Nocturnal increase in cerebrospinal fluid secretion as a circadian regulator of intracranial pressure

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.

Circadian Rhythms of the Blood-Brain Barrier and Drug Delivery

“…This may result in higher nighttime intrathecal (CSF) drug delivery when CSF flow is the highest. 143…”

Circadian Mechanisms in Brain Fluid Biology

“…In addition to serving as a fluid cushion, waste sink, and buffer for the brain, CSF plays critical roles in regulating the CNS throughout life, including distributing essential health-and growth-promoting factors. 74 CSF production, 70,75 composition, [76][77][78][79][80][81] and glymphatic clearance/distribution 56,73 change substantially throughout the 24-hour day. As a direct modulator of CSF volume and composition, the choroid plexus has been the subject of growing interest for its important roles in brain development and health.…”

“…For example, CSF production is higher in female mice, 68 but there is no difference in glymphatic function between healthy male and female mice. 69 Similarly, CSF production is increased during the rest phase in humans and during the active phase in rats, 70 while glymphatic function peaks only during the rest phase in humans, 71 rats, 72 and mice. 73 Circadian timing may be a way to compartmentalize these functions.…”

Hypertension: Causes and Consequences of Circadian Rhythms in Blood Pressure

“…269 Surprisingly, both in nocturnal rats and diurnal humans, intracranial pressure and CSF production (due to increased transporter activity in the choroid plexus [CP]) were increased during the dark phase. 270 Because the human data was obtained from patients with various diagnoses of acute brain injury, future studies are needed to verify these findings. CSF may relay diurnal signals within brain and perhaps to the SCN via diffusible molecules including vasopressin and other neuropeptides.…”