The role of feedforward and feedback inhibition in modulating theta-gamma cross-frequency interactions in neural circuits

Interactions among brain rhythms play a crucial role in organizing neuronal firing sequences during specific cognitive functions. In memory formation, the coupling between the phase of the theta rhythm and the amplitude of gamma oscillations has been extensively studied in the hippocampus. Prevailing perspectives suggest that the phase of the slower oscillation modulates the fast activity. However, recent metrics, such as Cross-Frequency Directionality (CFD), indicate that these electrophysiological interactions can be bidirectional. Using a computational model, we demonstrate that feedforward inhibition modeled by a theta-modulated ING (Interneuron Network Gamma) mechanism induces fast-to-slow interactions, while feedback inhibition through a theta-modulated PING (Pyramidal Interneuron Network Gamma) model drives slow-to-fast interactions. Importantly, in circuits combining both feedforward and feedback motifs, as commonly found experimentally, directionality is flexibly modulated by synaptic strength within biologically realistic ranges. A signature of this interaction is that fast-to-slow dominance in feedforward motifs is associated with gamma oscillations of higher frequency, and vice versa. Using previously acquired electrophysiological data from the hippocampus of rats freely navigating in a familiar environment or in a novel one, we show that CFD is dynamically regulated and linked to the frequency of the gamma band, as predicted by the model. Finally, the model attributes each theta-gamma interaction scheme, determined by the balance between feedforward and feedback inhibition, to distinct modes of information transmission and integration, adding computational flexibility. Our results offer a plausible neurobiological interpretation for cross-frequency directionality measurements associated with the activation of different underlying motifs that serve distinct computational needs.