The Science of Sleep: Melatonin to Neural Pathways

thanks very much coming out on a on a cold Thursday evening I'm I'm doubly happy to be chairing this not just because it's scientifically interesting but because before I was asked to chair this I actually bought myself a ticket so I get my money back and I get to hear it all anyway the reason I bought a ticket as a punter is that I think what we're going to hear tonight is about a subject which is special for a number of reasons one is that in terms of fundamental biology and psychology it's one of the big open books one of the big blank pages that we have in in modern psychology and and biological sciences the second is where as they will discover really very interesting things in the Large Hadron Collider that's not going to affect your everyday life is it you know you're really not going to lose any sleep over it or change the way you cook but what these people discover and what these people work on does interface with your everyday life in a way that I think many other areas of biology and science simply do not and I think sleep is for that reason and circadian rhythms are for that reason one of the most important subjects in modern day science just to give you before I turn you over to the speakers an indication of how important it is we have some very accomplished people in this audience very very accomplished people we have Pippi stop for example one of the most important horn players in the world last year made a landmark recording of Mozart's horn concertos he's played the horn and blond down a pipe every day for 40 years for hours and hours and hours but every ten years I saw that adds up to his 10,000 hours but he's actually four times as good at sleeping as he is at playing the horn because every four years he gets to his 10,000 hours that's so important sleep is no matter what it is you do what it is that drives your life how importance it is evolution has decided to give over more time to your biology mechanisms for sleep than anything else you might want to do we have James Smith here tonight from sleep deep who's one of the people responsible for you staying up late at night watching adverts of people taking their clothes off down to their boxer shorts in launderettes and things like that he spent hundreds and thousands of hours working on those adverts so you can stay up and look at like screens and not get a proper night's sleep but he's also slept several times more four or five times more every day than he works on those things so sleep is one of the primary functions that we've evolved to do in fact it might even be the point of life I'm going to hand you over to the speakers what will happen is first of all we'll hear from Stafford Lightman from the University of Bristol then we'll hear from Deborah skein from University of Surrey then we'll hear from Russell Foster from the University of Oxford they're going to speak to you for 15 minutes each when they get to 16 minutes I'll kind of go like that at you and I want you all to go okay because every minute they go overtime and their academics and nobody's told them to stop for years every minute that they go over time is time out of the time you get to us them those important fundamental questions that matter to you in everyday life so Stafford if I can hand over to you well thank you very much I'm very much the warm-up artist because I'm not primarily a sleep researcher but I will introduce you and move you into sleep but what I would like to talk to you about today is about rhythms now I think all of you are used to rhythms you'll have rhythms of one sort or another and I'm just going to start by bringing you back to the brain because the brain is the bit that is involved in sleep it's involved in almost everything that you do my particular research is on stress and my particular interest is how stress causes disease and there's lots of forms of stress from your external environment or from within yourself but these all affect a little bit of the brain right in the middle of the brain here are part of the hypothalamus which causes lots of changes in the way you behave in the way your body performs but very near to this area which is your stress responsive area you've got another area it's happens to be called the suprachiasmatic nucleus but it's a little clock and you've got a little clock there in the middle of your brain which actually tells you where you are during your day and it tells you when you need to go to sleep and it tells you when you need to wake up and this clock controls many many things that your body does now this body clock is a really powerful clock so it lives here and that in fact if you take this body clock out and you put it in the dish and you look at it in a dish what happens is all on its own without anything else going on every 12 hours it turns on it turns off it turns on and it turns off and actually you can look at this and you can actually see this is in a dish your body clock turning on and off every 12 hours so you've got this as controlling your sleep cycle is controlling your energy is controlling all of the things that you do is spontaneously going on in your head every single day so where do I fit into this where's my interest well this little body clock up here is very close to the part of the brain that controls your stress hormones so there's a little picture tree gland here and so it affects your pituitary gland which releases a hormone which is called ACTH which go right round the body and then it had lights on these two little glands here your adrenal glands which live just above your kidneys and these produce the stress hormone the stress hormone cortisol so if we look in little more detail here you've got your body clock