The Role of Feedforward and Feedback Inhibition in Modulating Theta-Gamma Cross-Frequency Interactions
Authors: Chalkiadakis Dimitrios , Sánchez-Claros Jaime , López-Madrona Víctor J , Canals Santiago , Mirasso Claudio R. 
Published: January 2025

AbstractInteractions 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 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, andvice 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.Author SummaryThis study investigates the interaction between various types of brain oscillations and their potential relationship with the connectivity of underlying neural networks. Brain activity encompasses slow oscillations, such as theta, alpha, and delta, as well as faster oscillations, including gamma. These oscillations interact through Cross-Frequency Coupling (CFC), a mechanism essential for cognitive processes like memory, learning, and attention. Given the higher spectral power and broader spatial propagation of slow oscillations, it has been proposed that CFC arises when slow oscillations modulate faster activity. However, recent evidence suggests that gamma oscillations can also predict the phase of slower oscillations, indicating a bidirectional and more intricate relationship. To explore this complexity, we developed a computational model that reproduces both forms of interaction observed experimentally. Our results demonstrate that while slow oscillations originating from distant regions can induce gamma activity, local connectivity and specific cell-type dynamics allow gamma oscillations to anticipate slow oscillations in certain conditions. The balance of inhibitory circuits modulates fast-slow oscillation interactions, creating distinct dynamical modes with varying computational properties and enhancing system flexibility. This work integrates competing hypotheses on oscillation interactions and offers a conceptual framework for linking these dynamics to the structural organization of neural circuits.