Functional Interactions between Entorhinal Cortical Pathways Modulate Theta Activity in the Hippocampus

SIMPLE SUMMARY: The activity in the hippocampus is characterized by a strong oscillation at theta frequency that organizes the neuronal firing. We have recently shown that different theta oscillations are present in the hippocampus, opening the possibility to multiple interactions between theta rhythms. In this work, we analyzed the functional connectivity between theta generators during the exploration of a known environment with or without a novel stimulus. The directionality of the interactions was determined using tools based on Granger causality and transfer entropy. We found significant interactions between activity components originated in CA3 and in layers II and III of the entorhinal cortex. During exploration with a novel stimulus, the connectivity from the entorhinal cortex layer II increased, while the influence of CA3 decreased. These results suggest that the entorhinal cortex layer II may drive theta interactions and synchronization in the hippocampus during novelty exploration. ABSTRACT: Theta oscillations organize neuronal firing in the hippocampus during context exploration and memory formation. Recently, we have shown that multiple theta rhythms coexist in the hippocampus, reflecting the activity in their afferent regions in CA3 (Schaffer collaterals) and the entorhinal cortex layers II (EC-II, perforant pathway) and III (EC-III, temporoammonic pathway). Frequency and phase coupling between theta rhythms were modulated by the behavioral state, with synchronized theta rhythmicity preferentially occurring in tasks involving memory updating. However, information transmission between theta generators was not investigated. Here, we used source separation techniques to disentangle the current generators recorded in the hippocampus of rats exploring a known environment with or without a novel stimulus. We applied analytical tools based on Granger causality and transfer entropy to investigate linear and non-linear directed interactions, respectively, between the theta activities. Exploration in the novelty condition was associated with increased theta power in the generators with EC origin. We found a significant directed interaction from the Schaffer input over the EC-III input in CA1, and a bidirectional interaction between the inputs in the hippocampus originating in the EC, likely reflecting the connection between layers II and III. During novelty exploration, the influence of the EC-II over the EC-III generator increased, while the Schaffer influence decreased. These results associate the increase in hippocampal theta activity and synchrony during novelty exploration with an increase in the directed functional connectivity from EC-II to EC-III.