The Circadian Rhythm

Dr. Hiroki Ueda, Professor, Graduate School of Medicine, The University of Tokyo; Dr. Andrew Coogan, Behavioural Neurologist, Maynooth University


Sleep is essential to our lives, but our perception of how it functions in our non-waking life is not always well understood. So in the mires of our busy daily lives do we overlook sleep by seeing it as a means of refilling our energy for a productive day? By questioning this assumption, one term rolls from out of the haze: The ‘Circadian Rhythm’.

Dr. Kaylee Byers speaks with Dr. Hiroki Ueda from the University of Tokyo in the Faculty of Medicine on demystifying the links between our sleep and genomics. Then neuroscientist Dr. Andrew Coogan shares the connection between sleep and ADHD. Finally, we hear from Dr. Ueda and Dr. Hiroshi Ono, from Hitotsubashi University Business School, on how their homeland of Japan is reckoning with an off-balance relationship with sleep and work.



Clocks in our bodies, understanding Circadian Rythms


Attention Hyperactivity Deficit Disorder and later sleep, a chicken or egg dilemma


Challenging overwork in Japan and the importance of sleep



Molecular Mechanisms of REM Sleep | Neurosci The ability to dream may be genetic | Canadian Broadcast Corporation (CBC) Next-Generation Mice Genetics for Circadian Studies | Neuromethods Evolution of temporal order in living organisms | Journal of Circadian Rhythms Learn about the bunker experiment to understand the human biological clock | Britannica Genetic sleep deprivation: using sleep mutants to study sleep functions | EMBO reports Circadian rhythms and attention deficit hyperactivity disorder: The what, the when and the why | Prog Neuropsychopharmacol Biol Psychiatry Insomnia: Definition, Prevalence, Etiology, and Consequences | Journal of Clinical Sleep Medicine No Sleep for Japan? Survey Reveals Half of Population May Have Insomnia | Nippon.com Why Sleep Matters: Quantifying the Economic Costs of Insufficient Sleep | Rand Corporation Japan has some of the longest working hours in the world. It’s trying to change | CNBC Announcement of the establishment of the nonpartisan "Parliamentary League to Promote Initiatives for People's Quality Sleep" | Sleeping Council Federation Founder/Director CTO Yasumi Ueda gave a speech at the inaugural general meeting of the nonpartisan "Parliamentary League to Promote Initiatives for People's Quality Sleep" | ACCELStars Free-running circadian activity rhythms in free-living beaver (Castor canadensis) | Journal of Comparative Physiology CREDITS: Dr. Rackeb Tesdaye Curbing death by overwork | Financial Times Why does Japan Work So Hard? | CNBC Explains Worked to Death: Japan questions high-pressure corporate culture | France 24 English Inside Japan’s growing ‘lonely death’ clean-up service | CNN International How can governments help stop overwork? | The Question | CBC News: The National



Kaylee Byers: Okay. What’s a memorable dream you have or like… Oh, hey there. It’s Kaylee.



Streeter: I have kind of a recurring dream.



Kaylee Byers: What’s a dream you’ve had over and over?

Read Transcript


Streeter: I’m in a work meeting, and people ask me for my opinion on something, and I can’t speak.



Streeter: Ooh, spookiest nightmares.



Streeter: My mouth is either sewn shut-



Streeter: Someone came in through the front door and the walls were sweating.



Streeter: … or I go to speak and I have no voice, like Ariel in The Little Voice, like I have no voice.



Kaylee Byers: For me, it’s always the same.



Streeter: It was water running down the walls.



Kaylee Byers: I’m standing on a beach, one where I spent most of my childhood summers, and the horizon, it starts to get smaller. The shore flows back and forth, higher and deeper, until suddenly a massive wave is in front of me. It’s a tsunami, and just before it crashes down I think, “I don’t have time,” and then I wake up.



Streeter: It’s really kind of bizarre. I don’t know.



Kaylee Byers: Welcome to my brain everyone, it is a wild place. I’ve wondered why this is one of a few recurring dreams my brain tends to conjure up. Is it my unconscious mind messing with me? Maybe signaling stress from my day- to- day life? What I do know is that unsettling or strong feelings that can occur in dreams seems to be something we share.



