Tonic and burst-like locus coeruleus stimulation distinctly shift network activity across the cortical hierarchy

Abstract Noradrenaline (NA) release from the locus coeruleus (LC) changes activity and connectivity in neuronal networks across the brain, modulating multiple behavioral states. NA release is mediated by both tonic and burst-like LC activity. However, it is unknown whether the functional changes in target areas depend on these firing patterns. Using optogenetics, photometry, electrophysiology and functional magnetic resonance imaging in mice, we show that tonic and burst-like LC firing patterns elicit brain responses that hinge on their distinct NA release dynamics. During moderate tonic LC activation, NA release engages regions associated with associative processing, while burst-like stimulation biases the brain toward sensory processing. These activation patterns locally couple with increased astrocytic and inhibitory activity and change the brain’s topological configuration in line with the hierarchical organization of the cerebral cortex. Together, these findings reveal how the LC–NA system achieves a nuanced regulation of global circuit operations.