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 could 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 catalog 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 RNA-seq and in the CSF metabolomics with ultraperformance liquid chromatography combined with mass spectrometry. We detected significant fluctuation of 19 CSF metabolites and differential expression of 2,778 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 toward 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.
ABSTRACT
BACKGROUND: It is crucial to maintain the intracranial pressure (ICP) within the physiological range to ensure proper brain function. The ICP may fluctuate during the light-dark phase cycle, complicating diagnosis and treatment choice in patients with pressure-related disorders. Such ICP fluctuations may originate in circadian or sleep-wake cycle-mediated modulation of cerebrospinal fluid (CSF) flow dynamics, which in addition could support diurnal regulation of brain waste clearance. METHODS: ICP was monitored continuously in patients who underwent placement of an external ventricular drain (EVD) and by telemetric monitoring in experimental rats. CSF was collected via the EVD in patients and the rodent CSF secretion rate determined by in vivo experimentation. Rodent choroid plexus transporter transcripts were quantified with RNAseq and transport activity with ex vivo isotope transport assays. RESULTS: We demonstrated that ICP increases by 30% in the dark phase in both species, independently of vascular parameters. This increase aligns with elevated CSF collection in patients (12%) and CSF production rate in rats (20%), the latter obtained with the ventriculo-cisternal perfusion assay. The dark-phase increase in CSF secretion in rats was, in part, assigned to increased transport activity of the choroid plexus Na+,K+,2Cl- cotransporter (NKCC1), which is implicated in CSF secretion by this tissue. CONCLUSION: CSF secretion, and thus ICP, increases in the dark phase in humans and rats, irrespective of their diurnal/nocturnal activity preference, in part due to altered choroid plexus transport activity in the rat. Our findings suggest that CSF dynamics are modulated by the circadian rhythm, rather than merely sleep itself.