Gero Miesenbock, Professor of Neural Circuits at Oxford University
Ever been up all night partying and then crashed out completely the next day? Thatís your brain sleep bank getting out of the red....
I caught up with Gero Miesenbock, Professor of Neural Circuits at Oxford University to find out what heís discovered from sleepless fruit flies.
Gero - So, flies actually sleep more than we do. They're quite lazy to spend about 16 hours a day of sleep and their sleep is usually concentrated during the night. They are active but they also take a very long siesta in the afternoon. So, they're most active in the morning and in the evening. It was actually controversial for a long time until about 14, 15 years ago where flies would actually sleep. But I think now, the evidence is quite clear, but you might wonder how does a sleeping fly look like. How do you know that the fly is asleep? Itís similar to how I would know that you are asleep. First of all, we donít move or we occasionally twitch when we sleep, but there's no walking around or running around or flying around. Second, we donít support our body weight well. A fly obviously won't lie in bed, slump in a chair, but it also sort of crouches on the floor when itís asleep. The third criteria is that it has heightened sensory arousal threshold. So, like you and I when weíre asleep, it takes a louder noise, a brighter light, a little shake to wake us up, right? And the same is true for flies. The fourth criterion is that, if you take away sleep, if you keep a fly forcefully awake, it sleeps more during the following day. So, it has to make up for that sleep deficit. And this, being able to make up for a sleep deficit is also the central theme of the research that I presented today. Itís widely thought that we have two control mechanisms in our brains that regulates sleep. One is the body clock which will be familiar to many of you and the other one is the strange device that senses that youíve got enough sleep or not. And that then determines that if you haven't got enough sleep, put it to sleep.
Hannah - And so, the body clock in the brain for example is as little kind of cluster of nerve cells. Itís a region called the suprachiasmatic nuclei thatís got about 10,000 I think nerve cells in there. So, about the size of a pinhead and itís, if you imagine, sticking a pencil up your nose, it would kind of eventually hit the suprachiasmatic nuclei and thatís the human brain body clock that will regulate whether you need to go to sleep or when you fall asleep and when you donít, and when you're awake. And then there's also Ė you're saying Ė a second system called the sleep homeostat which can cause you to compensate for lack of sleep if I haven't slept very well last night for example, hopefully, Iíll be able to get aligned tomorrow.
Gero - Exactly. You're probably normally not aware that there's two mechanisms that influence your sleep and waking because normally, these two mechanisms operate in sync. So, when your body clock says itís night time and you should go to sleep, your sleep homeostat which is this other mechanism Ė the one that determines whether youíve got enough sleep Ė your sleep homeostat also says, ďYouíve been awake all day, so please, go to sleep now.Ē But as you know, there are certain situations where you can dissociate the two things and they start fighting against each other. One such situation is, if youíve pulled an all-night Ė either for work or because youíve been partying Ė and then you will have no trouble usually going to sleep in the morning even though your body clock will tell you to stay awake. There's also another frequently experienced situation which happens after intercontinental travel. I for example then suffer these extremely painful situations where my sleep homeostats screens over fatigue, but I still can't go to sleep because the body clock keeps me awake. So, there's these two brain mechanisms. I think of the sleep homeostat is actually holding the key to the big mystery by every animal that has been looked at needs sleep to survive. Thatís a fact. Every animal needs to sleep. It will die without sleep. But nobody really knows what sleep is for. There's various ideas around, but nobody has really gotten to the heart of the problem. I donít think that by studying the circadian clock, you will. I view the circadian clock as an adaptive mechanism that makes sure that you do your essential sleeping at times when it hurts you least. I mean, taking your brain offline is obviously a risky thing to do. You are more vulnerable and you also have a cost of lost opportunity because you could be working or giving interviews. But if you time these inactivities so that they interfere least with your lifestyle then thatís an advantage.
Hannah - And so, the region of the brain thatís involved in this sleep homeostat is almost like a bank account which measures whether youíve got credits or deficits in terms of the sleep and whether you need to compensate or makeup for it.
Gero - The bank account is a very, very good analogy. The one that I use often is the thermostat on your living room wall. So, the thermostat measures temperature and switches on the heating if itís too cold. The sleep homeostat measures waking time and puts you to sleep if youíve been awake for too long. So, itís a similar feedback system, a regulatory control system that determines whether you need to go to sleep and make sure that you get enough sleep.