here it produces a compound which act on your pituitary gland which makes the hormone ACTH is what it's called which acts on your dream gland and your dream gland then makes your stress hormone cortisol okay so what would you expect happens to your hormones throughout the day what would you expect actually happens well what you would expect isn't this scissor you wouldn't expect your hormone to be the same flat throughout the day because you know you've got a body clock and you know that you need your stress hormones when you're awake but actually what happens isn't that so you've got this is this is what you would expect you would expect the hormone to go up so this is the daytime here and this is the nighttime here you're expected to go up before you wake up because it's an anticipate or hormone it's a hormone that gets your body ready for the stress of waking up and everything you do in the day you're expected to go up in the night to peak just as you wake up stay up in the day and then come down but actually that isn't what happens because when you look at it what you actually see is that and that's really weird that's just not what you would expect because actually although there's a day rhythm what you've got is an almost hourly rhythm of peaks of hormone and this is really interesting because why does your body want all these multiple oscillating levels of hormone over the 24 hours so we wanted to know a little bit more about this so what I've shown you is that you've got the pituitary gland it makes a hormone called ACTH and it acts on the adrenal glands the adrenal bands are really very strange because most of your hormone glands can store hormone so that when you stimulate the glands they produce hormone but actually the adrenal gland cannot store hormone it has to make it new all the time so every time it has a message to turn on it has to make cortisol what that means is there is a delay between ACTH acting on your adrenal gland and the adrenal gland making cortisol and so if I can give you an example of this of what delay means in a feed-forward feedback situation it's like this so you will recognize burns and Smithers and those of you who are a bit older will recognize that the type of showers you used to have you used to go in and it was too cold you turn the shower off and he went too hot you turned it down it was too cold and basically what's happening is this so Burns finds the Shahrukh also yells down for Smithers do something about it Smithers so he does so he turns it up so it turns it up but nothing happens because there's a delay before it comes through so turns up a bit more and so as this happens to begin with it suddenly gets warm just the right temperature and then ah it gets too hot and he screams ah that's awful so poor old Smithers get screamed at and he turns it down and it goes down and he tries to get it cooler but it doesn't go cooler so he turns it a bit more down and it gets a bit cooler again and then of course it goes from our lovely excellent Smithers to being are too cold and this is what happens when you got a delay in a message system it's a mathematical necessity any system like this has to oscillate and so what actually is happening is that you get an oscillating system and what's actually happening in the brain is this is that you've got activity in your hypothalamus which is activating the hormone goes to the pituitary the hormone to your pituitary then goes round the bloodstream and then it when it gets the adrenal gland there is a delay the adrenal gland after a delay makes the hormone cortisol and when the level of cortisol goes up high enough it quickly turns off the ACTH so you've got what's called a feed-forward and a feedback system with a delay in it it has to oscillate and that means your hormones have to oscillate and that basically means that your body always from the moment you're born is seeing oscillating levels of your hormone and it's adapted to it so what you have is you for the whole all of your life you have pulses of cortisol being secreted by your adrenal glands it causes pulses to go around the whole body and amongst other things it causes pulses of hormone to go to the brain does this matter well yes it does we have quite a lot of patients who can't make their adrenal hormones and we give them their hormone back and we give it to them by mouth when we give them by mouth they get very flat levels of hormone throughout the whole day and a lot of these patients just say I haven't any energy right there's nothing I just got known few Yasim for anything I can't do anything so what we've done is that we have looked at patients and we've given them back their hormone either as a constant amount or a flat amount of hormone throughout the whole day or we've given them pulses of hormone then what we've done is we put them in a scanner and in the scanner we've given them an emotional stimulus which is basically looking at sad and unhappy faces to see how their body emotionally responds how their brain emotionally responds so we're comparing people who've got nice pulses of cortisol to people have flat levels of cortisol so we put them in a scanner and when we put in the scanner this is what we find these are the patients were given flat levels of cortisol and they when we give them an emotional stimulus one of their amygdalas lights up just a little bit just like that and when we give the same people pulses of hormone what we see is this both of the amygdalas light up very very brightly so the emotional brain the part of the brain the response remotion is much more activated when it sees an oscillating signal - when it sees a flat signal and this is very important in our patients who actually don't show normal emotional responsiveness