 We look forward to your comments. Well thank you very much for the attention of speaking here, for truly working on participating such an ancient ritual. I should say that I hope you will forgive my New Zealanders and I must admit that I had to leave New Zealand because I no longer support what we are going to do. So, I have a review and I'm hiding away in my head. So, don't be afraid of the evidence growing up. But what I'd like to do is to tell you, not so much about my own specific research, but about the background in which my research sits, which is part of this ongoing project that's been going on for a well over 100 years now to understand one of the most amazing y mynd, rywysb y bydd y ddaw y bydd i'n cyffredineth mewn awr. Rydyn ni'n rhywbeth a gwbl i'r hyffredineth. Ymlaen i'r rheswm Caerdydd Gwyrdd hwn. Roedd ychydig yn gweld yn ei ddweud y gŵl, rydyn ni'n ymgyrch yn yr un i chi'n meddwl i'r cwrwm o'r pethau oherwydd ychydig? Rydyn ni'n ymgyrch ei bod ei fyddfa i'n ddefnyddio. Roedd yna wedi bod nhw'n wedi yw'n meddwl, a ma wnaeth i dim lleiaid i broses rydyn ni, Byddwn i, mae'n meddwl bod eu llyso powr yneth yn yr éch gwirionedd yma chi'n ymddangos. A mae'n resgwyddaeth. Mae'r myfyrdd y tîm oedd yn gwirionedd i'ch engagemiannol, ond mae fydd yn dda i gydig i'ch eu pethau whesgaf oherwydd maen nhw'n gweithio'r meddwl, ac mae'n dim ystafell y dyw sy'n gweithio. Mae'n gennyng y clywed o'i dod ystydd oherwydd yn gallu meddwl ar gyfer o'u meddwl mewn meddwl, ac y ddech chi'n gweithio cronwyr oherwydd. yma, dwi'n meddwl i'r ddweud ac yn ddefnyddio'r llyfr i'r fwyllref yn ymgyrch, a dwi'n meddwl i'r llyfr i'r wneud, mae'n meddwl i'r gweld, y tîm a ddwy'r gwrdd â'r hyn, ac mae'n meddwl i'r ystyried yma, mae'n meddwl i'r gwaith yn yw ymgyrch, o'r rhai gwrthangos, oherwydd mae'n meddwl i'r gwrthangos yma. Mae'n meddwl i'r gwaith eich gwrthangos, ac mae'n meddwl i'r gwaith eich gwrthangos, Byddw'r ffeindio ar eich dynnu – byddw'r edrych o'ch gweithio'n gwneud y dynnu cyhoedd yna. Byddw'n gwneud i'r ffein yn eich credu. Byddw'n gwneud yn eich greu am y dynnu ac gallu ei safod o'r ddeuglau a fyddydd i fynd i'r wneud i'r wneud i ei breng Ethereumau, a fel amser i ni'n ffigur ddiwethaeth, mae'r rwy'n meddwl am ddau cael ei ystyried ar hyn yn hynod gyda eu hynny i ddeuglau. that goes on to modern-day memory, node monestage monstlessness, are they in the same method of losiding? So we've learnt for a long time, space and memory are somewhat met. It turns out, actually, that they are extremely interro garments in a way. Psychology started to think about memory at the end of the 19th century and William James, who was often called father of psychology had some very very far reaching business to say about memory. And he had this intuition that memory was something to do ystod o'i bwysig ar hyn o'r ffodol, a yn ystod y byddol, mae'n ddarparu. Mae'r rhanigau yn gallu'n ddifogledig o'r ddweud o'r rhain sy'n ddweud ond y bydddo yn cael eu bwysig a'r bwysig o'r ddweud o'r ddweud o'r ddweud o'r ddweud o'r ddweud o'r ddweud o'r ddweud. Mae'n rhanigau diwyddo'n ddweud ond mae'n cael eu ddweud o'r ddweud o'r rhain. Ac mae'n gweithio i ymdочll yn y ddod yn gweithio. Mae'r ddod yn y ddod yn gweithio ac yn deilio'r cyflwyneu. Ac mae ydych chi'n gweithio'r ddod yn ddod yn gweithio'r ddod yn ddod yn gweithio'r ddod. Y dylaid ddod yn yr ymgyrchol yn meddwl fwy o'ch sgwrs, a'i gwneud o'r lluniau a'u ddod yn brif, a'r ddod yn y ddod yn meddwl ar gyfer y ddod yn meddwl, ac mae'r cwestiynau yw'r cyfnod i'r bwysig yn eu cyfnod i dda i'w gael gwahol, dwi'n ffasio'r ffordd o'r ffysiologistiaeth, roi'r wyf. Fy ffornol gwybod y ffornol o'r ddinwys yn ei ffornol ac yn ei bwysig Mae'r ffwrdd yn fwy o'r ffordd. Mae'r ffwrdd yn gallu ffysiologistiaeth ar y gynny. Mae'r ffwrdd yn ymwybod yn ymwybod am y ffysiologistiaeth angen ac mae'r ffyrdd yn'u ffyrdd o'r ffysiologistiaeth angen Mae gennym gobeithio'r gweithio. Mae'r cyfrifusedd ddeud. Mae'r cyfrifusedd mewn gwahanol a'u gwahanol. Mae'r cyfrifusedd ar y golleg sy'n ei wneud o cair o'u gwahanol. y gallwn wedi bod fy nifer o gyforfyniadau yn Llyfrgellfa, yn gwybod â'r ddau i agor i'r hyn o ffwrdd gwaith, a yn dweud yn dweud y ddau i'r hyn o ddau i'r hyn. Dwi'n ddigonol bod mae'n methu o'r ddeunyddol, a dyfodol y ddau i'r hyn o ddau i'r ddau i'r ddau i'r hyn o'r hyn o'r ddau, o'r ddau i'r ddau i'r hyn o ddau i'r hyn o gwybod, Yn y gallwm gwyllus newid, maes i gylwg y cyfryddiaeth, gyda'r cyfnod gyda'r gylwg yn unig, nad ydych chi'n seith yn y gyfnod yw'r gyfryddiaeth. Yn y gallwch chi'n seith y mae'r gyllidau nesaf hefyd i'r cyfryddio sydd wedi eu cyfrŷl ac y byddwn i'r cyfrannu cyfrannu'n gwyllus, iawn i'r cyfrannu cyfrannu cyfrŷl. Yn y gwyllwch gyda'r cyfrannu cyfrannu, mae'r gyfrannu cyfrannu cyfrannu'n gymrydau'u gwirioneddau, The un-conditioning stimulus is the one that normally produces a response, like in that case, and the conditional response is the learned response. And that method became the method of study for the next century. In fact, we still use these methods, so it's still really commonly used for formation of associations between simulator and responses, or simulator and other similies. So we realize now that memory could be forged in very, very complex connections between these methods. Ond yw'n meddwl am y cwestiynau y cwestiynau yn ei wneud. Yn y peth yn ei gwaith yn mynd i ddau y ddau, ac mae'n mynd i'n mynd i'n gwaith yn y ddau, mae'n gwybod yn ei cyfrifio'r cyfrifio'r cyfrifio'r cyfrifio. Yn y ddau, y byddwyd, y mynd i ymweld y byddiolol yn ychydigol. Felly, yn y rhai, byddai'n credu darwch chi'n dweud y ffordd, ychydigol yn y stwyl yn ei ddau ymweld, ychydigol yn y stwyl yn y ffordd. So, Lashley was a neurobiologist who developed methods for trying to find where these memory traces were. These memory traces were called the N-gram, and he felt it should be possible to find out where it was in the brain. So, you rattle the hole and the dog salivates. There's somewhere between the nerves that are generating the saliva in the ear, somewhere in that pathway. There's not really this new connection that's formed. And if you make a disconnection somewhere in the brain in that pathway, then you should be able to polish that condition as well. And he's been years