The Role of Feedforward and Feedback Inhibition in Modulating Theta-Gamma Cross-Frequency Interactions

Interactions among oscillatory 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. In this computational study, we demonstrate that the connectivity structure of common neural motifs crucially determines interaction directionality. Specifically, we found that feedforward inhibition modeled by a theta-modulated ING (Interneuron Network Gamma) mechanism induces fast-to-slow interactions, while feedback inhibition through a 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 modulated by synaptic strength within realistic ranges, with the feedforward recruitment of inhibitory basket cells playing a critical role in directionality. Finally, we report that each theta-gamma interaction scheme, determined by the balance between feedforward and feedback inhibition, prioritizes 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.