Streeter: And it was the most bizarre light you could ever imagine.



Kaylee Byers: Even though we don’t entirely know why it happens. Lots to unpack there.



Streeter: We’ll have to come back to that, but yeah.



Kaylee Byers: Let’s circle back. You’re listening to Nice Genes, a podcast brought to you by Genome British Columbia. I’m your host, Dr. Kaylee Byers, your scientific sandman slipping science- y tales into your dreams.


Talking about waking and our non- waking lives is like exploring two different worlds. On one hand, we have the daily conscious grind, cramming work, the latest hobby, and those essential bodily functions into each day. On the other hand, there’s the non- waking world. It’s pretty much anyone’s guess what happens over there. Float over cotton candy clouds? No problem. Dash madly for your fifth grade biology test while your teeth fall out? Hey, only had that one three times this week.


But these two worlds overlap, and our conscious life can dominate our unconscious one. Our assumption is that our daily lives are meant to be productive, and something like sleep is just to top up that energy for the next day. But I want to ask, in our need to optimize everything, have we been snoozing on the truth of this foundational aspect of our life, and what assumptions can we dispel around sleep and what it brings to our waking life?



Dr. Hiroki Ueda: Okay, okay. So I think it’s quite interesting in concept-



Kaylee Byers: So I spoke with Dr. Hiroki Ueda.



Dr. Hiroki Ueda: I’m a professor in graduate school of medicine, University of Tokyo, and working on sleep research.



Kaylee Byers: Dr. Ueda has spent his career trying to unlock sleep secrets. Can you tell us what drew you to that area of study?



Dr. Hiroki Ueda: Basically, I’m very much interested in biological timing. What is the biological timing within our brain, because sleep- wake cycle is a 24- hour reason of our brain. So I start my research career by watching the clocks in our bodies or in our cells. So therefore, I am very much interested in that kind of stuff.



Kaylee Byers: This led him to ponder what was happening to our brains when we were frozen in La La Land, or more academically, rapid eye movement sleep, REM sleep.



Dr. Hiroki Ueda: So REM sleep is usually called paradoxical sleep. Your brain activity looks like waking, very active, but your body is totally silent. You cannot move at all, which is alternating every 90 minutes, and every night we have four to five cycle of the non- REM sleep and REM sleep. We still don’t know why, kind of another mystery. So at that time, we start our research by focusing on the acetylcholine receptor genes.



Kaylee Byers: Briefly, acetylcholine is a chemical used to transmit information from our brain, through our neurons, and to our cells.



Dr. Hiroki Ueda: We find out acetylcholine itself seems to be important for the total sleep that is non- REM or REM sleep.



Kaylee Byers: So they looked for these genetics in mice to get an idea of what connections sleep had with brain activity.



Dr. Hiroki Ueda: And then, we tried to investigate one by one, and eventually two genes seems to be involved in total sleep.



Kaylee Byers: They found two genes, CHRM1 and CHRM3, were crucial to our REM sleep. But then they removed those genes from the mice.



Dr. Hiroki Ueda: And then, we find out REM sleep is totally gone in mice.



Kaylee Byers: Without REM sleep, the mice develop some issues.



Dr. Hiroki Ueda: Memory deficit, learning disabilities, and also sometime mice cannot find the food, and then sometimes they die, unfortunately.



Kaylee Byers: The mice only lasted a few weeks, and it was a bit of a wake- up call for what sleep, or a lack thereof, does to our brain.



Dr. Hiroki Ueda: But it’s interesting, because same genes are involved in learning, as well as REM sleep and we know REM sleep seems to be related to learning and memory, so that is why it’s very, very interesting.



Kaylee Byers: What Dr. Ueda and others have found is that our whole body, both during the night and day, is linked to a deep internal process called a circadian rhythm.



Dr. Andrew Coogan: Yeah, the circadian rhythm is basically our 24- hour body clock.



Kaylee Byers: That’s Dr. Andrew Coogan, a behavioral neuroscientist from The University of Maynooth, in Ireland.



Dr. Andrew Coogan: Yeah, yeah. So we know there’s a bit in the brain, in the hypothalamus in the brain called a suprachiasmatic nucleus.