when we give them pills and it's another way that we have to understand that the way we treat patients the timing that we treat patients is every bit as important as the actual hormone we actually give them to replace it so I've said that you've got a body clock and that the body clock controls the daily rhythm of hormones but one of the really interesting things too is that cortisol this particular hormone actually affects the body clock so let me just take you through this very quickly this is just shows your activity of a rat and the normal rat gets very active at night time and going up is how active it is it's very act so this is three different days was one two three days and it gets very active at night then it's not active in the daytime when it's asleep its active at night its inactive during the day and it's active at night similar with activity it has a daily rhythm of body temperature so when it's active its body temperature goes up and then it goes down again it goes up and down in a 24-hour cycle when we give these rats a constant level of cortisol so we just give them a level of cortisol constant over the 24 hours what happens is they leave lose their activity profile they no longer have a 24-hour cycle of activity they are say their activity is same throughout the whole of the 24 hours and then if we look at their temperature cycle that has also gone so this major hormone this stress hormone which is controlled by your 24-hour clock actually also controls the 24-hour clock and when we give it in the wrong way it can get rid of a lot of the activity of the 24-hour clock so this is all about sleep does this have any relevance for sleep well yes it does and I'm just going to show you this is a sleep diagram of a human being just to say basically sees a wake up here and this is deep sleep down here and these purple squares here are your levels of cortisol and in a normal night's sleep what you get is you get very low levels of cortisol throughout the night and then when you start waking in the morning so when your sleep when you become more wake up here your levels of cortisol go up what happens if your sleep is disturbed so this is a subject who's got disturbed sleep because there was a very loud thunderstorm you'll see that rather than having flat levels throughout the night he's having these peaks of cortisol throughout the night they don't normally happen at night but during this thunderstorm they were happening all throughout the night and then what happens to this a staff member who had been supervising experience and he was simply unable to sleep and him with his level his leg easily got pulses of cortisol actually going on throughout the whole of the night so we know that actually lie levels of these stress hormones can actually disturb your sleep and while we also know that disturbed sleep can disturb your stress hormones does it matter as well well this is just another example what I showed you is that if you've got higher levels of hormones you don't sleep so well so what conditions do you have bad sleep in or one of the classic ones is in aging as people get older their sleep gets much worse and if you look this is just averaging the levels of cortisol throughout the day so you don't see their pulses but if you look at a normal person so this is the average of a young people they have very low levels of cortisol at night which then come up again in the morning but a more older people have much higher levels of cortisol at nights so these people have much poorer sleep also have higher levels of cortisol so what do I conclude well I conclude that oscillations are absolutely vital for good health everything oscillates I mean really everything even atoms oscillates everything in our existence that we know about oscillates so the stress hormone cortisol needs rhythm it needs a rhythm as an anticipate rehome own preparing you for waking up in the morning it needs to go up before you wake up to prepare you for all the activities of the day but it also needs hourly science cycles to maintain your optimal responsiveness if it's not oscillating up and down you are not as a responsible person your reactivity your emotional reactivity is not normal and in fact your metabolic activity isn't normal either so it needs a lie cycles to maintain optimal responsiveness of the brain and other organs there's also a bi-directional relationship between your cortisol your stress hormone secretion and sleep so you have high levels of cortisol impair your sleep we know that awakening is late is linked with increased cortisol secretion and interestingly if you tell somebody that they're going to wake up the time in the morning that in itself is enough for their cortisol secretion to go up before that time so II their expectation of waking up is actually enough to increase their cortisol and there's increased nocturnal cortisol secretion in many conditions associated with poor sleep including aging and depression so that's really my introduction thank you very much I can see the attack of the oscillating hormones as a trilogy written by Stafford Lightman thank you very much Deborah can you take us on from that please I'm not any other retentive but that was 13 minutes and 37 seconds if you're interested great well thank you and hello everybody I'm just going to take on where Stafford left off and the hormone I want to talk to you about is called melatonin and it's synthesized in the pineal gland which is very small it's the size of a pea in your brain a day car called at the seat of the soul and it is where melatonin is made so it's working and it has a rhythm as well and in a sense it's the opposite of of cortisol it Peaks at night we call it the darkness hormone in every species that we studied