The Blood-Brain Barrier

Abstract

Sleep and its disorders are known to affect the functions of essential organs and systems in the body. However, very little is known about how the blood-brain barrier (BBB) is regulated. A few years ago, we launched a project to determine the impact of sleep fragmentation and chronic sleep restriction on BBB functions, including permeability to fluorescent tracers, tight junction protein expression and distribution, glucose and other solute transporter activities, and mediation of cellular mechanisms. Recent publications and relevant literature allow us to summarize here the sleep-BBB interactions in five sections: (1) the structural basis enabling the BBB to serve as a huge regulatory interface; (2) BBB transport and permeation of substances participating in sleep-wake regulation; (3) the circadian rhythm of BBB function; (4) the effect of experimental sleep disruption maneuvers on BBB activities, including regional heterogeneity, possible threshold effect, and reversibility; and (5) implications of sleep disruption-induced BBB dysfunction in neurodegeneration and CNS autoimmune diseases. After reading the review, the general audience should be convinced that the BBB is an important mediating interface for sleep-wake regulation and a crucial relay station of mind-body crosstalk. The pharmaceutical industry should take into consideration that sleep disruption alters the pharmacokinetics of BBB permeation and CNS drug delivery, being attentive to the chrono timing and activation of co-transporters in subjects with sleep disorders.

Endocytosis at the Drosophila blood–brain barrier as a function for sleep

“…We identify the barrier glia as regulators of sleep and propose that endocytic trafficking through the barrier is an important function of the sleep state. The specific differences between mammalian and invertebrate barriers notwithstanding, the identification of the glial/endothelial barrier as a population that can mediate changes in daily sleep aligns with emerging ideas of BBB involvement in behavior ( Hoxha et al, 2013 ; Parkhurst et al, 2018 ) and sleep function ( Pan and Kastin, 2017 ; Verheggen et al, 2018 ), and provides a readily identifiable cellular target to interrogate in other model organisms.…”

Neuroimaging of Cerebral Small Vessel Disease and Age-Related Cognitive Changes

“…The BBB is a dynamic interface between the cerebral circulation and the central nervous system that limits and regulates the movement of cells and molecules between these two spaces via an interdependent network of cells and cell structures (Sandoval and Witt, 2008). An intact BBB generally acts to protect the brain; however, facilitated permeability of the BBB also plays an important role in healthy brain physiology, such as during sleep that controls the opening of the BBB (Pan and Kastin, 2017).…”

Brain Mechanisms of COVID-19-Sleep Disorders

“…However, there is emerging evidence that the major complication of sleep loss is neuroinflammation, which induces BBB disruption (Table 1). Indeed, sleep loss per se, including sleep deprivation, sleep restriction, sleep fragmentation, or sleep apnea in human and rodents induces a systemic low-grade inflammation characterized by the release of several molecules, such as cytokines, chemokines, and acute-phase proteins; all of them can promote changes in cellular components of the BBB, particularly on brain endothelial cells [35][36][37][38][39][40][41][42][43][44][45][46]. In this session, we discuss the role of inflammatory mediators that increase during sleep loss and how these changes may alter the BBB permeability as well as we analyze hypothetical mechanisms by which sleep deprivation may induce the BBB disruption, emphasizing the regulatory effect of inflammatory molecules on tight junction proteins.…”

“…Recently, it has been discovered that sleep deprivation increases the BBB permeability to inflammatory mediators, immune cells, and exogenous tracers in humans and rodents [35,36,38,39,[41][42][43]45,50,[54][55][56]. Chronic sleep restriction diminished endothelial and inducible nitric oxide synthase, endothelin1, and glucose transporter expression in cerebral microvessels of BBB and decreased 2-deoxy-glucose uptake by the brain.…”

“…Pan W. and Kastin A.J. (2017) [36]. Review Hurtado-Alvarado et al observed that sleep restricted C57BL/6 mice exhibited an increase in the BBB permeability to Na-fluorescein, 10 kDa dextrans, and Evans blue in comparison to the same strain control groups.…”