'We are interested in how the clock breaks down’
What do you find particularly exciting about circadian rhythms?
Circadian rhythms are super exciting because they’re so pervasive, across organisms. So they coordinate physiological and psychological systems together in humans, but they’re also so basic that they run through all organisms. This system, of cycles repeating across a roughly 24-hour period, is a really nice model to explore the physiological basis of behaviour. And we’ve made a lot of progress, I think, in understanding the physiological basis of behaviour by looking at circadian rhythms. Almost everything you look at has an aspect that’s influenced by the timing and the synchrony of how those patterns work together.
And these rhythms are both externally queued and internally generated?
Yes. The various rhythms within your body need to be in synchrony with each other, for you to function optimally and to be efficient. They are influenced by external signals, and they also allow you to anticipate those changes that are happening in the environment.
The light pathway is the most pervasive: we’ve developed our circadian system in response to our external environment, so that’s the driver, the primary signal. But I’m also interested in exercise and social motivational signals. For many years as the field got started, people thought light was the only thing that could influence your circadian rhythms. Now it’s almost hard to find something that doesn’t influence your circadian rhythms!
…And animals which have evolved for 200 million years in caves and have no light whatsoever still display circadian rhythms.
That’s right. You don’t need an environmental cycle to have a clock. The cave salamander doesn’t experience changes in temperature, or light, but it shows robust 24-hour rhythms. Flowers can open and close on a 24-hour cycle, and if you take one bud off and put it in controlled conditions, it will continue to open and close.
A lot of your work has been with mice. What makes them a good model for gaining insights about sleep and light in humans?
There are a lot of tools available. If you really want to get at the physiological basis of something, mice are great. If you want to look at the pharmacology, the molecular basis, genetics, we know so much in mice. Obviously there are going to be differences, but it gives you a place to start… when you go to the human population, you don’t feel like you’re fishing. You go in with really good hypotheses, a physiological basis.
And what kind of questions do you ask?
Well, I got interested in circadian cycles through sleep. Sleep is something we can’t resist… it comes up every 24 hours. It’s an overwhelming urge, it doesn’t matter who you are or where you are, if you have to sleep you have to sleep. That’s an indication of how robust these circadian cycles are.
And you’ve asked how the system changes with age?
Yes. As you get older yourself, I think you get more interested in how systems change with age, so that’s something I’ve looked at more as I’ve gone on in my career. We’re interested in how the clock breaks down. This is important because sleep disruption is a risk factor in all manner of things, including obesity and depression.
So what changes do we observe with age, and what is that physiological control path? Well, we can put an infrared sensor in the cages of the mice, and measure when and how they move around. We find that in younger mice, the patterns are nicely consolidated during the night period – mice are nocturnal. If you look at the older animals, the activity bleeds out more into the light portion. Their behaviour is disrupted.
With an acute pulse of light, you can reset the clock just like you can reset a watch on your wrist – particularly if that pulse is administered towards the end of the wake cycle. But older mice don’t reset to a 15-minute light pulse in the same way as younger animals. By increasing the light level, you can get the response that you got to the lower dose of light in young animals. You can raise the bar a bit in the older animals, but still there’s a big difference. And of course that behavioural outcome in an ageing mouse, the outcome from the circadian clock, is very similar to what we would see in humans.
You mentioned the physiological control path.
We were trying to figure out where the deficit is… light was a nice one, because the signal is very defined. You have the retina, the optic nerves, the suprachiasmatic nucleus [SCN], which sits above the optic chiasm, with direct input from the eyes. It acts like the conductor, orchestrating different systems so they’re in time with each other.
With some of the other signals – social signals, some of the motivational signals – the pathways are more complex. With light, if there is an issue within the clock area itself, we could follow that pathway. We can test sensitivity of the retina, we can see whether the light is reaching the SCN, and then show that there is some of the deficit within the SCN itself. By recording electrophysiologically from that area, we find the peak firing rate is not as strong in the older animals. And if we look at the neurochemicals which mediate such a response – in particular the glutamatergic receptors, and specifically NR2B – we get differences in the ageing mice. That research is tracing the path all the way to cells in the dish, and then all the way back to the whole animal.