melatonin occurs at night and it's a hormone that prepares you for the things that your species does at night so of course in humans we sleep but animals like rodents they're awake so it's a hormone that is related to darkness behavior and it is also driven by this biological clock that Stafford told you about there it's sitting just above this optic chiasm in this area called the suprachiasmatic nuclei and it's essentially hardwired to this biological clock you can see the SCN here and it's quite as securities route because it goes all the way down to a part of your spine and then comes back up and these nerves innervate the pineal gland here so what happens in the biological clock is directly informing what is happening in the pineal and so it's driving the rhythm of tonin and we use this rhythm of melatonin to mark the the clock because we can't see the clock on our own I can't tell you where your biological clock is in time but I can measure this hormone and by measuring it and knowing what time for example the melatonin begins to rise or what time the peak is that tells me where your biological clock is in time and so we use it as a marker of internal time and we can use it to diagnose circadian rhythm disorders if we suspect that you may have a disorder of the circadian system we will measure melatonin to prove that and the reason we like melatonin is because it's not really affected by things like showering or eating or stress or sleep or meals so when we measure it it's not been confounded by other external factors we do have to do some conditions to make sure we get it right and that is we have to sample in dim light conditions so if we switched out these lights here and you you just had enough light to read we would be able to sample your melatonin and for some of you that would be beginning to rise now we also like to exclude medication if we can and you're all sitting down so I could keep you here all night and you could take saliva samples for me and I'd be able to measure who are the late types in the audience and who are the early birds in the audience and here are some measurements that we do in our lab down at Surry these are our early blood samples and you can see the melatonin rhythms almost like a fingerprint because on two different nights you can see they're very similar patterns in these four people except that when you look at the peak here is sixty picograms whereas here is only twenty five so we get different amounts of melatonin but the profile is the same for each individual we also can measure the metabolite of melatonin this is made in the liver and it's got a sulphate oxi group on it and that means we can then measure it in the urine and by measuring the melatonin and metabolites in the urine it means we can do studies in people's homes so we can ask you to collect a urine and then we ask you to collect all the urine over four hours across the day in the night and we we get a very good correlation between the urinary metabolite shown in the histograms and the plasma melatonin so we can use it in field studies you don't need to have blood sampling done and there again in the lab you can see how well the blue line shows you the hourly plasma melatonin and how well it correlates with these urine collections even if the urine collections aren't really at equal time intervals so now we have the tools it's easy to measure it's relatively cheap to measure you do need a lab though and it means you can get at the clock and where the clock is in time for diagnosis it also has helped us a lot when we want to look at for example what's the role of the eye and what's the role of light in the circadian timing system we know that light information is taken down this non-visual pathway to the clock and we've been able to study that and one of the ways of studying that is to study blind people now blind people of course have different diseases but they also have different amounts of visual loss and we measure that by working out whether they perceive light whether they can see shadows count fingers or whether they have no conscious light perception so there would be unaware that the lights are on and we found that the degree of visual loss that we see in blind people relates to whether they have sleep problems or not the more severe the visual loss the more high frequency of sleep problems and we wanted to look at what is the clock like in in these blind people so here's a blind person we studied for four weeks and each time we studied them the peak time of melatonin occurred here where it should at night about 3 o'clock in the morning and that person had light perception was blind but had some light perception and then we can study people have no eyes they're bilaterally enucleated and there you get a very different picture we have melatonin being produced it's peaking every time we measured it but can you see that it peaks at a different time each time we sampled meaning that the clock is D synchronized from the light-dark environment because there are no eyes and when we study bilaterally enucleated people you can see the peaks here the the symbols here show the peak time of melatonin and every week of the study the peak time changed if if they were synchronized the peak time would be here at 4 o'clock every morning so we're having a de synchronised system and that inferred or told us how important the light-dark cycle is how important our regular 24-hour light/dark cycle is to synchronize the biological clock and we know that it's ocular light and why it's important even for blind people is here you see a sleep map here's a typical sleep diary we asked our subject to tell us when they go to bed and when they wake up and they also mark when they have some naps you see SS