Circadian control of brain glymphatic and lymphatic fluid flow

Nature Communications volume 11, Article number: 4411 (2020) Cite this article

Abstract

The glymphatic system is a network of perivascular spaces that promotes movement of cerebrospinal fluid (CSF) into the brain and clearance of metabolic waste. This fluid transport system is supported by the water channel aquaporin-4 (AQP4) localized to vascular endfeet of astrocytes. The glymphatic system is more effective during sleep, but whether sleep timing promotes glymphatic function remains unknown. We here show glymphatic influx and clearance exhibit endogenous, circadian rhythms peaking during the mid-rest phase of mice. Drainage of CSF from the cisterna magna to the lymph nodes exhibits daily variation opposite to glymphatic influx, suggesting distribution of CSF throughout the animal depends on time-of-day. The perivascular polarization of AQP4 is highest during the rest phase and loss of AQP4 eliminates the day-night difference in both glymphatic influx and drainage to the lymph nodes. We conclude that CSF distribution is under circadian control and that AQP4 supports this rhythm.

Introduction

Sleep is an evolutionarily conserved biological function, clearing the brain of harmful metabolites such as amyloid beta that build up during wakefulness1 and consolidating memory2. Acute sleep deprivation impairs cognitive function3,4, and sleep disruption is often an early correlate of neurodegenerative disease5. Sleep quality is highly dependent on both sleep deficit and sleep timing controlled by circadian rhythms, 24 hour cycles in gene transcription, cell signaling, physiology, and behavior6. Understanding how circadian rhythms contribute to sleep quality is necessary to promote long-term brain health.

During sleep, there is increased cerebrospinal fluid (CSF) movement into the glymphatic system, promoting waste clearance1. The glymphatic system is a network of perivascular tunnels wrapped by astrocyte endfeet7. The localization of the water channel aquaporin-4 (AQP4) to astrocyte vascular endfeet promotes CSF movement through the brain8. This fluid movement is also dependent upon arterial pulsation9,10, and correlated to decreased heart rate11. Although the cardiovascular system and sleep, two main influencers of the glymphatic system, are tightly regulated by circadian rhythms12, it remains unknown whether glymphatic fluid movement is under circadian control.

CSF moves not only into the brain and spinal cord via the glymphatic system, but also drains out of the central nervous system to the lymphatic system of the body13,14. In fact, lymphatic drainage may prevail when the animals are awake and glymphatic influx is low15. The immune system is also regulated by circadian rhythms16,17, yet whether lymphatic drainage of CSF to the lymph nodes is under clock control has to be determined.

Here, we test the hypothesis that glymphatic influx of CSF tracer from the cisterna magna (CM) into the brain, and clearance of solute from the brain varies across the day independent of arousal state. We also test whether AQP4 may have a role in rhythmic glymphatic function. We show that glymphatic influx and clearance of a small tracer from the parenchyma is increased during the day compared with night in mice independent of the type of anesthesia or light/dark cycle, corresponding to day/night changes in AQP4 localization. These rhythms in influx, clearance, and AQP4 persist after 10 days in constant light, indicating that the glymphatic system is under circadian control. AQP4 knockout (AQP4 KO) animals exhibit no day/night difference in glymphatic influx. In fully anesthetized animals, in vivo imaging of mandibular lymph nodes showed increased tracer outflow during the night compared with day, when entry of CSF to the brain is low. This day/night difference in lymph node filling persists in constant conditions, and is absent in animals without AQP4.

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About S. R. Zelenz 67 Articles
S.R. Zelenz has worked in education for 20 years. Working with students from all walks of life, cultures, races, and social diversity, Zelenz’s research in Educational Leadership led to finding a better way to approach learning for students with trauma histories. Many were juvenile offenders, gang members, diagnosed with varying behavioral disorders, or had family histories of violence, murder, or narcissistic parenting. This research could not be effectively accomplished without further understanding: how epigenetic trauma inheritance may be impacting these students; how brain development from trauma may be impacting their behavioral and emotional development; as well as deep understanding of psychology and its varying classifications for behavioral and personality disorders. The goal is to find solutions for changing the conversation and making a real difference for these students. She has also worked with nonprofits of varying focus areas for the last 25 years. Her undergraduate degree in Arts Administration and Music prepared her for managing nonprofits of any size as well as procuring funding so that they can achieve their goals. Pairing her nonprofit background with her education background, she has been able to make a difference for over 200 nonprofits worldwide, written curriculum for schools across the globe, and assisted many arts organizations through performance and management.