Title: Sleep loss, adrenergic inhibition, cognitive performance and cerebral water diffusion in humans

Postdoc Fellow: Sebastian Holst, NRU

Abstract:

Sufficient sleep is a key determinant of health, and sleep loss is associated with severe health risks. Nevertheless the underlying biological and molecular mechanisms of sleep-wake regulation remain only poorly understood. Recently, a novel molecular function of sleep was described in rodents. The ‘glymphatic system’ is a sleep dependent macroscopic pathway in the central nervous system, which facilitates the clearance of interstitial waste products. So far however, it remains to be described whether this sleep dependent clearance of neurotoxic waste products may explain why all species, including humans, spend a large fraction of their lives sleeping, and whether the glymphatic pathway is linked to the cognitive impairments associated with sleep loss. Moreover, manipulation of glymphatic clearance is of considerable interest, as it may define entirely new approaches for enhancing sleep quality and reduce or delay our need for sleep.

Here, we propose for the first time, to investigate the glymphatic system in humans in vivo. Specifically, we will measure cerebral water diffusion with magnetic resonance (MR) diffusion weighted imaging (DWI) in the human brain across the sleep wake cycle. By comparing DWI between wakefulness and sleep, we will be able to establish if, and to what extent, the glymphatic system operates in the sleeping human brain. Moreover, the level of water diffusion may predict cognitive performance measures, which we will assess immediately before and after imaging sessions. Secondly, we propose to interfere with the glymphatic system by administering adrenergic antagonist in a placebo controlled crossover manner. Such antagonists have previously been shown to enhance glymphatic clearance, which will allow us to test if increased glymphatic activity, measured with DWI, can improve sleep-intensity and cognitive functions.

Taken together, this study will provide the first evidence for a sleep dependent human glymphatic system.