REM Sleep Loss and Recovery Regulates Blood-Brain Barrier Function

Abstract

The functions of rapid eye movement (REM) sleep have remained elusive since more than 50 years. Previous reports have identified several independent processes affected by the loss and subsequent recovery of REM sleep (hippocampal neurogenesis, brain stem neuronal cell death, and neurotransmitter content in several brain regions); however, a common underlying mechanism has not been found. We propose that altered brain homeostasis secondary to blood-brain barrier breakdown may explain all those changes induced by REM sleep loss. Therefore, the present report aimed to study the consequences of REM sleep restriction upon blood-brain barrier permeability to Evans blue. REM sleep restriction was induced by the multiple platform technique; male rats were REM sleep restricted 20h daily (with 4h sleep opportunity) during 10 days; control groups included large platform and intact rats. To study blood-brain barrier permeability Evans blue was intracardially administered; stained brains were sliced and photographed for optical density quantification. An independent experiment was carried out to elucidate the mechanism of blood-brain breakdown by transmission electron microscopy. REM sleep restriction increased blood-brain barrier permeability to Evans blue in the whole brain as compared to both control groups. Brief periods of sleep recovery rapidly and effectively restored the severe alteration of blood-brain barrier function by reducing blood-to-brain transfer of Evans blue. The mechanism of blood-brain barrier breakdown involved increased caveolae formation at brain endothelial cells. In conclusion, our data suggest that REM sleep regulates the physical barrier properties of the blood-brain barrier.

A2A Adenosine Receptor Antagonism Reverts the Blood-Brain Barrier Dysfunction Induced by Sleep Restriction

“…Sleep restriction was performed by the multiple platform technique, which abolishes rapid eye movement (REM) sleep and decreases 30% of non-REM sleep, by placing rats over small platforms surrounded by water as previously reported [3]. Rats were kept in the conditions of the multiple platform technique during 20 hours for 10 consecutive days; every day they were allowed to sleep 4 hours in their home-cages during the last 4 hours of the light phase.…”

“…Evans blue administration was performed at the end of the 10 th day of sleep restriction in the control group plus DMSO (Con, n = 3); sleep restriction plus DMSO (SR, n = 3); and sleep restriction plus 0.1mg/kg (x3) of SCH58261 (SR+0.1 n = 3 per group). Evans blue was administrated as previously described [3]; briefly, 0.2mL/100g body weight of Evans blue was administrated in the left heart ventricle. Evans blue circulated during 10 minutes; at the end of that period subjects were perfused with saline solution (0.9%), followed by 4% paraformaldehyde in 0.1 M saline-phosphate buffer (5 minutes each).…”

“…Evans blue extravasation was quantitatively analyzed by measuring mean optical density of cortex, hippocampus, basal nuclei, and cerebellar vermis using ImageJ software. Optical density was quantified using the calibrated optical density step tablet and the Rodbard function provided by ImageJ software [3]. …”

“…In this way, chronic sleep restriction induces blood-brain barrier hyperpermeability to Evans blue and sodium fluorescein, increases pinocytosis, and decreases mRNA expression of tight junction proteins in rodents [3, 4]. Interestingly, after brief sleep opportunity periods of 40 and 120 minutes, the blood-brain barrier permeability to Evans blue in almost all brain regions decreases to basal levels excluding cerebellar vermis [3]. Hence, levels of potential molecules involved in blood-brain barrier disruption during sleep loss may increase during waking and are rapidly cleared during sleep restoration.…”

Adult Neurogenesis: Lessons from Crayfish and the Elephant in the Room

“…Sleep deprivation, for example, also increases BBB permeability [Gomez-Gonzalez et al, 2013;He et al, 2014], but BBB integrity is restored with a normal sleep-wake cycle. Even microbiota in the gut are known to alter BBB permeability [Braniste et al, 2014].…”