Direct Entorhinal Control of CA1 Temporal Coding

During behavior, hippocampal neurons fire in consistent theta sequences, organized by the theta rhythm, which have been linked to predictive coding of future actions. The mechanisms of sequence generation are yet unclear, but in the hippocampal CA1 subfield, are thought to involve both major input streams into CA1 neurons, from CA3 pyramidal neurons and directly from entorhinal cortex. We disentangled the role of these two afferent input with highly specific optogenetic inhibition limited to the direct entorhinal afferents of CA1, thereby leaving the rest of the hippocampal-entorhinal circuit intact. While CA1 spatial firing properties were largely unaffected, theta phase precession was largely abolished. Surprisingly, while theta phase precession is thought to generate theta sequences, theta sequences were actually strengthened when it was suppressed. These results suggest that sequence generation is internal to the hippocampus, while the entorhinal inputs may act as a supervisory signal driving learning and representational updates.