and years and years trying to do these experiments. And this picture shows you as kind of a summary picture of all of the various lesions that he made, that sort of cuts that he made in the brain. So, this is the brain of a dog, I think, looking down from the top and looking to the side. And each of those lines is an experiment that he did, making what he was trying to do, making a disconnection. And, as you can see, he made a lot of experiments, a lot of these connections, and never really managed to polish the condition response in God's. And he wrote when he kind of summed up his work in this monograph of the 1940s. He said, I sometimes feel reviewing the evidence on the localisation of memory trace, but the necessary conclusions are only just as much possible. So, it just seemed like it was really resistant to damage. But what he did find, actually, that seemed quite important, is that he could somewhat degrade memory if he made enough damage. So, the more of the cortex, you know, the outer part of the brain, the more of that there was damage, the worse the animal's behavior got. But he never really managed to be just obliterated in a simple way that he thought. So, that suggested that maybe memory wasn't just in the A part, but maybe it was distributed across quite wide dimensions of the brain. And that's why no one of these experiments was able to have this effect. So, picking up on this idea, people started to think about the possibility that memory might be distributed across a wide variety of brain tissue. And one of the people who was really, really foresighted in thinking about this is Donald Head, who was a neuropsychologist working in the Guild in Canada. And he wrote this book in the 1940s called The Organization of Behavior, which laid out, in this really beautiful way, his ideas about how knowledge might be organized in the brain. So, he's thinking now not just about these simple stimulus responses, but actually more cortex ideas, concepts, and so on and so on. And he came up with this idea that he called the cell assembly, which is basically that if you activate in your mind some concept or other, let's say you think of a cat, then some number of neurons in your brain become active simultaneously. And he called this the simultaneous active group of neurons, a cell assembly. And the idea that he was trying to articulate is that knowledge is formed by these cell assemblies, which get constructed on the basis of your experience. And when you retrieve them, somebody shows you a drawing and that makes it look like a cat, that activates that cell assembly and those neurons become active together. So, what this picture is showing is a kind of a cartoon of bunch of neurons and red ones are showing the active ones. And the idea that he had, which was really simple in retrospect, but really profound, and has had enormous influence, is that, at the beginning, when you first encounter, let's say you first encounter a cat, you're a baby, you first encounter a cat, then there aren't, there's nothing special about the connections between these neurons. So bunch of neurons come active. Let's say, for example, that there are neurons that respond when you see pointy ears and have neurons that respond when you see fern. How bunch of these neurons get activated altogether when you see your first cat. And his intuition was that the simultaneous activity of these neurons should cause the connections between them to get stronger. So that the next time something activates some of those neurons, because of those strong connections, they will activate all the rest of them and the whole assembly will spread into life. So somebody shows you a pointy ear and a ffer and you get the cat. So you reactivate with that cell assembly. And so his idea was that synchronous activity between neurons should cause connections between them to become stronger. We now call that the head rule, and it falls to the basis of more of every neural network model of thinking. All of the stuff that's coming on now, D-Mind, AI and all of that stuff. It's all fundamentally based on the head rule, this idea that connections strengthen, form and strengthen between sequencing active elements of your representation that you're trying to pull. Now neurons that participate in a cell assembly may also participate in a different cell assembly. So when you see a dog, some of the same neurons, when you see a dog, won't come active as when you figure out the cat or see a cat. So not only are these concepts distributed across the brain, but they share some of the substrates. So really, when you're thinking of a dog and you're thinking of a cat, what's different is the pattern activation of neurons in your brain, as well as which neurons that have that. So the rest of the paper message is that memories are there for distribution across the entire brain, and that, of course, means that it's really very difficult for neuroscientists to study them, because how are you going to go about testing memory in the way that Blashley was trying to do if it's distributed across the brain? How are you going to reach in and pull out a cell assembly for a cat? It just seems to be incredibly difficult. And we also have a scaling problem, so if you look into the brain, and you see lots and lots of neurons, they're very, very tiny. Here's a micrograph of neurons. Each one of these little balls is smaller than a hair, so they're very tiny. And we have lots and lots of them. So I googled it quickly. There seems to be around about 100 million people taking a few tens of millions in the human brain. So there are lots and lots and lots. And when you think of the number of connections, so each neuron has maybe thousands and thousands of placements on its branches that can connect to other neurons. So the number of connections between neurons is more than the number of particles in the neurons or something like that. It's very, very large numbers. Not only that, but even just the connections between regions of the brain are really more stewness. So this is a very famous sub-diagram by David Bannett, and he's a neuroanatomist. And he's spent most of his career tracing which parts of the brain are connected to which other parts of the brain. And it looks like pretty