Hannah - So, you're investigating this in the fruit fly. Are you keeping the fruit flies up, partying all night and then messing with their bank system so they're massively in the red and then trying to figure out how the brain senses that they need to put some sleep credit into their bank account?
Gero - Thatís exactly what we do, except we donít keep them awake all night partying. Itís more sort of a Zero Dark Thirty, if youíve seen that movie about torture in Iraq. Itís more of that approach for a sleep deprivation like the secret service would do. What we have is, we have our flies in sleep monitors and we rattle them all night. So, whenever they try to nod off, the heavy weight drops down and rattles the whole apparatus. And so, they can't go to sleep. We found mutant flies that cannot put in these extra few hours of sleep. So in them, the sleep homeostat is broken. So, you sleep-deprive them and they donít sleep more and also their basal sleep. So, if you just measure how much they sleep during a regular day as I said before. A normal fly sleeps about 16 hours. These mutant flies, they sleep only 7 or weight. There's a result of this chronic sleep deprivation. They have severe cognitive impairments. How do you measure cognitive impairment in a fly that you can't talk? You test its ability to learn and remember. Like humans, if you sleep-deprive flies, they donít remember their lessons well. So, cramming before an exam is never good.
Hannah - And there's many mental illnesses that were associate with sleep destruction. So for example, Alzheimer's, dementia, even depression, and lack of motivation for example. And so, itís really crucial that we try to understand this bank of sleep monitor that we have on our brains. How on Earth are you measuring this in this miniscule fruit fly brain with their very small circuits of nerve cells in their brain whilst you're rattling and keeping them awake?
Gero - First of all, how do we measure sleep in a fly? We measure sleep by putting individual animals into glass tubes that are about 5 cm long and these glass tubes gets bisected by an infrared light beam and then when the fly walks up and down the tube, it crosses the light beam every few seconds or so. And we simply count how many beam breaks occur over time. sleep in flies is defined as any pause. There's no beam breaks for at least 5 minutes. So, itís not that flies have extremely fragmented sleep. They tend to sleep in shorter bouts than we humans do. But there's many episodes of sleep that extend for many, many hours. The project that we did started with a post doc (Jeff Donley) looking for flies that had neurons in their brain that could be activated artificially. He found that when he activated a specific small group of neurons, just about 12 cells in each hemisphere of the brain out of 300,000 of cells, when he turned on these neurons artificially, the flies would nod off. They would go to sleep. And then he looked at some of the genes that were active in these neurons and he found one that when it was mutant, (11:10) the fly is insomniac and also, unable to compensate for a sleep deficit. At that stage, a second post doc tried the project and he had the fabulous (11:21) skill of being able to insert a tiny, tiny glass tube into the brain of these flies and actually measure the electrical currents from these neurons. What he discovered was that in the mutant flies, there neurons were electrically silent. As I've told you before, Jeff discovered these cells because they become electrically active when a fly is sleeping. So, if you can switch these cells on, you'll sleep less.
Hannah - And thatís exactly how the human brain works as well using Ė if we scale it up a bit, thatís 100 billion nerve cells or so in the human brain but we use as electrical activity, electricity essentially that uses to switch a light on in your house in order to switch on particular areas of the brain and nerve cells in the brain switch on a circuit. So, the same kind of thing is going on in this fruit fly to switch on sleep using a very discreet 12 nerve cells within their brain.
Gero - Yes, brains are devices that run on electricity. Thatís something that was discovered about 230 years ago in Italy by Luigi Galvani who showed that when he touched a frogís slumber nerve to essentially a battery, the frogís legs twitched. So, this showed for the first time that all information in the brain is encoded in the form of electrical impulses. So, strings of electrical impulses represent what we see as stream of electrical impulses emitted by your ear as you listen to this podcast are then interpreted by other structures in the brain. Streams of electrical impulses are fired in my brain now hopefully as I'm trying to make sense and explain what's going on and also, streams of electrical impulses control the movements of the muscles that are important for me to produce the speech. What was surprising was that there's also dedicated cells whose streams of electrical impulses encode the need to sleep.
