Medial entorhinal cortex mediates learning of context-dependent interval timing behavior.

Episodic memory requires encoding the temporal structure of experience and relies on brain circuits in the medial temporal lobe, including the medial entorhinal cortex (MEC). Recent studies have identified MEC 'time cells', which fire at specific moments during interval timing tasks, collectively tiling the entire timing period. It has been hypothesized that MEC time cells could provide temporal information necessary for episodic memories, yet it remains unknown whether they display learning dynamics required for encoding different temporal contexts. To explore this, we developed a new behavioral paradigm requiring mice to distinguish temporal contexts. Combined with methods for cellular resolution calcium imaging, we found that MEC time cells display context-dependent neural activity that emerges with task learning. Through chemogenetic inactivation we found that MEC activity is necessary for learning of context-dependent interval timing behavior. Finally, we found evidence of a common circuit mechanism that could drive sequential activity of both time cells and spatially selective neurons in MEC. Our work suggests that the clock-like firing of MEC time cells can be modulated by learning, allowing the tracking of various temporal structures that emerge through experience.

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

Episodic memory requires encoding the temporal structure of experience and relies on brain circuits in the medial temporal lobe, including the medial entorhinal cortex (MEC). Recent studies have identified MEC 'time cells', which fire at specific moments during interval timing tasks, collectively tiling the entire timing period. It has been hypothesized that MEC time cells could provide temporal information necessary for episodic memories, yet it remains unknown whether MEC time cells display learning dynamics required for encoding different temporal contexts. To explore this, we developed a novel behavioral paradigm that requires distinguishing temporal contexts. Combined with methods for cellular resolution calcium imaging, we find that MEC time cells display context-dependent neural activity that emerges with task learning. Through chemogenetic inactivation we find that MEC activity is necessary for learning of context-dependent interval timing behavior. Finally, we find evidence of a common circuit mechanism that could drive sequential activity of both time cells and spatially selective neurons in MEC. Our work suggests that the clock-like firing of MEC time cells can be modulated by learning, allowing the tracking of various temporal structures that emerge through experience.

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 minutes1,2. 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 epoch6. 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.