Mie Andersen: "Dynamic fluctuations of the locus coeruleus-norepinephrine system underlie sleep state transitions"

PhD student, Nedergaard Lab

Abstract: Regulation between brain states is fundamental for survival. One important player in this, locus coeruleus (LC), is a norepinephrine (NE)-releasing nucleus which activity is closely associated with vigilance state. LC releases NE to cortex where it acts on adrenergic receptors. Astrocytes responds to α1 activation by increasing intracellular Ca2+ levels, and recent evidence suggest this to be an integral part of the LC-NE response. Medial prefrontal cortex (mPFC) receives many LC terminals, and microdialysis studies show that NE levels in mPFC are high during wakefulness and low during sleep. However, due to the temporal limitations of microdialysis, real-time dynamics between LC activity, prefrontal NE, and astrocytic Ca2+ activity are unknown. Therefore, using a new NE biosensor we set out to study said dynamics by combining fiber photometry with EEG recordings during the sleep-wake cycle. We found that LC exhibits phasic firing during NREM sleep, which induces NE oscillations in mPFC that most often do not lead to wakening. Oscillatory NE decreases during NREM correlates with sleep spindles while extended NE declines are associated with transitions to REM sleep. Finally, we show that cortical astrocytes have reduced sensitivity to NE during sleep. Our results suggest that progressive reductions in LC-NE activity and astrocytic Ca2+ is an integral and dynamic part of sleep processes and transitions.