Dr. Hiroki Ueda: SCN.



Dr. Andrew Coogan: This, otherwise, is a super obscure little bit of the brain.



Dr. Hiroki Ueda: Kind of a tiny piece of tissues, 20, 000 cells.



Dr. Andrew Coogan: Has this amazing clock and it’s to do with how the genes involved in the clock interact with each other to switch themselves on and off. And you can even take the SCN out of the brain, and it ticks away. It keeps ticking. The clock keeps running.



Dr. Hiroki Ueda: Yes, yes. Yes, actually, clock is everywhere.



Dr. Andrew Coogan: We now know, actually, we have clocks over the body, so our hearts have a clock, our livers have clocks.



Dr. Hiroki Ueda: Our hair have a clock, our nose have a clock, our eyes have a clock.



Dr. Andrew Coogan: Guts have clocks.



Dr. Hiroki Ueda: Our immune system have clocks.



Dr. Andrew Coogan: There’s clocks all over the brain, and they’re also the synchronizer. This SCN clock is like the orchestrator, and the rest is the orchestra, and it sort of conducts all those various bits, to sort of keep them in line. So they regulate our digestive system, they regulate our cardiovascular system, they regulate our various behavioral and cognitive systems in the brain.


So there were these cool experiments done in the ’60s where they took, in Germany, medical students, put them in these old World War II bunkers, with no outside light and they lived in this sort of isolated world and they still had these 24- hour rhythms, or near 24- rhythms.


And that shows that the circadian rhythm comes from within. It’s a biological clock, it’s not just us reacting to our environment. Now, what obviously happens is, in the real world, our internal clock synchronizes with our environment, and particularly with the light, with the solar cycle, so the sun comes up, sun comes down, when we’re awake, when we’re asleep.



Dr. Hiroki Ueda: So I’m working on the only mechanism of sleep, but also the function of sleep. One of the long- lasting assumption is sleep is good for resting, sleep is good for forgetting. Partly true, but what we found is completely opposite. During that wake, your brain connection will be decreased, and then sleep is very good for connecting your brain, and then during the sleep, your brain connection will be enhanced, and our neurons, they are very active. So wake inhibitions and sleep enhancement, WISE. So to have a sleep, you can be wiser, so that’s what I found recently.



Kaylee Byers: To recap, as our earth rotates, our body’s finely tuned to elevate hormones, digestion, and metabolic processes at ideal times throughout its 24- hour cycle. What’s happening internally in our body is we’re mostly responding to changes in light throughout the day. Every little piece of you, like your hair or your immune system, is responding and operating on its own clock, in relationship to that circadian rhythm. And finally, the fact that sleep is only a means to restore energy is a little short- sighted. It helps create new brain pathways we rely on in the daytime.



Dr. Andrew Coogan: So there’s nearly no aspect of our physiology that isn’t influenced by the clock.



Kaylee Byers: Just as Dr. Ueda mentioned, while sleeping, our brain is in a sort of overdrive. Maybe that’s why we have those weird dreams. Researchers took a genetic analysis of sleeping people, and found that there was an increase in genes flipping on and off. That gene expression is used in forming new proteins and growing our brains, which directly effects memory formation and learning.


So does going to sleep later pose a dilemma for those connections and short circuit our circadian rhythm? Dr. Coogan and a colleague started noticing a trend with those who have a delayed bedtime, and attention deficit hyperactivity disorder or ADHD.



Dr. Andrew Coogan: I was just setting up my research group at the time, and a colleague called Johannes Thome, who’s an adult psychiatrist, had just joined the school of medicine where I was working. And his particular interest was in adult ADHD, which certainly, at the time, was a bit of a sort of Cinderella condition, people talked about ADHD in kids, but not so much in adults. We think probably about 2% of the adult population probably has adult ADHD, so there’s a lot of it out there, it’s not diagnosed.



