Summary We normally regard sleep and wake as two distinct opposing brain states, where sleep requires silence of wake-promoting structures such as the locus coeruleus (LC)-norepinephrine (NE) system. We set out to investigate how cortical NE dynamics and NE-related astrocytic activity relates to LC population activity during sleep states. We show that LC displays regular phasic activity bouts during NREM sleep leading to a slow oscillatory pattern of prefrontal NE levels of which the majority of NE increases does not lead to awakening. NE troughs link to sleep spindles and continued NE decline transitions into REM sleep. Last, we show that prefrontal astrocytes have reduced sensitivity towards NE during sleep. Our results suggest that dynamic changes in the activity of wake-promoting systems during sleep create alternation between crucial sleep processes and broadening of sensitivity towards incoming sensory input. Highlights Extracellular levels of norepinephrine display dynamic changes during NREM and REM sleep Phasic activity of locus coeruleus neurons during NREM underlies slow norepinephrine oscillations Spindles occur at norepinephrine troughs and are abolished by norepinephrine increases Increased spindles prior to REM reflect the beginning of a long-lasting norepinephrine decline REM episodes are characterized by a sub-threshold continuous norepinephrine decline The responsiveness of astrocytic Ca 2+ to norepinephrine is reduced during sleep

Dynamic fluctuations of the locus coeruleus-norepinephrine system underlie sleep state transitions