Day–night fluctuations in choroid plexus transcriptomics and cerebrospinal fluid metabolomics

Abstract

The cerebrospinal fluid (CSF) provides mechanical protection for the brain and serves as a brain dispersion route for nutrients, hormones, and metabolic waste. The CSF secretion rate is elevated in the dark phase in both humans and rats, which may support the CSF flow along the paravascular spaces that may be implicated in waste clearance. The similar diurnal CSF dynamics pattern observed in the day-active human and the nocturnal rat suggests a circadian regulation of this physiological variable, rather than sleep itself. To obtain a catalogue of potential molecular drivers that could provide the day-night-associated modulation of the CSF secretion rate, we determined the diurnal fluctuation in the rat choroid plexus transcriptomic profile with RNAseq and in the CSF metabolomics with ultra-performance liquid chromatography combined with mass spectrometry. We detected significant fluctuation of 19 CSF metabolites and differential expression of 2778 choroid plexus genes between the light and the dark phase, the latter of which encompassed circadian rhythm-related genes and several choroid plexus transport mechanisms. The fluctuating components were organized with joint pathway analysis, of which several pathways demonstrated diurnal regulation. Our results illustrate substantial transcriptional and metabolic light-dark phase-mediated changes taking place in the rat choroid plexus and its encircling CSF. The combined data provide directions towards future identification of the molecular pathways governing the fluctuation of this physiological process and could potentially be harnessed to modulate the CSF dynamics in pathology.

The circadian clock in the choroid plexus drives rhythms in multiple cellular processes under the control of the suprachiasmatic nucleus

“…Although Cry1 has recently been shown to be arrhythmic in the rat hippocampus [ 73 ], to our knowledge, ChP is the only tissue with a robust clock and arrhythmic Cry1 expression. Nevertheless, the presence of possible diurnal variation cannot be ruled out, as a recent publication comparing the rat ChP transcriptome between one daytime and one nighttime time point found differential expression [ 74 ].…”

Breakthroughs in choroid plexus and CSF biology from the first European Choroid plexus Scientific Forum (ECSF)

“…For example, this plasticity is reflected in CSF adaptation during various physiological states and its influence on the regulation of neural stem cells [ 41 ]. CSF secretion and composition exhibits variations during day and night [ 8 , 43 ].The ChP is instrumental in this regulation, functioning as a circadian gatekeeper that modulates CSF composition in response to circadian rhythms [ 9 , 26 , 34 ]. It is therefore important to better understand how the ChP regulate CSF composition and how these processes could go wrong in certain diseases.…”