Spatiotemporally dynamic noradrenergic regulation of cortical networks.

Brain activity and cognition exhibit state-dependent fluctuations that may reflect the influence of neuromodulatory systems, including norepinephrine (NE). Although the activity of noradrenergic neurons is strongly coupled to sleep-wake cycles and pupil dynamics, suggesting a global arousal signal, recent evidence suggests potentially modular partitioning of these cells. In addition, it is unclear whether different neuromodulatory signals exhibit distinct spatiotemporal patterns. We performed simultaneous, dual color mesoscopic imaging of either NE and calcium or NE and acetylcholine (ACh) signals across the neocortex, along with high-density electrophysiology, to investigate the relationship between NE release and neural activity. We find that the pattern of cortical NE signaling varies with behavioral state and is associated with enhanced functional connectivity. Simultaneous imaging of NE and ACh reveals spatiotemporally dynamic coupling between signals. Finally, NE signaling and functional connectivity are disrupted by sleep deprivation. Overall, our findings demonstrate that NE provides a multimodal signal that links transitions in behavioral state to cortical network interactions.