Regulation of the Blood–Brain Barrier by Circadian Rhythms and Sleep

Abstract

The blood-brain barrier (BBB) is an evolutionarily conserved, structural, and functional separation between circulating blood and the central nervous system (CNS). By controlling permeability into and out of the nervous system, the BBB has a critical role in the precise regulation of neural processes. Here, we review recent studies demonstrating that permeability at the BBB is dynamically controlled by circadian rhythms and sleep. An endogenous circadian rhythm in the BBB controls transporter function, regulating permeability across the BBB. In addition, sleep promotes the clearance of metabolites along the BBB, as well as endocytosis across the BBB. Finally, we highlight the implications of this regulation for diseases, including epilepsy. The Blood-Brain Barrier Is a Dynamic StructureA growing body of evidence demonstrates that the blood-brain barrier (BBB) is not a static structure, but instead is a site of active regulation. As a cellular structure that separates circulatory fluids (e.g., blood and hemolymph) from the brain, the BBB imposes strict regulation on molecules moving into and out of the central nervous system (CNS). Here, we focus on recent studies demonstrating that both circadian rhythms and sleep regulate the movement of molecules across and along the BBB.Circadian rhythms are biological processes that endogenously oscillate with a period of~24 h. This rhythm is driven by a molecular clock and can be synchronized with, but is not reliant upon, external cues (e.g., light, temperature, and feeding patterns). While the central circadian pacemaker is in the brain (e.g., the suprachiasmatic nucleus in mammals), other cells, including the cells of the BBB [1,2], have autonomous circadian rhythms driven by molecular clocks [3]. In addition, the large arteries that perfuse the brain in mammals themselves contain endogenous circadian clocks [4,5]. Critical studies originating in Drosophila melanogaster and then extended to mammals revealed that molecular clocks comprise transcriptional feedback loops. The core of this auto-regulatory loop in Drosophila involves the proteins Period (PER) and Timeless (TIM) inhibiting their own transcription at a specific time of day by acting on the transcriptional activators Clock (CLK) and Cycle (CYC) [6]. HighlightsRecent evidence from fly models reveals an endogenous circadian rhythm at the BBB. This rhythm controls function of the permeability-glycoprotein multidrug transporter, which actively pumps both endogenous and exogenous molecules out of the CNS. Function of this transporter is decreased at night, increasing permeability to multiple substrates into the brain overnight.Endocytosis is a newly appreciated important function for sleep. Endocytosis across the BBB is increased during sleep and, when inhibited, increases the need for sleep.Sleep also promotes the clearance of metabolites out of the brain along paravascular spaces. During sleep, the interstitial spaces of the brain are larger, allowing for more robust movement of metabolites from interstitial spaces ...

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