much every part of the brain is connected to every other part of the brain. So this is a little fragment of the visual system. I know we have a lot of visual and gross scientists in the audience. And this is just the visual cortex. And there's just some regions of it. You can see every one of those lines is connected between one bit and one other bit. So again, we have this huge scale problem where we're trying to understand how the score works. OK, so that was in the sort of 1940s, very redistricted throughout the brain. And the thinking was really that memory was not really dependent on any one particular structure. But that picture began to change as a result of a very important event in the 1950s, which was this neuropsychological case which came to public attention. And this is the story of H.M. who is one of the most famous neuropsychological patients of all time. And he was a young man. So this picture is from a very size of his life. He lived with him until his 80s. And as a young man, he had really terrible epilepsy, temporal lobe epilepsy, which is epilepsy which starts deep in the temporal lobes of the side of the brain. And what happens is that a seizure will start in that part of the brain. People will feel that we are the last ones that are hallucinating. And then the seizure spread right across the brain. And they'll have a full node, 12 miles seizure, and they'll fall to the floor twitching with the prophet, and they lose consciousness, and they lose control of the man, and sometimes can die, but not usually. But it's very debilitating, obviously. And he was having many of these seizures in a day. And it was completely incapacitated. He had to quit his job and came to the neurosurgeon where he was in Skogel and was there and said, can you help me? And Skogel did some tests and started, but he had a focus for the seizures. So it's at the beginning of the seizure. Started on both sides of his brain. So in both temporal lobes. So neurosurgeons have found that, and there used to be a temporal lobe epilepsy, you could remove a temporal lobe, and seizures would never start. So basically, the best thing they would be cured. And also, people seem to be quite fine afterwards. So Skogel said to ATM, we're going to do this procedure on you, on both sides of the brain, because you see no focus on both sides. But you'll be fine. So it was a very serious operation. But actually, Skogel had done a lot of few patients by then. And people did seem to be fine. But the patients that he had done along were a schizophrenic people who were very, very severely compromised in other areas of their lives anyway. So they seemed to be fine as far as they didn't seem to be much different after this that we looked for. For ATGM, it was really different. It was immediately powerful. He had very profound amnesia, and couldn't remember anything that happened from that moment, from the moment that he woke up from his surgery for the rest of his life. So you remember pretty much all of his life up until that point, so you, who he was, and what his job was, and where he lived, and his parents were, you know, basically you could ask him all sorts of questions and he knew all about his past life. But he didn't remember that he met you 10 minutes previously. You'd been out to get a coffee, and you'd come back again, and you'd completely forgotten it. So he could remember for as long as his attention was on something, but at a moment his attention was on something else. Everything was gone. So it seemed that whatever surgery he had done to him better to destroy a memory part of his brain. So Skogal teamed up with a psychologist Brenda Milner, and they studied ATGM. And they studied him for many decades after this. And they concluded that in the temporal lobe there's a structure called the hippocampus. And they concluded that the hippocampus must be a memory structure of some sort. So this is a picture of the hippocampus. So this is ATGM. This is a schematic. This is the brain seen from underneath. And you can see that this is a normal brain. And these are temporal lobes here on the sides. So they're kind of behind the ears and quite deep and low in the brain. And then this is where the surgery was. So he's just got gaps where the temporal lobe should be. So it's quite a big procedure. And if you look at the cross-section of the brain you can see that down here so this is the cut that's been made parallel to the face. So this is the temporal lobe here. And this is the hippocampus here. And you can see that it's gone here. So the hippocampus is very harsh in the temporal lobe. And so Scoville and Lila concluded that hippocampus might be something to do with memory formation. So on one hand we've got memory distributed throughout the brain but on the other hand we've got what looks like any structure that's important to memory. So what's going on with that? So it became very important for people to look at hippocampus and try and understand what was going on. Now it's quite deep in the brain as I mentioned. This is it here. So this is the red as an hippocampus. This is a glass-brain picture. It is dissected out. And the natinists love seeing patterns in what they find. I don't see what does this make me think of. So I've activated some cells in their brains and for some reason this can activate an hippocampus to cell assembly in the natinist brains. So the hippocampus has agreed to seagorse. So it's by their negative hippocampus. So it does look remarkably like seagorse actually. So this is it here. Now it became a kind of imperative to find and understand what was going on with hippocampus. And to really understand how a red structure is working you need to be able to actually go in and look at the neurons and find out what are the neurons doing and what are they saying to each other. So you need to be able to get the electrodes into the brain and listen to the neurons. Now how do we do this? Obviously humans are somewhat resistant to having electrodes based on their brains. Although actually quite a few humans send electrodes in their brains and that's set up to be really useful. So these days we still do this temporal though removal procedure to cure epilepsy. Now they do it just on one side of the brain and it's