Hannah - And there's particular genes within these fruit flies that render those particular subset of nerve cells sensitive to electrical impulse. If you donít have the right version of those genes and you basically can't get sleep.
Gero - Thatís correct, yes.
Hannah - And so, does a similar thing happen in humans that suffer from insomnia?
Gero - So, there's a homologous structure of nerve cells in the human brain. These are also neurons that are electrically active while we sleep. These neurons like those of the fly that we have studied are the targets of general anaesthetics. So general anaesthetics activate these cells. As you know what the effect of general anaesthesia is, it puts you to sleep.
Hannah - And so, have you basically found the bank of sleep that can figure out whether you're in credit or debit for sleep?
Gero - I think we have found an element of the bank. We donít know whether itís the actual area that the account is kept, right where your balance sheet is being monitored. What we know is that what these neurons do is that they convey the message that you are in debit and that you need to go to sleep. How credit and debit get accounted is one of the pressing questions for future research. Weíd love to be able to discover what actually is monitored in the brain to determine how high or how low your sleep balance is.
Hannah - What are the next steps for your research in the fruit fly in order to find out more about how problems with sleep might possibly lead to Alzheimer's for example, so problems with learning and memory, and problems with mood and depression?
Gero - In terms of learning and memory, this is a problem thatís relatively straightforward to tackle in flies because we know how to measure their ability to learn and to remember. Now, they also and can control their sleepiness or their sleep deficit. So, what we are now trying to do of course is link these two processes in a series of very simple experiments. As far as something like depression is concerned, thatís much trickier because we donít really know whether flies do get depressed or whether they're anxious, or whether they have any kinds of emotions like that. I think it would be surprising if they didnít have an element of fear or anxiety, but there's no well-established way to measure that yet.
Hannah - In terms of the gene that your post doc formed in the lab, is there a human homologue for that thatís involved in insomnia?
Gero - There is many human homologues of this gene. Unfortunately, at this stage, too many. We donít know exactly which one the right gene is to look for and to my knowledge, nobody has really linked any of these genes to insomnia in humans, but that may just be because nobody has looked for an association.
Hannah - ; So, one of the things that you're really excited about or about your future work in your lab, can you mention some of the exciting studies that you're looking forwards to conducting?
Gero - I think sleep is a wonderful and exciting process because itís deeply mysterious and I think we have now sort of gotten into the stage where you can see the fork lifting a little bit. You can see the underlying mechanisms, the nuts and bolts, the wheels impacting with another gear, and so forth. So, it becomes more like clockwork rather than just a mystery. They're just very exciting. Theyíve also recently found a way in which arousal promoting substances can actually alter that sleep switch. Thatís something thatís very interesting. So, the general problem that I find myself thinking about more and more is the representation of time in the brain and processes that require time to unfold. So, sleep obviously is something that occurs on a regular temporal rhythm. If you think of, for instance the sleep homeostat having to monitor changes that occur gradually over many, many, many hours, itís not really clear how neurons do that, how they change the activity over many, many, many hours because as I've said before, information is encoded in tiny, very short impulses, electrical impulses. So, how can such a tiny electrical impulse that lasts a thousandth of a second be used to represent information over timescales of hours. A related question that we are currently studying is how information is represented over timescales of a few hundred milliseconds to a few seconds or minutes. And in order to gather that problem, we study how flies make up their minds. You probably know if you are faced with a difficult choice, you think long about the hard choice then about the easy one. Weíve recently discovered that flies take a moment too and we found neurons that are involved in that. Again, we found a gene that interferes with the process. And so, we can now study what's happening during these few seconds while a fly considers its options and then makes a choice which fundamentally is a problem thatís similar that you have to hold information in your mind over time-periods, that alarmer than the impulse of a single cell.
Hannah - Itís how the fly decides to stay, taking information in for a longer period of time until it makes its decision because itís a tricky decision that itís based with. So, itís abiding its time to collect more information before it makes its decision and you're trying to figure out what's going on in the brain in the fly when itís doing that.
Gero - Thatís exactly what weíre trying to do.
Hannah - Will that information also give us some concept of the perception of time within our own minds?
Gero - I'm not sure. Possibly.
Hannah - Thanks to you Gero Miesenbock, Professor of Neurocircuits at Oxford University.