including so-called interval timing on the scale of seconds to minutes(1,2). Episodic memory (i.e. the ability to remember specific, personal events that occur in spatial and temporal context) requires accurate temporal processing and is known to require neural circuits in the medial temporal lobe (MTL), including medial entorhinal cortex (MEC)(3-5). Recently, it has been discovered that neurons in MEC termed time cells, fire regularly at brief moments as animals engage in interval timing behavior, and as a population, display sequential neural activity that tiles the entire timed epoch(6). It has been hypothesized that MEC time cell activity could provide temporal information necessary for episodic memories, yet it remains unknown whether the neural dynamics of MEC time cells display a critical feature necessary for encoding experience. That is, whether MEC time cells display context-dependent activity. To address this question, we developed a novel behavioral paradigm that requires learning complex temporal contingencies. Applying this novel interval timing task in mice, in concert with methods for manipulating neural activity and methods for large-scale cellular resolution neurophysiological recording, we have uncovered a specific role for MEC in flexible, context-dependent learning of interval timing behavior. Further, we find evidence for a common circuit mechanism that could drive both sequential activity of time cells and spatially selective neurons in MEC.