still fine if you do it just on one side. But also to try and minimise the damage we try and identify the exact place where the focus is on the epilepsy and to do that they put the electrodes into the brain. And so the neuroscience has capitalised on this and we've been able to listen to the human hippocampus as well. But mostly we look at animals. So animal models have been tremendously important to neuroscience for all sorts of things. And the rat is the animal choice because we know so much about rats and it's born the reason you look after it. And they're quite like humans in many ways. And we should be able to consult with that. Rats are really smart. They're really friendly and resusible. And they do all the things that we do that they navigate around and they form memories and so on and so on. So the rat brain is a really, really good model of the human brain. And so we spend a lot of time studying it. This is the rat brain here. It's much smaller obviously because rats are smaller but also it's simpler because it lacks the very folded cortex that the human brain has. But everything is still there. It's just smaller and a bit simpler. So if you look at the rat hippocampus and cross-section it's got this really amazing structure. So this is a close-up micrograph of a hippocampus. And so this is the cortex over the top here. This is another one of these coronal sections that's been made parallel to the face. So the cortex is up here. You can't really come to see it. But this kind of curved structure around here and this curved structure here, these two interlocking regions, that's the hippocampus. And it's just very regular and very beautiful. It's just an amazing thing to see on a microscopic section. And because on the rat it's quite large you see almost any cut that you actually ran into. So to understand what the neurons are doing in the hippocampus you have to put the wire. So this is actually the representation of a physical wire. So it's exactly what the wires are about that we put into the hippocampus. There is fibers ahead and we kind of twist them up to give them some rigidity and also to give us more recording opportunities. And what we do is we elicitise the animal by tying it to the whole of the skull with a dental drill and put one of these to the wires then lower it through the brain and then to the hippocampus and then seal up the whole of the skull and then attach it to the connector and then let the animal cover for the roots of it. So now it's got the sort of cat on its head which that's as in mind that it's got to be puzzled by the cat but they now have a little cat on their head. But that then provides the possibility to connect that connector through a little cord and wire to the computer and actually listen to what the neurons are saying. So what happens is that this wire that's sitting among these neurons is detecting the electrical activity of these neurons. So they're very, very tiny neurons and the electrical pulses that they make are like a few tens of microphones. They're really small. But that's enough to be able to to take through the wire and then amplify and then to take through the computer and you can actually hear if you feed the apple through it asking you you can actually hear the neurons and I'll tell you why in a second. So people got very excited about the hippocampus because of HM and one of the people who got excited about this historic key food at the time had just started his new album and he's a young man at the time and he'd come to University College which is a program and he had decided to try and understand what the hippocampus is doing and so he started applying this technique to put in lack of electrodes into the brain and he felt expected of recording from free moving animals. So up until that time people had always done these experiments with anaesthetised animals so they wouldn't move around and that's very easy to record. They found that as soon as the animals moved around the electrodes that neurophysiologists usually used were made glass at that time and glass is very rigid and they found that the neurons the moment the animal moved, the brain would move and the neuron would pale itself on the glass electrode and stop firing but they keep developing these metal electrodes and they're very flexible so as the animals were walking around the electrodes kind of walked around and followed them around so actually he felt that he could not only record a neuron but he could follow as the animals were moving around for some number of hours or days that turned out or sometimes even weeks a record that's in the literature is 154 days so it's an extraordinary state of progression. So what he did was he would have the animal walking around on some kind of surface usually just in a box or on a little platform or something like that and he was collecting these nerve impulses which look like this on a oscilloscope screen so this is for traits that you would see and if you pick off the spikes which are the action potentials the nerve impulses then you can do things with those spikes you can kind of do various type of analysis about how fast is the neuron firing and is it firing the regular way or is it firing the versus off and what he found was this is a very extraordinary thing that he noticed which is that if you listen to where the cell is firing you find that the action potentials all occur in one place in the environment so every time the rat goes to that corner this neuron was something coming really active and every time it walks away again it would fall silent and it would walk around a bit and it would be silent and it would come back to that corner and something would start firing it again and if you record for maybe 10 minutes or so you find that all of the action potentials in that one neuron are trusted in this one place in that box and I keep this going a few times so we found that this was very reliable so different cells fire different places but each one had this kind of case that it likes to fire so he called these cells place cells and he proposed that these cells were forming a representation of where the animal was in the environment so something like a measure of that if you like so it was a bit of a controversial idea and