here Saturday and Sunday so you're having these naps when our subject isn't working and sleeping and you see that the melatonin rhythm peak showing in the red stars is synchronized and entrained all is well because the circadian system and the sleep are together now look at that very different this subject is totally blind no light perception look at the very poor sleep short sleep the freerunning D synchronized melatonin you see here and where the biological night is you see how much more napping you get and this slide is a sort of prototype of what blind people suffer from if they have no light perception and it's known as non 24-hour sleepweight disorder because it's not synchronized to the 24-hour and it's characterized by a cyclic disorder because sometimes when that person when their melatonin is peaking at the right time like 4 o'clock in the morning do you see here the very good night's sleep and no napping during the day but when the clock moves out into an abnormal place peaking here during the day then you see you get lots of naps during the day and very poor night's sleep so it's a cyclic disorder sometimes the sleep is good and sometimes the sleep is poor and it shows you how important the light-dark cycle is we need good to give us good sleep at night and for us to be alert during the day and so when you have this mismatch between the the circadian system and your light-dark cycle for example when you travel across time zones or when you do night shift work you get all the symptoms that I'm sure some of you have felt you feel tired during the day you of course you reduce performance you risk accidents and then you can't sleep when you want to at night and so and here's your classic jetlag situation here where you've got to you you fly eastward and then you've got to take some time to adapt to your new time zone or take some time to adapt to you and you work schedule and we study shift workers in this way we've studied people who work on the oil rigs in the North Sea they have these 14-day shifts and here's a person on a day shift so they sleep at night here their melatonin is peaking at night all is well and then they go on to two weeks of night shift and can you see of course they're working here during the night and they're sleeping here on the black bars during the day but can you see how it takes some time about six days before they adapt to the new schedule so while they're adapting they're suffering from symptoms of jetlag and another of sleep problem that involves the clock is what we call problems of sleep timing some people can't go to bed at a normal time they go to bed very late at night and wake up very late very late in the day you might say yes all those adolescents all those teenagers that's it that's exactly what they do for that period of time suffer from and then inversely some people go to bed very early and wake up early and that is more associated with as you get older you tend to go to bed earlier and wake up earlier so all of these things as well as some other possible disorders or disorders of mood depression possibly aging and Alzheimer's disease may involve clocks being dysfunctional and affect sleep and so we've spent some time trying to work out how we can try and treat these disorders and the two things that we currently know can work are light appropriately timed and melatonin that is as a tablet as a drug taken because we know they can shift the timing of the clock and the complicated part here is that both of these compounds can advance the timing of the clock or they can delay the timing of the clock and it depends on when you give it now that shows here because this isn't a straight line this is a curve and it means that if you give light here before four o'clock in the morning when your temperature is at the minimum you'll get a delay in the climb timing of the clock whereas if you give light in the morning you will get an advance so it's very important to know when to give the light to do what you want to do with the clock and melatonin is the same if you give melatonin here about now if I gave you also melatonin before the natural rise in melatonin it will advance the clock and if I give you melatonin in the morning it will delay and the trick here is that they almost twelve hours apart light and melatonin so if you want to use both of these to treat circadian rhythm disorders you shouldn't be giving them at the same time you must take your melatonin when you're not getting a lot of light so with wearing sunglasses perhaps and and put more simply melatonin here in the evening will advance your clock if you see the red line here and that's sort of the full list of all the circadian rhythm disorders you can get and knowing what goes wrong here means you can appropriately time your light and melatonin to correct that problem and that's what researchers have done and that's what we've done too so thank you for your attention thank you very much Dover Russell you've got 50 minutes and 49 seconds to tell us everything you would like about many thanks indeed what I thought I'd do in the next 15 minutes and was it 49 sounds was to pull some of the themes that Stafford and Deborah have talked about and then drill in in some detail about the mechanisms whereby the eye detects light so let's kick off with with a framework of thinking about sleep so the first point I'd like to make and it's been touched on by my colleagues that a profound amount of our time is spent asleep across the entire lifespan 36% of our entire lives will be spent asleep it's just absolutely extraordinary and to put that into some sort of context is anybody here who's celebrating or just about to celebrate your 60th wedding anniversary anybody I know well when you do be aware that 21 