We Are What We Remember, with Dr. Eric Kandel

Eric you can still pull a crowd it's so impressive um good evening everybody my name is Tom Jessel I'm one of the co-directors of the zukan mindbrain behavior Institute um of Columbia University and on behalf of the Institute and the large world of Colombia I'd like to welcome you all to this first of this set of stavos Neos Foundation brain Insight lectures so I just want to give you two words of explanation about this wonderful Collision if you like of the niakas foundation and The zukan Institute The zukan Institute as many of you know is Colombia's new hub for inter disciplinary research which will provide a new center for exploration of issues of brain and mind that engages researchers in the biomedical Sciences in the School of Arts and Science the engineering the business school and no stone of Colombia will go unturned in terms of the zukan institute's impact and the niakas foundation has added enormously to this initial um burst of energy um surrounding the zukan Institute because it provides two things in the form of this lecture series it introduces some of Colombia faculty who will then um provide um insight as the lecture series says to what they're doing um designed for a general group of Faculty colleagues a group of local community Comm those curious and essentially everyone in New York that is alive should be attending these lectures and you can see most of them are um and the other thing the niakas foundation has done is that it is realized that the future of the science of brain and mind is vested in the Youth of today so it has sponsored at Colombia a teacher scholar program where we equip teachers who have enormous innate talent to go out and do perhaps a better job in engaging um the future neuroscientists the brine brain mindology of tomorrow and what's particularly pleasing about tonight is that many of the people I've just been talking about are here in person so um Mort zukerman Andreas dracopus steelos um and all of those teachers are hovering over there so rather than um you know um they're all a shy and retiring mob so maybe if you just wave your hands um on the front those the people can appreciate what you've done for Colombia I think would be wonderful um but I think you're all here to listen to tonight's lecturer who is someone who I think embodies the heart and soul of Colombia brain and mind and that is Eric candell so I want you to imagine that you're going to any city of reasonable size in the Western Hemisphere and you're standing in a street and you accost the first thousand people that walked by and asked them to name a neur scientist I think you'd learn two things from that exercise the first is that most people wouldn't have the faintest idea what a neuroscientist was and the second thing is that those of few who did would without doubt have named Eric candell as the one neuroscientist that they know but Eric is so much more than a neuroscientist um he is and has acquired the skills of molecular biology he is a trained psychi iatrist and so in my opening remarks I just want to sort of point out this multifaceted aspect of Eric's accomplishments that provides a challenge and an inspiration to all of us here at Colombia so when I think of Eric as molecular biologist I'm reminded of um another distinguished molecular biologist Alfred Hershey who um himself also a Nobel Prize for his work on bacteria phase when someone asked Hershey for his definition of scientific happiness he said it's when I do the same experiment every time and it always gives me new insight and Eric has created his own world of hery Heaven as it's called I call it sort of um what shall I call it um candel um let's think El contentment should we call it because if you see a smile on Eric's face it's because he realizes that he's only had one aim scientifically in his career and that is to understand The Human Condition through the study of memory and with each Progressive set of experiments spread over this 50 plus year time scale he's moved ever closer to that goal so Eric as I'll show you in a minute minute is in Hershey Heaven the psychiatrist in Eric represents a different provenance it's the provenance of Alois Alzheimer and Emil crelan the first describers of Alzheimer's disease Alzheimer you know revealed the pathological basis and crelin postulated that there was a specific pathology underlying each of the major psychiatric disorders that afflict humans and Eric in a sort of crelin like way I think maintains this confidence that it will someday be possible to identify the pathological basis of psychiatric disorders and I think you'll hear this in the lecture recently he's begun to address this fascinating problem of the distinction between memory loss that is a function of normal longevity and that with a more corrosive pathology underlying it and these advances at a molecular level together with Colombia colleagues are very significant and now finally I want to turn to the neuroscientist in Eric and this is just my editorial view that the real Brilliance of Eric was to take the large psychological Cannon of phenomenology and condense that and reduce that to a single synapse with two or at most three interaction neurons and to show how that explains many aspects of our underlying psychology but you get I've just touched on the science of Eric there's so much more to Eric these days you cannot run into an art historian who hasn't invited Eric to write a little essay on Kim sutin or duning or Jeff Coons even these days and so you know we are dealing with a phenomenon here in Eric where I