it wasn't really anything to do with memory as far as we were going to tell but it was a very, very interesting idea and people got kind of intrigued by it so this is a real place cell I'm hoping that in this video we'll play it down so this is a rat in a box a sheep by a sound is the lower box and see how it would drive the rat by that little bit in the north of the box that fires and then everywhere else it's pretty silent notice that there's a couple of bits there as well that's a place cell and place cells have turned out to be a credible goal of information about how the mind works that's what the case is so based on this I keep and his colleague and they tell them this is a psychologist they wrote this very controversial book called the hippocampus's cognitive map so they impose that the hippocampus is making a map of space and that map is used to organise memory so if I have a method of loci in a way the brain has kind of come upon space as a really useful way to keep your memories organised and to help you retrieve them again so people sort of rammed this idea but said oh ok so if the hippocampus is involved in space then we ought to be able to see some evidence that you need it for doing spatial things and various experiments were done a lot of the way and hundreds and hundreds of experiments but one of the very very influential experiments that I ran was by Richard Morris who was working in so he started these experiments actually in St Andrews and then he moved it to Emile and he was my PhD supervisor so when I got to Edinburgh in the early 90s I wrote for Richard Morris and he had developed this method for measuring the spatial capabilities of rats it's called the water maze it's a kind of swimming pool for rats but there's an escape platform hidden somewhere in the pool and it's just below the surface so the rat can't see it or smell it and they can't really tell where it is by any sensory means and when you first put the rat in a pool it swims around randomly and then a box into the platform climbs onto it and kind of looks around and clearly kind of notices where it is because the next time you put it back in the pool it's much quicker to find the platform and after about three or four times it goes straight there so it seems to have figured out where the platform is even though it can't detect it directly so to do that it must have had to somehow figure out where it is in the pool based on things that you can see in the room around it so here's the picture of a swimming rat and what Morris found was that if you take a normal rat and take the platform away and swim round and round in the place where the platform was so the platform was there so this rat was hunting round and round and trying to find the platform so clearly it knew where it ought to be however if you found that if you make lesions or damage to the cat that's kind of similar to HM and this isn't to be found actually because I'm writing to John and Keith then you put the rat back in the pool and it just needs to search aimlessly so it looks it's clearly searching so clearly it remembers that there's a platform there somewhere but it doesn't seem to know where it is it seems to have just lost its ability to find it this way around it so all sorts of experiments since then have found similar findings so practically any task any kind that's got a special component will be affected by HM and that's also a few for humans and in fact with humans we've also got to look at what happens when humans have chemical damage and that's actually quite common so if people have some traumatic event that's trying to brain-oxid and hemocampus is often the first thing to be damaged because it's so busy it has a very high oxygen consumption so there are quite a few people walking around with damage to the cat life and also people without time this disease are developing chemical damage as they're very very first thing that happens so we have a large number of people with chemical damage and every test of special navigation that we've come up with they seem to be affected Eleanor Mawir has done some pioneering work at the University College looking at not just the people with damage to the chemical but also just looking at what parts of the brain of the normal brain are active when people do navigation tasks and she published this really eye-catching study of studies at London taxi drivers so she picked London taxi drivers because that's been all their long navigation so the navigation control starts and we're going to go ahead with it so she got these guys into the scanner most of the guys got them into the scanner and said okay, either imagine if you're riding around or Sony developed a virtual reality taxi driver game that involves riding around London so she got them to play this virtual reality game and either way she found out that they were having to think about the route from one place in London to a different place in London and then the campus would have come very active and with Hugo Spears who was in the student at the time on the post office they showed that no idea is an influence activity but they showed when the jury were the course of thinking got where they were going exactly when it's active so it's a really amazing study once she's really thanks for it and she did some structural analysis of the brain of the taxi driver and she found that the ones who have been a taxi driver for a long time actually developed an enlargement of the back part of the in-campus which is the part that in ramps have been associated with navigation so that's the part where if you make the damage then they can't solve the walkways task so the taxi driver's back part was enlarged so you can stand the goal of this and then reduce this and it's really powerful the spectrum of this so the canvies thought this was fantastic but they were participating really happily and just honouring the spectrum studies and she won the ignoval prize so I don't know people who doesn't know what that is but it's basically that there's a counterpart to the Nobel prize and it's for a study that's first made people laugh but in Nobel prize studies they're genuine science they're really genuinely good science so that's who it came to be O'Pief meanwhile was becoming