So the clock, or at least part of it, is broken… and you’re finding out how by using different levels of explanation.
Yes. With humans you’re unlikely to solve a problem by just looking at the biology. That’s why I’m a psychologist and not a biologist. But it remains fascinating and important to study different facets of the explanation. To give just one example, if we give our ageing mice access to a wheel for a short amount of time during the day, and if they’re motivated and interested to use it – perhaps because we’ve cooled the cage – then the activity seems to reset their broken clocks. It’s similar to the effect of neuropeptide Y, which can phase shift the cycle if you inject it into the SCN.
It’s not simply that old mice / people are less active, so they have less need for sleep in the night?
No. Even if you have animals that have the same level of activity as younger animals, the consolidation is what’s different. There are older animals that still have higher levels of activity, and younger animals that have lower levels. But even if the younger animals have a low level of activity, you still see the consolidation; with older individuals who have higher levels, you still see the disorganisation. And with the wheel, the mice do get more sleep if they’ve done more exercise, but it’s in no way proportional. That’s not all that’s going on.
As an aside, I remember we had a student in the lab, using an activity watch, and we downloaded the data and said, ‘oh, your watch isn’t working’. We gave him a new one. We gave him three watches. ‘Do you not move during the day?’ He was the most sedentary we’d looked at, but you could still see that there was consolidation, a pattern to it: a peak in the morning and evening.
I think we’ve both got teenage sons, so we’re right in the midst of changes in the circadian rhythm. My son is starting to get particularly active around half nine when everyone else is wanting to wind down…
Teenagers are in a really difficult position, because they have this biological delay of their circadian clock. Then they have all the psychosocial pressures around wanting to stay up at night, and they have the light from their screens… the wavelength of 450 nanometres of light that is beamed out of the phone when they pick it up is going right along the optic nerve to the SCN in the early part of their night, which will cause a further phase delay. And then some have the cognitive things around ‘fear of missing out’ when they do decide to put their phone away and go to sleep. Most of them are using their social media to facilitate their face to face relationships, and they’re worried about not being there for their friends. So there’s a whole host of things.
Those cognitive effects, you think that’s more significant than the physiological effects of the blue light?
It’s hard to say… certainly in some people, it is more. The field has worked with industry to attack that light issue. You can download apps that change the relative wavelengths of light. You can do the experiment… if I use my phone without the 450 nanometers of light does it still impact on my sleep? Yes, it does, in a big way. But you should still use the apps, because we all have that phase delay portion of our cycle, it’s not just the young people.
So even if these are neurochemical effects, the whole psychology around sleep becomes vital.
Yes, even that cognitive activity and arousal is impacting on the sleep and the circadian system by acting on the clock, so it’s a chemical acting on the SCN to reset your clock.
So with your son, he might cognitively override that urge to come to life, and he’ll go to bed at 9:30, and then spend an hour and a half in bed not sleeping. What that does is set up a cycle where they associate their bed will not sleeping, and that’s a big problem in developing insomnia.
Throughout history people have taken all sorts of medication to help them sleep, but this is really just sedation and leads to that REM rebound the following night. Trouble sleeping is actually a leading reason, after pain, that people over 65 go to their GP. We have worked with a supported living unit in Edinburgh, using activity monitors, and found similar patterns to in our mice. So we’re now looking at the impact of light, of CBT to address beliefs around sleep, and an activity class.
And you’ve also worked with Sleep Scotland to train better beliefs around sleep?
Yes, there are now sleep counsellors who are trained to go into schools, but also working with families who have children with special learning needs or developmental disorders where there might be more issues with sleep. In Scotland we’ve trained more than 700, and in England and Wales over 500.
There are so many areas of interest here… sleep disruption in new parents, or during the menopause, or in hospital – particularly in relation to levels of ambient light. These applied topics are really rewarding… as you go on in your career, get older, you feel like you want to make sure that you’re trying to have an impact.
- See also our collection on sleep and dreaming.
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