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| The brain and spinal cord comprise an isolated environment immersed in cerebrospinal fluid (CSF). Circulation of CSF is important for brain homeostasis, the composition of which varies in circadian fashion, following the body's intrinsic ~24-h clock. Production and resorption of CSF are integral functions of the glympathic pathway that clears brain metabolites from the interstitial fluid. As a consequence of intense neuronal activity during the day, synaptic connections undergo sleep-dependent homeostasis, which also activates a lymphatic-like glial clearance system. Therefore, glympathic clearance is sleep-dependent, not circadian clock-dependent. However, there appear to be sleep-independent clearance mechanisms in the brain, and we discuss our discovery of strong circadian clock activities in the choroid plexus (CP), the organ that produces CSF. The brain has multiple loci that maintain autonomous circadian rhythmicity, but among all brain loci we examined, the most robust rhythmicity resides in the CP. Along with the cerebral arterial pulsation, CSF production likely contributes to the glympathic clearance system. The combined action of sleep-dependent and sleep-independent clearance systems is an interesting new avenue of research for some neurodegenerative disorders such as Alzheimer’s disease (AD), which can be caused by accumulation of amyloid-β. AD is strongly age-dependent, and it also manifests age-dependent desynchrony between the sleep-wake cycle and internal circadian rhythms. We speculate that coordination of sleep and circadian rhythms could be important in maintaining normal brain homeostasis and in reducing the risk of AD. |