very famous for this study of place cells because place cells were becoming increasingly important and we were actually going to realise how critical they were for our understanding of space and he was the co-recipient of the 2014 Nobel prize Nobel prize and stuff so O'Pief was my post-bots supervisor actually so I've been privileged to work with oh and Hugo Spears is now one of my associates in the Institute for Hades of Neuroscience so I've worked with some of the really seminal players in this field that's been really amazing to me ok so we've got the impacts that's used to be recorded for Spatial Economy but what about non-spatial memory so memory in general because HM had not just his ability to find a way around but he'd forgotten everything at least everything that you consciously can bring to mind so in fact there were certain things that he could learn he could learn he could learn new motor skills but he couldn't learn to remember the things that happened to him so we learned from him that there are at least two kinds of memory one is some automatic motor memory like that of the cars and the other is a more conscious memory we had to call to his mind and we called that type of memory episodic memory or to character memory and that's what was gone with it and not just memory so along the way I've also found that people can't handle damage also but not only can they not remember the things that happened to them but they can't even imagine possible things that might happen to them so if you get people who can't handle damage to imagine standing on a beach and to describe what they could see in their mind's eye they can tell you what should be there they can tell you, well, let's come stand in the sea and so on but they don't seem to be able to create it in any kind of spatial framework so they can't say, well I'm standing on the sand in front of me as a sea and over there there's a box there's no special coherence to their imagination so it's beginning to seem like the head of canvas is sort of the like the sort of I think of it as like a stage on which you kind of assemble of your memory if you like and if you don't have that stage you haven't got any way to assemble your set and then you can't something we've talked about the mind palace the creation that you construct in your mind that you use to organise your mind so now we have this problem how do we go about studying memory given what I said earlier about the fact that it seems to be disputed throughout the break so in the 1990s a few things came along that made it possible to to ask questions that had never been asked before and one of the really important discoveries was the sequencing of the genome so this was a project that began way back from what's been correctly proposed that DNA will discover that DNA is the start of the universe so for those of you who don't know I'm sure it's not the DNA but DNA is two strands of molecules that are kind of twisted together and the molecules have on a distance called base pairs and base pairs come in four flades and the sequence of those base pairs is essentially the genetic code so each strand has a sequence of base pairs and the complementary strand has kind of a complementary set of base pairs and together they form or essentially the genetic code so this is kind of hunt on that began right back in the 1950s really picked up speed in the 1990s and new methods came out to find out what was the actual ordering of these base pairs so these four kinds A, G, C what was the order and there are millions and millions of these things so it was a really, really big job but in the 1990s it became impossible to automate this process and to do it in a hugely faster way than before and so they started to find whole genome sequences so in 1995 their first sequence was a virus which has one protein in base pairs so even though it's a tiny little virus there's quite a lot of stuff quite a lot of information packed in that tiny little bit and then it takes an entry increase so three years later their sequence of the first multicellular organisms C, L, E, N which is amazingly it's been amazingly useful to neurobiologists because although it's just a tiny little word it doesn't sort of spend so useful like it moves in an organized way and it can show informed memories maybe not it's solid memories like we do but it's certainly symbolizing memories so it's been a really good model of organism and all sorts of fundamental biological processes and then in 2002 their sequence of mass genome and that's been really important because mice and rats are some of their favourite raw organisms and then in 2004 they declared the human genome sequence although actually it turns out there's a few things we've sort of figured out but basically most of it this is pretty much there so we now have the sequence but the trick now is to find out what the sequence means so knowing the sequence is not the same thing it's just like knowing all the neurons in the brain tell you how the brain works so we'll be able to decode quite a lot of it so chunks of these base pairs form genes and a lot of these genes are the code for the proteins which then go on for more cellular machinery so we'll be able to identify huge numbers of genes and that's given us incredible tools for asking the same questions so in 1990 it's not only the sequence of genome but we've figured out how to manipulate it and we can do that in the three main ways that we've introduced the last one to them so you take your genes so here's a kind of schematic of a double-stranded DNA and you've got a sequence of base pairs of neurons of your gene so there are various things you can do one of them is that you can take that gene out and you can put a different gene in so you can, for example, take out the gene around ours and put in the gene you can just take the gene out so you can do what's called a knock out so for example you can knock out the gene that makes a certain kind of neuroclasing to the receptor and then say now what when you're on the stool now that the animal is missing these receptors now often when you do that the organism that is sort of surviving because you've taken out something really critical for its life so people have had to find ways of knocking