and a half of those years you'll have actually been asleep so so when you cut the cake really it's not 60 that should be on it but 38 and a half years but the key point of course is that the quality of the sleep that you get will to a large extent dictate the quality of the waking day because sleep is not a down state so much is going on in fact some parts of the brain are more active during the sleep state than the wake state and really important biology is going on when we sleep so memory consolidation the ability with all this information coming in to actually consolidate it that absolutely critical sleep is critical for that and it's not just the retention of facts it's also the manipulation of information Yan born in the United in Germany has been able to show that a night of sleep can enormous ly enhance our capability of coming up with novel solutions to complex problems now these are kind of intuitive stuff but now we have the scientific evidence to back it up toxin clearance so some recent stuff suggesting that beta amyloid which has been associated with a buildup in the brain with dementia is actually cleared during sleep a tissue repair the brain is regulating the release of growth hormone growth growth hormone is very important in tissue repair and growth hormone is released during the first half of the night while we're asleep so much tissue so much tissue repair is going on there the rebuilding of metabolic pathways that have been burnt up as it were during the waking State a rebuilt at night and indeed energy replacement so it's a really really fundamental and important part of our biology and no great surprise that the generation of the sleep/wake cycle involves essentially every brain neurotransmitter and multiple brain structures you can think of the seaquake cycle on the slip the generation of sleep as being a network property of the brain it's a global brain event and that's really important for some of the stuff we're going to discuss in a moment now in addition to this sort of set of networks that we've discussed as I say every new your transmitter multiple brain structures you've got a range of important drivers and modulators we've already heard from Stafford about stress and of course societal demands as indicated here by the alarm clock can have a huge impact upon the sleep/wake cycle in a sense society can impose a sleep-wake cycle but if that sleep-wake cycle is out of sync with the biological desire to sleep then you can activate the stress axis and cause real problems and we touch on that in a moment so uniquely took in our species we have essentially a societal drive that distort sleep the second driver and modulator is perhaps the most intuitive part about sleep which is the longer you've been awake the greater the need for sleep the greater the build up of sleep pressure and a number of different substances have been associated with that with the development of tiredness so from the moment you wake in the morning then the sleep pressure builds up and up and up and up and up now you don't fall asleep invert usually sometimes there's a mid-afternoon dip and we may want to discuss that later because of the other thing we've heard about already which is the biological clock the biological clock is essentially saying now is the appropriate time to be awake and now is the appropriate time to be asleep and so what happens is clock drives asleep window so as the sleep window opens up the sleep pressure kicks in and then you go to sleep and of course if the clock and the sleep pressure are out of sync urine problems the clock as we've heard is centered around the suprachiasmatic nuclei the SCN and what's also extraordinary is these are the yellow cells here and these are the red fibers you can take one of those individual cells out stafford showed you of a slice ticking away in the dish actually that that's that property of the clock exists within a single cell so you can take one of those cells out stick it in a dish and you see 24-hour oscillations and so what that tells you of course is that the generation of these 24-hour circadian rhythms and is not essentially cell-cell interaction some sort of circuit property but in fact it's a sub cellular molecular oscillation and we now know quite a bit about that molecular feedback loop and in fact tiny changes in those genes and their proteins that make the molecular clock have been associated with morning nurse and evening us so morning less and eveness has a sort of a bit of a genetic basis as well as a developmental basis okay in addition to clock cells here essentially every cell in the body has its own clock so what's happening is that this master clock in the base of the brain is sending a signal out to regulate the rhythmic activity of billions and billions of individual cellular oscillators scatter throughout the the organ systems of the body so you have a fantastic circadian Network and then of course this internal time signal is of absolutely no use whatsoever unless it's course it's set to the external world miss Deborah saying the light-dark cycle perceived by the eye is the most important regulator of this internal molecular clockwork the eye is also doing something else it's sending projections to a whole range of structures within the brain some of which have been associated with alertness so when I look around the room now and I see lots of people falling asleep I know it's nothing to do with me at all it's the load of light if I were to increase the levels of light I would increase levels of alertness and that is something that can have a big effect upon the sleep/wake cycle many people before they go to bed stand in the most brightly lit room in the house you know cleaning their teeth now that will