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.
Highlights
Drainage of CSF tracer to the mandibular lymph nodes is highest in anesthetized mice during the night, when animal activity will be at its peak
Day/night differences in glymphatic influx, solute clearance, and CSF drainage to the lymph nodes persists under constant light, supporting the hypothesis that these are endogenous circadian oscillations
Circadian glymphatic function is supported by circadian regulation of AQP4 polarization in astrocytes, and genetic deletion of AQP4 effectively eliminates the circadian regulation of CSF distribution detected as an absence of day/night differences both in cortical tracer influx and in drainage of tracer to the lymph node
Summary
We compared the Center of Gravity (CoG), a measure of phase and mesor of the data sets, and found similar results to our 95% confidence intervals above, where anesthetic changed the mesor but each phase estimate was approximately mid-day (Supplementary Fig. 1c–e) These experiments demonstrate that regardless of anesthesia, glymphatic influx of CSF tracer into the brain exhibits diurnal variation with peak influx around mid-day. We found no significant difference of CSF tracer between the day (ZT4–8, n = 7 mice) and night (ZT16–20, n = 9 mice) in total influx, anterior to posterior distribution, or in distinct subregions (Supplementary Fig. 1f–h) This was unsurprising as the awake brain has limited glymphatic function[1]. Mice were implanted with a microdialysis cannula into the striatum 24–36 h a ZT 2
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