Kaylee Byers: We’re still learning about ADHD by looking at our genomes, because it has strong genetic links. Studies with twins found that 77 to 88% of ADHD is due to genetic variation and there’s no single gene we can point at as the underlying cause. It’s what’s called a polygenic trait, multiple genes are involved. Now, to really bake your brain, this is where pleiotropy come in. Pleiotropy is where one of those genes associated with someone’s ADHD can also be related to other neuropsychiatric disorders, such as autism, depression, anxiety, and substance use disorder. It’s complicated.



Dr. Andrew Coogan: And one of the things we know about people with various different mental health diagnosis, is that sleep problems are super common in them. So we got interested in thinking about what sleep looked like in adults with ADHD. Adults with ADHD, they suffer from a lot of sleep problems, but the nature of their sleep problems is what term a sort of phase delay. So that means that they tend to go to sleep a lot later than other people in the population, so it’s sort of maybe a 2:00 am or a 1: 00 am going to sleep time, might be usual. For other people in the population it might be 11: 00 at night.


Now, in and of itself, that’s not necessarily a problem, but it becomes a problem when you’ve got to get up in the morning to go to work, to go to school, to do all the things that society demands of you. And we think this is really interesting, because in ADHD, it’s really, really, really consistent, this finding. And it’s one of the things, often when you talk to people you’re like, “Oh my god. Yeah, this makes so much sense to me now. I’ve always struggled with my sleep, I could never figure out why or what to do about it or anything like that.” And then, we sort of think about, “Well, okay, what’s the explanation for this?,” and we sort of fall into a chicken or an egg situation here.



Kaylee Byers: The classic chicken and egg dilemma has entered the chat.



Dr. Andrew Coogan: Is it the sleep problems that may be causing ADHD?



Kaylee Byers: Or did those with ADHD simply have later sleep cycles?



Dr. Andrew Coogan: Because if you take you or me or anyone and we sort of disrupt sleep, we know our attention gets worse, our impulsivity gets worse. All these other classic hallmarks of an ADHD diagnosis. And the answer to the chicken or egg question is we don’t know.



Kaylee Byers: Well, why should we give a cluck?



Dr. Andrew Coogan: So our main finding is that ADHD is really associated with a shift in our sleep timing towards eveningness towards a preference for going to sleep later in the day, so the people with the greater ADHD symptoms tend to have the even later sleep timings. What we’re trying to do now as a field is to leverage that and to say, “Well, if we apply an intervention that sort of helps move the sleep timing back to a more normal time, does that both improve sleep, but does it improve ADHD symptoms, as well?” It’s not to replace other treatments that’s out there, it’s to add to the toolbox of what we can do for the super common condition.



Kaylee Byers: If someone with ADHD is having trouble with sleep, Dr. Coogan noticed that melatonin light therapies might help their internal clocks align with the demands of the following day. However-



Dr. Andrew Coogan: If I’m not getting enough sleep, then it makes it much more likely that you’re going to have more sleep problems.



Kaylee Byers: An ADHD diagnosis isn’t the only determinant exacerbating a lack of sleep.



Dr. Andrew Coogan: And now we’re in this sort of worry loop.



Kaylee Byers: What if you, like millions of others, simply struggle to have a full sleep or can’t sleep at all?



Dr. Andrew Coogan: And actually, we know that’s super important in insomnia.



Music: (Singing)



Kaylee Byers: You’re listening to Nice Genes, a podcast all about the fascinating world of genomics and the evolving science behind it, brought to you by Genome British Columbia. I’m Dr. Kaylee Byers, your host, and we want to get more people to listen to the genomic stories that are shaping our world. So if you like Nice Genes, hit follow on Apple Podcasts or wherever you get your shows. Get your friends in sync by sharing a favorite episode with them.


I wonder if we could, I mean, sort of take that, what we’ve chatted about… Okay, so for this next part, I want to take you to land of the rising sun, Japan. Your homeland of Japan. When we were doing some research for this episode… It has one of the highest rates of insomnia in the world, meaning either having difficulty falling asleep, or being-



Dr. Hiroki Ueda: Within all the cities and countries-



Kaylee Byers: … entirely unable to do so.



Dr. Hiroki Ueda: … Japan is kind of the worst country for insomnia, so-



Kaylee Byers: A 2018 survey suggests that nearly half of Japan’s population is effected by insomnia.