increase levels of alertness and actually can delay sleep onset at night okay what else have we got oh yes so what I want to say now is what Deborah talked about which is the pioneering of melatonin the biological marker of the dark and we know that melatonin can feed back upon the sleep/wake cycle in important ways in fact in some individuals taking melatonin at night can reduce the time it goes off to sleep by a significant amount so melatonin is doing lots of interesting things and as much as Deborah said it's a marker of the darkness and the appropriate physiology that we that we experience during the dark okay the point I wanted to make with all of this stuff is that sleep is immensely complicated or the seaquake cycle is immensely complicated and we see huge potential for disruption if for example you're a shift worker your misaligning activity with the biological need for sleep and so you can activate the stress axis if you're drinking a lot of coffee the caffeine and coffee can block the rise of the sleep pressure so that's how caffeine is interacting and of course it can delay sleep immediately if you have an abnormal light-dark cycle as deborah was explaining within shift workers and jetlag this can all be horribly disrupted and what we see of course is disruption of sleep largely driven perhaps by the by the stress axis you get real problems in overall health one thing we know about increased levels of stress is it suppresses the immune system and it may be that suppression of the immune system which is associated higher rates of breast cancer and colorectal cancer which have been studies in night shift nurses higher rates of infection also activation the stress axis will increase cardiovascular problems and indeed matter BOTS metabolic abnormalities such as diabetes - in addition to overall health disruption you have the ability of the brain to process information cognitive health the laying down of memory the coming up with new ideas and finally as we'll touch on very briefly our emotional and mental health sleep disruption is intimately associated with mental illness for example and finally of course all of these are connected together so you have this incredible framework of thinking about sleep within the broader context of our biology and our overall health now one way to think about the association between illness and sleep disruption is depicted here psychiatric illness in fact in severe psychiatric illness such as schizophrenia and bipolar there is immense sleep disruption I mean really profound sleep disruption as you see in neurodegenerative diseases as Debra touched upon in ocular disease shift working aging and stroke and trauma so why do you always find sleep disruption associated with these important diseases or part of the explanation is that sleep in circadian rhythm disruption may arise because the neural circuits that derive normal let's say psychiatric behavior are also shared by the sleep systems so a defect here that predisposes you to mental illness will actually have a defect here so there are common and overlapping pathways so for example we've shown that if you take a gene that's been linked to human schizophrenia and you have a mutated form of that gene in a mouse the mouse sleep-wake patterns start to collapse so genes that were never associated with the clock and the sleep systems initially when mutated have a big effect upon the clock systems so there's that shared pathways that's not the whole explanation of course because in addition to the overlap annealing pathways of mechanisms the psychiatric illness via stress social isolation and indeed the medication can impact upon the sleep/wake cycle and indeed the disrupted sleep via poor health for cognitive health and again stress can feed back and exacerbate these pathologies here one thing that's turning out to be really interesting is that in again psychiatric illness if you can partially stabilize the sleep/wake disruption in patients with schizophrenia you can actually not only improve the overall health consequences in these individuals but reducing one experiment levels of delusional paranoia by 50% so there's a very very intimate relationship between these pathways here okay what I want to talk about now in the last few moments is really to strip away this complex network and then talk exclusively on the relationship between the eye and the master clock within the brain now if you think about it we're asking the eye to perform two fundamentally different things the familiar function of the eye is as an image detector either a black and white an object against this background or indeed using color vision and what the eye is doing is grabbing light in a fraction of a second for getting it seen it and then is using that information to build up an image of the world but that's not the sort of information the clock once the clock wants an overall impression of the amount of brightness in the environment at dawn and dusk so that it can regulate internal time and these are very very different sensory tasks and and way back in the early 90s we began to ask the question will have a help can the I do this how can the understood function of the eye as an image detector also allow reliable brightness detection and so we took another look at the eye and just to orientate you what you see here is the eye and we've taken a little section here which is the retina and you see these are the visual cells the rods and the cones the rods providing us with our black-and-white vision and the cones are color vision and then there's various layers these layers here are associated with the first processing of the visual image and then these are the ganglion cells and then they collect this information and far this information