out genes or the passing genes in a way that's much more restricted and in our sort of decade or two it's been possible to target the manipulation not to every cell in the body but just to some cells at some times of the animal's life so you could localize its effect in space and also in time and that means that you can kind of reach in into the vector horses and just tweak something so for example you can give an animal an ejection of a drug that will temporarily silence the genes that make a certain kind of neurotransmitter in the receptor just and into campus for example so now the animal is just missing that neurotransmitter in that part of the brain but everything else is fine and you see what it can't do and then you come back on screen and go back to normal and then you see what it can do and so on and so on so that's been really amazing advanced and the other thing that you can do is just to add new genes so you take the genes that are ordinary that you need to add new ones so using these methods we can able to do two things that have been really getting changing for neuroscience so one of them is to see what's going on so there's a whole bunch of organisms that are out there in the world that do something that humans can't do which is that they have bioluminos so if you go on holiday to mediterranean or something like that and you're already walking on a beach in the evening you see the sea look like luminos that's a beautiful and you go into a doerocase and you see that example you have to go on a doerocase which is really really popular because it's starting to start that's bioluminos and it happens because there are genes in these organisms which are able to live light when they're simulated in particular ways so after we sequenced those genes people thought hey why don't we take some of these genes and stick them into animals so they did that and then the other thing I'll show you about that in a second I'll take other kinds of genes not just one of the fluorescence but things for example to the kinds of receptors so here's an example of putting fluorescence genes into animals so this is a mouse it's a baby mouse that has one of these genes green fluorescent protein in every cell that is boiled so when you shine that fluorescent light on that mouse it will also close green which is a thick somebody may now be trying to mark it for the rest of the pets but they get the mouse out of it for sure but from a neurobiological point of view it's not that useful but it's kind of pretty physical but what is useful for neurobiologists is that we can now insert these genes into neurons for example and so when we are now trying to fluorescent light on the neurons light up in a particular way you can see it and the way that you can get these genes into these neurons there are different ways so you can actually do genetic engineering on the embryo so that the animal will have these genes in every cell that the body mouse might have showed you but the other thing you can do is you can attach the gene to the genome of the virus so for example the animal virus or the other virus and you can get that virus into the brain so that it's modified so that it's not disease causing to humans usually but the virus its job like what viruses do is they dig into cells and they attach themselves to the genome of the cell and they get that cell to start making more viruses so if you pitch a gene to that virus it will also get into that cell and cells start making that gene as well and so doing that you can get only certain cells to express for example green fluorescent protein for example you might want to light up only cells in the canvas so that's been a really good way of looking at the neurons and I was using a method that we were able to get a really beautiful picture that I showed you earlier on where the cells it's not just a green fluorescent protein but there's also a yellow fluorescent protein and a red one and a blue one and what they did was by which they were just randomly infecting cells in one of these they had better control over the cell so they ended up with just a whole bunch of modified cells and that protein is expressed right throughout the cell and not just in the cell while you're also in the axon so you can see using these colours you can kind of trace simple axons right through so this brainwave mouse has been really useful for anatomists so it also makes fantastic pictures for neuroscience tools it's really good so that's a way that's been an officer way of getting cells to light up with this fluorescent protein more recently still a group in the states found a way to get cells to express green fluorescent protein only if they have been active so this is a method called tagging activity tagging and the way it works is that when a neuron comes really, really active so let's say for example an animal was walking around where it goes into the place field of a place cell the place cell suddenly becomes really, really active that active is associated with the switching on of some genes and in particular there's one gene called CFOX which is just it's part of the basic housekeeping for that cell but it's a really good marker for activity for that cell when the CFOX gene switches on you know that cell is active so what they did was they found a way of getting green fluorescent protein only to be expressed in cells in which the CFOX gene had been turned on so I won't go into details of how they were but basically it's a way of lighting up only cells that were active so by doing this you can for example see which were all of the neurons in the canvas which were place cells for them to get into place so this way of activity of tagging neurons is very, very important because remember I said that memory is distributed throughout the brain and that makes a really, really different study so now we have a method for looking at which cells in a cell assembly were active you can just see which are the ones that are lighting up green when you shine a fluorescent light on they were the cell assembly before that particular experience so reporting on active cells has been one really important function that's been given to us by a methodology the other one is you can actually change the function of