Dr. Hiroki Ueda: Okay, so 2016’s famous report by RAND Institute, they said 2.9% of the entire GDP of Japan suffered from sleep loss. At that time, $ 138 billion US dollars, which is an enormous amount of money, lost by sleep deprivations.



Kaylee Byers: One of the leading reasons behind this national issue-



Dr. Hiroki Ueda: Our culture, in Japan, old Confucius, so we are working hard.



Kaylee Byers: … is the daily demands of an ingrained work culture.



Hiroshi Ono: Right. So there’s a very interesting work done about sleeping during the day, it’s called inemuri, in Japanese.



Kaylee Byers: That’s Dr. Hiroshi Ono.



Hiroshi Ono: I am a professor of human resource management at Hitotsubashi University Business School in Tokyo, Japan, and I study work cultures and how people work. So my interpretation of inemuri is that people are almost allowed to doze off, because it’s a sign of a serious commitment to work. In Japanese offices, you might see people during lunch and during tea hours or something, their heads might be buried on their desks or something and sleeping.



Dr. Hiroki Ueda: Actually, including me, we are watching something about seas after maybe 12: 00, many people are sleeping on the bench.



Hiroshi Ono: It’s rather bizarre that you might see people just sleeping during meetings.



Dr. Hiroki Ueda: Or on the train.



Hiroshi Ono: You see politicians dozing off in the dais. Right? And this is shown on television. It’s almost like they’re allowed to do that, because oh, they must be working really hard, so they must be tired. It’s not really, really shunned.



Kaylee Byers: He says the work culture of Japan is exemplified by a 2015 drama series called Shitamachi Rocketo.



TV Voice: (Japanese)



Hiroshi Ono: Shitamachi Rocketo, Downtown Rocket, that was the biggest hit of 2015, and this is a story of a Japanese man in his 40s who owns a very small manufacturing company, and his dream is basically to build a rocket and to launch it into space. The TV commercial and the posters that was promoting this TV series said, “It’s the story of a man who refused to give up his dream, nothing else matters.” Right? Work is central, and he kind of drives his entire workforce into pursing his dream. He would basically give up the time that he spends with his family to pursue his dream. And the second part of this is that it’s a story of a man. Right? That’s how you define Japanese work culture, that’s how you define Japanese masculinity.



TV Voice: (Japanese)



Kaylee Byers: Despite the jovial ambition of the lead character-



Soundbite:  Overwork in Japan is a real problem-



Kaylee Byers: The term karōshi was coined to describe the more harmful reputation of this work culture.



Dr. Andrew Coogan: People are literally working themselves to death.



Streeter: There’s no more regular workers.



Soundbite:  It pushes employees to stay late.



Streeter: They have a sense of duty.



Soundbite:  There is even a Japanese word for it. Karōshi.



Soundbite:  Karōshi.



Soundbite:  Karōshi, as it’s known-



Hiroshi Ono: Karōshi is literally death by overwork. People might work so hard to the point that they start to suffer physically and they just collapse and die. And sometimes we have cases of suicide, which you’d associate with karōshi suicide.



Kaylee Byers: Even though the phrase karōshi stems from Japan, Dr. Ono says it’s not isolated to his island home.



Hiroshi Ono: US and other countries do have people. Like 10% of the working population, 20% of working population are at the risk of karōshi. People in Silicon Valley, it’s like a no sleep culture, right? And the rewards are huge. They work crazy hours and they do die, the result of it.


Now, having said that, I would say maybe the one aspect that might distinguish Japan is that a lot of times Japanese people are working long hours involuntarily. There are many, many pressures, peer pressure, social norms, expectations, such as collectivism, hierarchy, considered almost like a virtue to show how dedicated you are to your work. And one of the ways that they show this is to stay long hours at the office. It’s almost like it’s publicly condoned.



Kaylee Byers: With respect to our daily lives and sleepy nights, it can feel like finding a healthy balance between these two worlds is a monumental task.



Dr. Hiroki Ueda: Yes, so last year-



Kaylee Byers: But Dr. Ueda-



Dr. Hiroki Ueda: … so 22 congressman-



Kaylee Byers: … now hopes to find that path-



Dr. Hiroki Ueda: … get together-



Kaylee Byers: … and is doing so alongside the government of Japan.



