A single research study can have the potential to change the future significantly. Across the globe, countless studies hold untapped potential and promise. With a mission of “Advancing the world through the power of science,” the Stellar Science Foundation (SS-F) seeks to pursue the essence of scientific research and elevate its impact to new heights.
In the series “Invent Innovation,” we focus on groundbreaking research through interviews with scientists who are inventing the knowledge that serves as a key to driving global innovation. We delve into the background and processes of creating transformative insights, exploring the possibilities and influence that the research itself holds.
For the first installment of this series, we interviewed Dr. Yu Hayashi, who conducts research on the theme of “sleep.” In September 2024, Dr. Hayashi published a groundbreaking study in the journal Cell, reporting the discovery of the nerve cells that govern human REM sleep. This research has attracted significant attention as it holds the potential to aid in the prevention and treatment of intractable diseases such as Parkinson’s disease.
After more than a decade of studying the question, “Why do we sleep?” Dr. Hayashi reflects, “I finally discovered the ‘switch’ for REM sleep.” How might his research transform the future?
Why Do We Sleep?—Confronting the Great Mystery of Sleep
Can you tell us about your research?
In simple terms, my research theme is “sleep,” with a particular focus on understanding its roles and purposes.
There are still many mysteries about sleep that remain unsolved. One of the biggest mysteries is “why we feel sleepy.” What is the nature of sleepiness, and where does the unique sensation of “feeling sleepy” come from? The exact cause and origin of this feeling remain unclear.
Another significant mystery is the “purpose of sleep.” For instance, it is known that some animal species cannot survive without sleep. However, we still do not understand why lack of sleep leads to death.
Sleep is an integral part of our lives, yet it seems that its fundamental mechanisms and purposes remain largely unknown.
Exactly. My research aims to unravel these mysteries and uncover the true meaning and roles of sleep.
In recent years, I’ve been particularly focused on understanding the “purpose of REM sleep.”
Sleep is broadly categorized into two types: REM sleep and non-REM sleep. While this classification has been well known for some time, the specific roles of each type of sleep remain ambiguous. I believe that clarifying the roles of REM and non-REM sleep will also help answer the broader mysteries of sleep.
Figure: Copyright Prof. Yu Hayashi (Translated by SS-F)
What exactly is REM sleep?
The hallmark of REM sleep is, simply put, “vivid dreaming.”
REM sleep was first reported in 1953 when researchers observed rapid eye movements beneath the closed eyelids of sleeping individuals. For example, if you watch a sleeping child’s eyes, you’ll notice periods of slow movement and others of rapid, intense movement. The latter is what we refer to as REM sleep. During this phase, breathing and heart rate also increase. This phenomenon is why it’s named “Rapid Eye Movement (REM) sleep.”
If someone is woken during this phase, nearly 100% of them report, “I was dreaming.” This phenomenon was first documented in a 1953 paper.
About five years later, similar states were observed in cats during sleep studies. These studies showed that the brain waves resembled those seen in wakefulness, but muscle contractions, as measured by electromyography, were notably weak. Observing this paradoxical activity, researchers in Europe coined the term “paradoxical sleep.” To this day, American researchers typically use the term “REM sleep,” while European researchers often refer to it as “paradoxical sleep.”
In simple terms, can we say that REM sleep is a state where the brain is awake but the body is inactive?
That’s correct. Of course, “awake” doesn’t mean the brain functions exactly as it does during wakefulness. However, in terms of brain waves alone, REM sleep is quite similar to being awake.
At the same time, the body’s muscles are completely relaxed, similar to the state experienced during “sleep paralysis.” This ensures that the body doesn’t act out dreams, allowing us to sleep safely.
After More Than a Decade of Research: Discovering the “Switch” for REM Sleep
How have you approached your research on REM sleep?
In our lab, we use two main approaches to study REM sleep.
The first is observing the brain’s neural circuits. We identified the nerve cells in the brain that generate REM sleep and developed genetically modified mice that allow us to manipulate these cells artificially. By increasing or decreasing REM sleep in these mice, we observe the resulting effects.