neurons by inserting new genes and the way that this has been employed to incredible effect in the last 10 years is to exploit a property that some organisms have that is to be light sensitive so most of the cells that I've always aren't light sensitive because they're a case of bone and light never really gets in but there are quite a lot of organisms who are really simple and they don't have much tissue and they're essentially transparent so light will penetrate light through and blue green army is an example and these have lots of genes that are actually switched on by light and the way that that happens is that the light activates a receptor in the cell membrane and the receptor gets up in ions and cells and then that triggers the chemical process of those genes so I made the biologist and said why don't we take this gene for light sensitivity in these blue green army and spit them into a mammal you know I've done it before and I'm very interested in why I'm doing it this one and he said well why would you do that because there's no light inside the body anyway so but what happens when you do this is that you make these cells potentially sensitive to light so you can spit them in a mouse and you can make cells in that mouse and then you can shine a light into that mouse and an optic fibre so this is a really clean tissue but here's an example of that actually this an optic fibre so we're at work as we would normally use a wire recording cable this mouse rat has an optic fibre going into this brain and when you shine a light done with optic fibre it will activate light sensitive proteins and membranes of those cells that you can spit around or whatever and the membranes proteins will change their shape and let the ions flow and that will activate the cell as if an action potential have activated the cell so from the point of view of the neuron it doesn't know whether it was another neuron that stimulated it or whether it was like that all of those there's more of these ions coming into the cell and that's a method called optic genetics so basically you've used genetics to make these cells light sensitive such that when you shine a light on, they're not active now how can you use this to study memory so what you do is couple this with an activity tag and I don't know how many of you are still with me because this is a couple of me but I'm just going to tell you this last fully normal or the scale which I think is one of the most amazing developments of my time so what you can do is you can create a new memory and an animal that's had this optic genetic manipulation so that's exactly what Tiger did he took a mouse and he gave it an experience and what he did was he gave it an unpleasant experience and that activates the hippocatus because the hippocatus is the thing that becomes active when you go into the place and you have the experience and that activated all of these place cells and because the place cells were all activated that turned on the sephos that activated that turned on the fluorescent protein and said, sorry, not the fluorescent protein the light sensitive protein so he attached the light sensitive protein to the sephos gene so that only the cells on which sephos was turned on would express this light sensitive protein so only those ones would be light sensitive are you with me so when you shine a light into that mouse only the cells that had been activated by that experience would respond to that light so that's what he did he took the mouse he put it into another environment another planet had never happened and with some of the mice he just didn't do anything and those mice didn't do anything either they weren't around to mouse things they weren't bothered about that because they didn't have any reason to trade but some of the mice had shone the light down their optic fibre and those mice froze in fear now the reason and he did various kind of control experiments to rule out some of the other possibilities but the reason that's a pretty compelling argument is that when he shone that light on those mice that activated those neurons that had been activated by a spiritual experience and reminded the mouse of that spiritual experience and you know ringing the mouse oh my god I'm in that horrible place again we don't exactly know what's going on in the mind of the mouse but we do know that the mice froze in fear you can shine the light on a mouse and have that experience you can shine a yellow light down that fibre which doesn't activate those neurons only the ones with the light that activate those circuits so the inescapable conclusion is that the cell assembly for that experience had been reactivated by the light so these scientists had been able to manipulate the brain essentially and manipulate that memory so that's been gone to a whole bunch of even more common experiments so what they've done for example is they've been able to take a mouse make it afraid of the place give it some experiences together with the activation of those cells by light that make it unafraid of that place and then put it back to the original place and the mouse is no longer afraid and so on and so on so in other words they've been able to edit the memory such amazing science fiction type of stuff because not only are we looking into the brain and seeing these memories but we're manipulating them afterwards and you know there are a lot of weird and wonderful possibilities but there are a few possibilities as well because it gives us the time we've got to imagine being able to edit some of these traumatic experiences to make them slightly less traumatic so that they're going to deal with it and so on but just from an experimental research point of view it's given us this tool to understand how memories are stored and where they're stored which fits the store where it's on but we could only have dreamed about that in the last century so it's been a really exciting development and I feel very privileged to have seen it come out three months I can't wait to see what happens in the next session so I'm going to just put it there and thank you for your attention I've given you a lot of information I hope I've just professionalised it too fast so I'm very happy to take questions and talk about what this is