Press Release2021.8.26｜International Institute for Integrative Sleep Medicine (WPI-IIIS)

Brain Refreshing:
Why the Dreaming Phase Matters
Researchers from the University of Tsukuba and Kyoto University find thatcapillary blood flow in the brain, which is important for delivering oxygenand nutrients and removing waste products, is increased in mice during thedream-active phase of sleep
Tsukuba, Japan—Scientists have long wondered why almost all animals
sleep, despite the disadvantages to survival of being unconscious. Now,
researchers led by a team from the University of Tsukuba have found new
evidence of brain refreshing that takes place during a specific phase ofsleep: rapid eye movement (REM) sleep, which is when you tend to dreama lot.
Previous studies have measured differences in blood flow in the brain
between REM sleep, non-REM sleep, and wakefulness using various
methods, with conflicting results. In their latest work, the Tsukuba-led teamused a technique to directly visualize the movement of red blood cells in thebrain capillaries (where nutrients and waste products are exchanged
between brain cells and blood) of mice during awake and asleep states.
"We used a dye to make the brain blood vessels visible under fluorescentlight, using a technique known as two-photon microscopy," says seniorauthor of the study Professor Yu Hayashi. "In this way, we could directly
observe the red blood cells in capillaries of the neocortex in nonanesthetized mice."
The researchers also measured electrical activity in the brain to identify
REM sleep, non-REM sleep, and wakefulness, and looked for differences inblood flow between these phases.
"We were surprised by the results," explains Professor Hayashi. "There wasa massive flow of red blood cells through the brain capillaries during REMsleep, but no difference between non-REM sleep and the awake state,showing that REM sleep is a unique state"
The research team then disrupted the mice's sleep, resulting in "rebound"
REM sleep—a stronger form of REM sleep to compensate for the earlier
disruption. Blood flow in the brain was further increased during reboundREM sleep, suggesting an association between blood flow and REM sleep
strength. However, when the researchers repeated the same experiments
in mice without adenosine A2a receptors (the receptors whose blockade
makes you feel more awake after drinking coffee), there was less of anincrease in blood flow during REM sleep, even during rebound REM sleep.

"These results suggest that adenosine A2a receptors may be responsible forat least some of the changes in blood flow in the brain during REM sleep,"says Professor Hayashi.
Given that reduced blood flow in the brain and decreased REM sleep arecorrelated with the development of Alzheimer's disease, which involves thebuildup of waste products in the brain, it may be interesting to address
whether increased blood flow in the brain capillaries during REM sleep isimportant for waste removal from the brain. This study lays preliminary
groundwork for future investigations into the role of adenosine A2areceptors in this process, which could ultimately lead to the developmentof new treatments for conditions such as Alzheimer's disease.
###This work was supported by the Japan Agency for Medical Research andDevelopment (grant numbers JP19dm0107138, 19gm1110008 [to YuHayashi], and 19lm0203023 [to Michael Lazarus]); the Japan Society for thePromotion of Science (KAKENHI grant numbers JP20H03353, JP20K21456,and JP21F21109); the Ministry of Education, Culture, Sports, Science andTechnology (KAKENHI grant numbers JP21H00199 and JP21H00414, and theWorld Premier International Research Center Initiative); the Japan Scienceand Technology Agency (grant number JPMJPR13AC); The World PremierInternational Research Center Initiative Program; the Cell Science Research
Foundation; the Asahi Glass Foundation; the Astellas Foundation for
Research on Metabolic Disorders; the Daiichi Sankyo Foundation of Life
Science (to Yu Hayashi); and the Japan Foundation for Applied Enzymology(TMFC, to Yu Hayashi and Tsuyoshi Saitoh).
About IIIS
IIIS was launched by the Ministry of Education, Culture, Sports, Science andTechnology of Japan with the aim of building globally visible research
centers with high research standards and excellent research environments
to accommodate globally prominent researchers. IIIS is the world’s premierinstitute aiming to elucidate the fundamental principles of sleep/wakebiology, develop new strategies to diagnose, prevent, and treat sleep
disorders, and contribute to promote human health through research
activities. The research was funded by the Japan Society for the Promotionof Science and the Japan Science and Technology Agency.

Bibliographic information
Tsai CJ, Nagata T, Liu CY, Suganuma T, Kanda T, Miyazaki T, Liu K, Saitoh T, Nagase H,Lazarus M, Vogt KE, Yanagisawa M, and Hayashi Y, , (2021) Cerebral capillary bloodflow upsurge during REM sleep is mediated by A2a receptors.
Cell Reports
doi: 10.1016/j.celrep.2021.109558
Media Contact
Alliance and Communication Unit, International Institute for Integrative Sleep Medicine(WPI-IIIS), University of Tsukuba, Japan
E-mail: wpi-iiis-alliance@ml.cc.tsukuba.ac.jp