The second approach involves observing changes within the brain itself. Since observing the human brain is challenging, we mainly use mice for this purpose. Using specialized microscopes, we study changes in the brain during REM sleep.
What discoveries have you made so far in your research?
Most recently, we conducted a study to deepen our understanding of the mechanisms and significance of REM sleep and dreaming. The findings were published under the title, “Elucidation of the Neural Circuitry Inducing REM Sleep and Investigation of the Cause of REM Sleep Behavior Disorder.” The study demonstrated that we’ve gained substantial control over the ability to induce and manipulate REM sleep.
This was made possible by our discovery of the nerve cells in the brainstem responsible for REM sleep.
The brainstem is a central part of the brain that regulates essential functions like breathing and blood pressure. It’s a highly complex structure, containing nerve cells that control REM sleep, non-REM sleep, wakefulness, urination, and breathing—all in the same area. Because of this complexity, we had to carefully categorize each type of cell using molecular biology techniques to uncover their specific functions. Without this level of detailed examination, it would have been impossible to understand the role of individual cells.
After more than 10 years of research, we finally identified the nerve cells that control REM sleep. We then created genetically modified mice in which we could activate or inhibit these cells artificially. Activating these REM-sleep-inducing cells resulted in a state dominated by REM sleep, while suppressing their activity eliminated REM sleep entirely. This breakthrough allows us to explore the role of REM sleep in unprecedented ways.
Figure: Copyright Prof. Yu Hayashi (Translated by SS-F)
Does this mean that you can now intentionally induce REM sleep?
Yes. While it’s been possible in the past to temporarily increase or decrease REM sleep by altering certain brain circuits, what we achieved in our 2015 Science paper, and have further developed since, is unique. We were able to induce prolonged REM sleep and even transition directly from wakefulness to REM sleep—a first in the field.
What I find particularly significant is that we discovered the actual “switch” for REM sleep. Normally, healthy individuals transition from wakefulness to non-REM sleep, and then to REM sleep in that order. However, by activating these newly identified nerve cells, it’s possible to enter REM sleep directly and sustain it.
While previous research had identified factors that indirectly influenced REM sleep, this is the first discovery of a mechanism that directly controls it—a true “switch.”
Figure: Copyright Prof. Yu Hayashi (Translated by SS-F)
Of course, I don’t consider this discovery to be perfect. While activating these nerve cells strongly induces REM sleep, destroying them doesn’t entirely eliminate REM sleep—about half of it remains. This suggests that there are complementary cells working alongside these, and identifying those cells will require further exploration.
What factors contributed to identifying these nerve cells after more than 10 years of research?
To investigate the different types of cells, we needed to create new strains of genetically modified mice for each experiment. This meant producing a substantial number of mouse strains over time. More than using any special technology or techniques, I think the ability to persist with research for such a long period, despite no guarantee of success, is what ultimately led to our breakthrough. It feels like the result of many trials and errors finally coming together.
Another key factor was the guidance of Dr. Spyros Goulas. I met him through SS-F’s Editor Connect program (an event that invites editors from top journals like Nature Publishing and Cell Press to share insights on publishing and presentation techniques at a global standard).
Dr. Goulas provided thorough advice on various aspects of the paper, from refining the explanations for reviewers to strategies for communicating with Cell editors. His external perspective was invaluable. In Japan, we still lack access to such third-party advisors who offer rational and constructive feedback. Thanks to his guidance, I was able to make necessary revisions with confidence.
During the decade-long research, we also made an incidental discovery: nerve cells that “turn off” REM sleep. Unlike the cells we’ve discussed so far, these cells suppress REM sleep when activated. It was a chance finding, but we reported it in our 2015 Science paper. Even these unexpected findings can have significant implications.
From REM Sleep Research to Predicting and Treating Parkinson’s Disease and Depression
How might this discovery contribute to societal transformation or address key challenges in the future?
