GABAergic inhibition as a dynamic organizer of cortical activity

Abstract

Most studies of cortical function have focused on excitatory neurons and their circuit dynamics, while inhibitory GABAergic dynamics has been examined primarily at the level of local microcircuits. As a result, GABAergic dynamics at the mesoscale and large-scale network level remain poorly understood. To close this gap, mesoscale wide-field imaging employing the genetically encoded GABA sensor iGABASnFR2 was employed to resolve cortical inhibitory dynamics during sensory processing and hippocampal–cortical interactions. During sensory stimulation, GABA release was evoked across multiple modalities, including whisker, forelimb, hindlimb, and visual inputs. Inhibitory responses were spatially specific and localized to the appropriate primary sensory cortices, with stronger activation in the contralateral hemisphere. Inhibitory dynamics appeared to differ with brain state, with quiet wakefulness associated with faster, stronger, and more widespread GABA responses than anesthesia, while the spatial organization of sensory maps was preserved. Increasing extracellular GABA with tiagabine was accompanied by a loss of detectable sensory-evoked GABA responses and changes in largescale cortical connectivity. Examining cortical GABA dynamics around hippocampal sharp-wave ripples (SWRs) revealed large-scale, coordinated inhibitory activation across the cortex. During NREM sleep, GABA activation emerged earlier and propagated from medial to lateral cortical regions, whereas during wakefulness, activation followed the ripple and propagated from lateral to medial cortex. In both states, a global increase in inhibitory tone was observed, but with distinct spatiotemporal organization. The spatial distribution and timing of these components differed between wakefulness and NREM sleep, indicating that hippocampal ripples recruit distinct inhibitory network depending on behavioral state. These results identified cortical GABA signaling as a large-scale network process involved in sensory processing and hippocampal–cortical communication.