Norepinephrine-mediated slow vasomotion drives glymphatic clearance during sleep
Natalie L Hauglund1, Mie Andersen2, Klaudia Tokarska2
1Center for Translational Neuromedicine, University of Copenhagen, 2200 Copenhagen N, Denmark; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK; Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Rigshospitalet, 2600 Glostrup, Denmark.
Abstract:
As the brain transitions from wakefulness to sleep, processing of external information diminishes while restorative processes, such as glymphatic removal of waste products, are activated. Yet, it is not known what drives brain clearance during sleep. We here employed an array of technologies and identified tightly synchronized oscillations in norepinephrine, cerebral blood volume, and cerebrospinal fluid (CSF) as the strongest predictors of glymphatic clearance during NREM sleep. Optogenetic stimulation of the locus coeruleus induced anti-correlated changes in vasomotion and CSF signal. Furthermore, stimulation of arterial oscillations enhanced CSF inflow, demonstrating that vasomotion acts as a pump driving CSF into the brain. On the contrary, the sleep aid zolpidem suppressed norepinephrine oscillations and glymphatic flow, highlighting the critical role of norepinephrine-driven vascular dynamics in brain clearance. Thus, the micro-architectural organization of NREM sleep, driven by norepinephrine fluctuations and vascular dynamics, is a key determinant for glymphatic clearance.
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