One possibility is its potential application in the early prediction and treatment of Parkinson’s disease, a government-designated intractable disease. Parkinson’s disease is known for its significant abnormalities in patients’ REM sleep. Often referred to as REM sleep behavior disorder, this condition typically begins more than 10 years before the onset of Parkinson’s disease, making it a notable indicator for early diagnosis.
As mentioned earlier, healthy individuals experience a state of sleep paralysis during REM sleep, which allows them to safely dream without physical movement. However, individuals with REM sleep behavior disorder lack this paralysis, causing their bodies to act out their dreams. This abnormal behavior during sleep is a strong predictor of Parkinson’s disease, with a high likelihood of eventual diagnosis. Additionally, it’s known that in the later stages of Parkinson’s, REM sleep often disappears entirely.
Through a collaborative study with the neurology department at Osaka University, we examined the brains of deceased Parkinson’s patients. We discovered that the same REM-sleep-inducing cells identified in our mouse studies are also present in humans. However, in the brains of Parkinson’s patients, these cells were nearly entirely absent. This suggests that the loss of these nerve cells may be directly responsible for the REM sleep abnormalities seen in Parkinson’s patients.
This discovery could significantly change how we predict and treat Parkinson’s disease.
Yes, and in addition to Parkinson’s disease, I’m also interested in its implications for depression. One reason is the unique nature of cerebral blood flow. Unlike other parts of the body, where blood flow can fluctuate with changes in heart rate or activity levels, cerebral blood flow remains remarkably stable. This is because brain cells cannot store energy and must continuously receive glucose and oxygen from the blood. As a result, the brain has evolved mechanisms to maintain constant blood flow.
However, until recently, little was known about how cerebral blood flow changes during sleep. In one study, we used a specialized microscope to observe the capillaries in mice during sleep. By administering fluorescent dye intravenously, we were able to measure the flow of red blood cells in different areas of the brain.
We found that during REM sleep, cerebral blood flow doubled compared to wakefulness, even in highly active states. While REM sleep is often described as similar to wakefulness in terms of brain waves, our findings revealed that blood flow during REM sleep is significantly higher.
In conditions like dementia and depression, decreased cerebral blood flow is a common feature. Our findings suggest that REM sleep, by increasing blood flow and distributing it evenly throughout the brain, may help mitigate these conditions. Conversely, a decrease in REM sleep could increase the risk of developing depression or dementia.
Of course, it’s still unclear whether decreased REM sleep is a cause of these conditions or a consequence of underlying health issues. Understanding this causal relationship is a key challenge for future research. Given that many Parkinson’s patients develop dementia as the disease progresses, I am also eager to investigate the connection between reduced REM sleep and the onset of dementia.
Yu Hayashi, PhD.
Professor, Department of Biological Sciences, Graduate School of Science, The University of Tokyo
Visiting Professor & Principal Investigator, International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba
In April 2008, joined the RIKEN Brain Science Institute (BSI) Behavioral Genetics Technology Development Team as a Special Postdoctoral Researcher. From April 2011 to March 2013, served as a Researcher on the same team. From April 2013 to December 2015, worked as an Assistant Professor and Principal Investigator at the International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba. Concurrently, from October 2013 to March 2017, served as a JST PRESTO Researcher. From January 2016 to March 2020, held the position of Associate Professor and Principal Investigator at WPI-IIIS. Subsequently, from April 2020 to March 2022, served as a Professor at the Graduate School of Medicine, Kyoto University, in the Department of Human Health Sciences, followed by a position as Designated Professor in the same department until March 2023. Since May 2020, has been a Visiting Professor and Principal Investigator at WPI-IIIS, University of Tsukuba (current position). In April 2022, appointed Professor at the Department of Biological Sciences, Graduate School of Science, University of Tokyo (current position).
His research focuses on understanding the physiological significance of sleep and dreaming, as well as developing new treatments for sleep disorders. He studies the neural circuits and molecular pathways that regulate sleep.
(Written by Tomohiro Kurimura, Photography by Kayo Sekiguchi, Interview and Editing by Masaki Koike)