into the brain via the optic nerve and we started to study mice with different ocular diseases but let me give you some background first here we have our mouse here we have a light dark cycle here we have a normal retina and you see it's a nocturnal so it's active broadly speaking when it's dark and it's asleep when it's light now how do we notice the eye well if we cover up the eyes this ability to entrain the circadian system is gone and the clock will drift through time and the clock is a bit shorter than 24 hours so it gets up a bit earlier and earlier and earlier and runs in it's in it's running wheel now we used a whole bunch of different sorts of mutants whereby the rods and cones had been affected and the animal was visually blind and what was extraordinary is that you can lose large numbers of these rods and cones and you can still regulate the clock and this really puzzled us and even we know back in the early 90s we were thinking well maybe there's something else maybe there's something else in the eye and when we proposed that there was huge opposition the argument was we've been studying the eye for 150 years are you seriously telling us we've missed an entire class of light sensor and what's more your experiments aren't that good because actually you haven't wiped out all of these cells there are still a few left and that's probably all you need to regulate the clock so finally we use the mouse model whereby all of the rods and cones had been eliminated these animals showed no visual responses whatsoever they had lost all of those cells and so the question is without any vision without new rods and cones what would happen to the animals ability to regulate its clock and to our intense pleasure we saw that they could regulate with perfectly normal sensitivity and then the argument was well okay well you remove the rods and cones but something else outside the eye has taken over so what we course had to do was but the old black glass is on again and the animal-free ran so very clearly there must be another light sensor within the eye and so what the hell is it if it's not the rods and cones what have you got left and we now know that it's these ganglion cells about one in every hundred of the ganglion cells is directly light-sensitive these photos to retinal ganglion cells and they are exquisitely sensitive to blue light so when you're looking at the screen now your photosensitive retinal ganglion cells are getting really quite excited and it's this signal that is primarily responsible for regulating the clock and there are as Debra said major clinical implications for this we like Debra have been looking at visually blind individuals visually blind individuals but it doesn't necessarily mean that you've lost your ability to regulate the clock so visual blindness does not necessarily mean clock bind blindness but sleeping 24-hour rhythms abnormalities are largely ignored in clinical ophthalmology so I've been working with my colleagues in the I Hospital Oxford and around the country and we've been looking at a whole range of eye diseases at an exquisite a level of detail and I won't show you the specific results but I will just show you the broad conclusions so there are two classes of patients there are patients with visual cell loss like our rod loss comas mice but they've still got the photosensitive retinal ganglion cells now normally what's happening is that the clinician will say well I'm sorry you're blind there's nothing more I can do with you that it what they should be saying is expose if they've if these receptors are still here and it's fairly easy to see if they're still active then these individuals need to expose their eyes to sufficient daytime light to regulate their sleep wake cycle it gets worse actually because of an ignorance about these cells there's been a tendency to say well your eyes are no use to you you can't see to look after your eyes they're going to be a source of infection it's so much simpler if we just well just pop them out and put a couple of those in because then it'll be so much simpler and of course what unwittingly the clinician might have done is of course they've already lost their sense of space but then of course they've lost a sense of time they'll drift through time for the rest of their lives an experience essentially unremitting jetlag and the second group of patients of course they'll have their rods and cones but as in severe glaucoma the inner Aetna is gone so the rods and cones can't talk to the brain and indeed those photosensitive ganglion cells have been lost but as Deborah said all is not lost one can in these individuals consolidate sleep weight to some extent with melatonin and there's a whole raft of new drugs on the horizon so the last slider and the last point I want to make is that clinical ophthalmology must appreciate that the eye provides us with both our sense of space and our sense of time and this is a great example of how a fundamental question driven bit of research how the hell does the eye regulate internal time and the sleep/wake cycle has led to the discovery of a completely new photoreceptor system within the eye and is now changing our understanding of the nature of the blindness and indeed in the clinical realm how you might treat blindness and the advice you give to patients suffering severe ocular trauma and with that I'll finish thank you

Channel: The Royal Institution

Views: 230,062

Rating: 4.8750806 out of 5

Keywords: Ri, Royal Institution, science, sleep, russell foster, melatonin, neural pathway, how to get more sleep, how to fall asleep, how much sleep, debra skene, stafford lightman, circadian, biology, health

Id: O0Uzy35uJzU

Length: 52min 35sec (3155 seconds)

Published: Wed Jun 29 2016