Dr. Hiroki Ueda: … and then they are seriously discussing about the introduction to sleep checkup. So in Japan, we have a very unique healthcare system called health checkup. So every year, we have to have a health checkup, which is mandatory, and it is fully supported by the either company or your own salary, written by law. And then, this April number of congressmen get increased up to 33 congressmen.

They are now serious to addressing the issues, I hope, but there are many, how to say, company who are interested in sleep checkup already. So therefore, it’s kind of becoming the large movement in Japan.



Kaylee Byers: Trying to make a change may also have to come from society as a whole.



Hiroshi Ono: The more unhappy you are, the more unproductive you become. Right? And if you’re unproductive, you have to spend more work hours at the office, so it’s this really bad cycle. Sometimes people get stuck in the cycle, to the point of sleep deprivation, with some people. The key, to me, is people should just think a little bit more about their happiness, because, I mean, if you’re really spending so much time on work, to the point that it makes you unhappy, then you’re not being productive and it’s not good for you, it’s not good for society.


The countries that work short hours, Scandinavian countries, many western European countries are much more productive than the long working countries. Now, this is a correlation, not a causation. You have to think about this rationally and say, “Is there a way for me to work short hours and become more productive?” I think that would be a benefit for all of us.



Kaylee Byers: Protecting sleep is important.



Dr. Hiroki Ueda: Yeah, so I think-



Kaylee Byers: Dr. Ueda shares exactly why.



Dr. Hiroki Ueda: So I have a friend, who is investigating the Japanese monkey, and she said, in wildlife, for Japanese monkey, they couldn’t have a longer sleep, because they sometimes wake up and then go back to sleep, because they have to watch their environment.



Kaylee Byers: Animal circadian rhythms can vary from our own. For example, the tenacious Canadian beavers circadian rhythm differs when it’s wintering in dams versus when it’s out living its best life in the summer. In the winter, its circadian rhythm is 27 hours, in the summer it’s 24. For humans, this evolutionary story of sleep and rhythms changes, too.



Dr. Hiroki Ueda: We humans are kind of a unique animal who enjoys a very long sleep. And then, within very long sleep, there are cycles between non-REM sleep and REM sleep. During non- REM sleep, a selection of new connections will be eliminated. So it seems like an evolutionary process. So within the human brain, every night, we have four to five times selection process, so that is why I think it’s quite interesting and important for human nature.



Kaylee Byers: So if the pace of life is overstepping those sweet hours of rest, remember that catching some Zs is all a part of the evolution of our circadian rhythm.



Music: ( singing)



Kaylee Byers: Our guests for today were Dr. Hiroki Ueda, with The Laboratory of Synthetic Biology at The University of Tokyo, behavioral neuroscientist, Dr. Andrew Coogan, from The University of Maynooth, and Dr. Hiroshi Ono, with the Hitotsubashi University Business School.



Music: ( singing)



Kaylee Byers: You’ve been listening to Nice Genes, a podcast brought to you by Genome British Columbia. If you like this episode, go check out some of our previous ones wherever you listen from. Share us with your friends, and leave us a review. You can also DM the show on Twitter by going to @ genomebc. And if you’re listening with kiddos or you’re a teacher looking to spice up your lessons, we’ve got learn along activity sheets added to the show description of each episode.



Josh Griffith: It’s a little boggy here.



Kaylee Byers: It’s painful to miss a night’s rest.



Josh Griffith: First net check. What did we find? Anything?



Kaylee Byers: But join us next time when our producer, Sean, takes one night-



Josh Griffith: Tucked away in this small little community.



Kaylee Byers: … to see if we can solve-



Josh Griffith: The cure for chronic pain.



Kaylee Byers: … pain.



Josh Griffith: I don’t know. Let’s see.



Kaylee Byers: We look at a genomic talent from a furry, slick, and billed creature that could help us put a stopper on pain.



Josh Griffith: There’s usually a pretty healthy population of them here.



Music: (Singing)



Kaylee Byers: Thanks for listening. Sleep tight, and don’t let the overproductivity bite.



Music: ( Singing)

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