Available online 17 May 2024

Author links open overlay panel, Abstract

As the central regulatory system of an organism, the brain is responsible for overseeing a wide variety of physiological processes essential for an organism’s survival. To maintain the environment necessary for neurons to function, the brain requires highly selective uptake and elimination of specific molecules through the blood-brain barrier (BBB). As an organism’s activities vary throughout the day, how does the BBB adapt to meet the changing needs of the brain? A mechanism is through temporal regulation of BBB permeability via its circadian clock, which will be the focal point of this chapter. To comprehend the circadian clock’s role within the BBB, we will first examine the anatomy of the BBB and the transport mechanisms enabling it to fulfill its role as a restrictive barrier. Next, we will define the circadian clock, and the discussion will encompass an introduction to circadian rhythms, the Transcription-Translation Feedback Loop (TTFL) as the mechanistic basis of circadian timekeeping, and the organization of tissue clocks found in organisms. Then, we will cover the role of the circadian rhythms in regulating the cellular mechanisms and functions of the BBB. We discuss the implications of this regulation in influencing sleep behavior, the progression of neurodegenerative diseases, and finally drug delivery for treatment of neurological diseases.

Section snippetsBlood-brain barrier (BBB)

In this section, we will discuss our current knowledge of the blood-brain barrier structure and function in mammals and Drosophila. Maintaining a stable and controlled environment within the brain is crucial, given the high sensitivity and susceptibility of the central nervous system (CNS) to damage. While the brain needs to maintain a selective barrier against harmful agents (xenobiotics, pathogens, overactive immune cells), it also requires abundant nutrients and oxygen to sustain its high

Circadian clock

Have you ever wondered how a rooster anticipates the sun by crowing before sunrise? Chronobiology, the study of biological rhythms, provides insights into this question. This ability to anticipate the environment is due to an organism’s daily internal biological oscillation, known as its circadian rhythm. “Circadian” comes from the Latin words “circa” meaning around and “dies” meaning day. Circadian rhythms are ubiquitous: nearly all organisms, ranging from single-celled cyanobacteria to

Temporal regulation of the BBB

The BBB cells possess a circadian clock that is regulated by the TTFL to control barrier maintenance and transportation functions. In this section, we will discuss how the circadian clock in the BBB regulates barrier function by influencing changes in transporter and enzyme activity. Then, we will examine the crosstalk between BBB transport and sleep. Lastly, we will delve into neurodegenerative diseases impacted by a dysregulated circadian clock and disrupted BBB.

Chronotherapy

Chronotherapy refers to the leveraging of our knowledge of biological rhythms to enhance treatment of disease. It has long been recognized that the timing of treatments yields different outcomes. With a deeper understanding of the molecular origins of biological rhythms, we can make improvements to many treatment paradigms. Three approaches to chronotherapy have emerged: training the clock with zeitgebers, synchronizing drug administration with the clock’s rhythm (Clocking the drug), and

Conclusion

This chapter explores the complex interplay between the circadian clock and the blood-brain barrier (BBB), offering intriguing insights into neurovasculature dynamics. Our aim is that this perspective opens new avenues for therapeutic interventions, in particular chronotherapies that can exploit the knowledge of BBB rhythms to deliver drugs to the brain. While the current data provides a profound appreciation for the rhythmic orchestration of the blood-brain barrier, it also highlights pressing

Acknowledgments

This was supported by the National Institutes of Health, National Heart, Lung, and Blood Institute grant number R00HL147121 and diversity supplement.

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