Different theta frameworks coexist in the hippocampus and are coordinated during memory-guided exploration and novelty detection

Hippocampal firing is organized in theta sequences controlled by internal memory-related processing and by external sensory cues. How these computations are segregated or integrated, depending on the cognitive needs, is not fully understood. Although theta activity in the hippocampus is most commonly studied as a unique coherent oscillation, it is the result of a complex interaction between different rhythm generators. Here we investigated the coordination between theta generators as a possible mechanism to couple or decouple internally and externally driven computations. We separated and quantified three different theta current generators from the hippocampus of freely behaving rats, one originating in CA3 with current sinks in CA1 str. radiatum and two with current sinks in CA1 str. lacunosum-moleculare and dentate molecular layer, mainly driven by entorhinal cortex (EC) layers 3 and 2, respectively. These theta generators followed non fully coherent dynamics and presented epochs of higher and lower phase coupling, suggesting a flexible interaction between them. Selective optogenetic inhibition in CA3 depressed the str. radiatum generator without affecting the EC-driven theta oscillations, indicating that theta rhythm generators can be modulated independently. In addition, band-specific gamma interactions with theta oscillations selectively occurred with the corresponding pathway-specific theta current generator, supporting the existence of different theta-gamma coding frameworks to organize neuronal firing in the hippocampus. Importantly, we found that epochs of highly synchronized theta rhythmicity across generators preferentially occurred during memory-guided exploration and mismatch novelty detection in familiar environments, two conditions in which internally generated memory representations need to be coordinated with the incoming sensory information about external cues. We propose a mechanism for segregating and integrating hippocampal computations based on the coexistence of different theta-gamma frameworks that flexibly couple or decouple accommodating the cognitive needs.