want to try and indicate with data how when you engage Eric you get more than you could possibly have imagined you get more sometimes than you bargain for and sometimes you get more than you really wanted um so this week is Nobel week the Nobel prizes are being awarded and it's perhaps no coincidence that in physiology and Medicine the prizes were awarded to people studying the phenomenon of memory the ability of individuals or of animals to work out where they are in this big world around us through coding of neurons in the hippocampus and area that Eric loves dearly and this Nobel theme allows me to provide data that supports the idea that when you engage Eric you get more than you bargain for because one of the things the Nobel Foundation requires you to do is to write a short autobiographical essay on how you came to be where you are and so what I'm going to do is present to you six very distinguished eminent neuroscientists tabulated as the length of their autobiographical essay and I'm going to ask Andreas here to pick out which one he thinks might be Eric's autobiographical essay so these are the six Andreas come on use your neurobiological skills to Hazard a guess there uh we'll see who these are actually so this is David hubel Eric Rita L molini Irvin n Charles sharington and coming in at 527 words as opposed to the 16,000 that Eric fell compelled to give is torst and weasel another New York fixture here so this indicates Eric's uncanny ability to describe his passions and enthusiasms in science through the written word and maybe because of that it wasn't a big surprise that on the in the wake of this Eric started to write books that documented his account of his life in Neuroscience r large and those books in some cases became films and so here we have two of these here is Eric in Hershey Heaven smiling away here um and this is a film made of the book in search of memory by Petra seaga and on the right is Eric's latest contribution which begins to express his vein of artistic interest and talent and enthusiasm in um constructing in a remarkable way the consilience of activities in Vienna in the turn of the century so I cannot begin to describe how everyone at Colombia has benefited from Eric's Insight his challenge the standards he holds others to and so it's a particular pleasure tonight to introduce Eric to invite him to give this lecture we are what we remember um memory and age related memory Disorder so Eric come up here and relieve me of this this burden of introduction that is the most remarkable introduction I have ever received and um I'm not as young as I look I've been around the block a little bit but that was absolutely wonderful thank you um I simply wish my parents were here to really hear you because my father would be proud and my mother would have believed you I'm really delighted to have the chance uh to join you this evening and to talk about U memory uh memory is really one of the most magical capabilities of the Mind learning as you know is the means whereby we acquire new information of the world and memory is a process whereby we retain that knowledge over time most of the knowledge we have about the world we've learned and most of our skills are not built into our brain but are also learned as a result of this knowledge built over our lifetime we are in good measure who we are of what we learn and what we remember moreover as Tom pointed out specific disorders of learning and disturbance of memory haunt the developing infant as well as the mature adult mental retardation affect the quality of life for young people while the norming of weakening the normal weakening of memory with age and the devastation of Alzheimer's disease haunt the elderly memory is the glue that holds our mental life together without the unifying force of memory our Consciousness will be broken into as many fragments as there are seconds in the day without memory our life would would be empty and meaningless imagine a life without memory we see this in the tragic fate of a person we're going to hear from in a second Clive wearing whose image I depict here wearing is a brilliant musician who more than 20 years ago suffered from a brain infection herpes and sephtis that destroyed his hippocampus in medial temporal lobe and produced a dramatic loss of memory here is Clive warar how many years have I been out about 20 about 20 can you imagine to have one night 20 years long with no dream that's what it's been like just like death no difference between day and night no thoughts at all in this s s been totally painless which is not something which is very desirable really is it because it's precisely like death if you have no senses of pain you have no senses of any kind working either I don't remember sitting down on this chair for example all the city as it is that was unknown to me I've never seen a human being since I've been that's the first photograph I've seen of anybody and who is that photograph one of my sons I can't remember his name tragic the problem of memory can be simp simply divided into two parts the systems of problem of memory which ask the question where in the brain is memory stored and the molecular problem of memory how at each of these sites does dorage occur let me begin with the systems problem of memory by the middle of the 20th century we knew that many fairly complicated metal processes such as language could be localized to specific regions of the brain so we know the articulation the motor aspects of memory were located in the front of the brain in broker's area right near the vocalization area that controls the vocal cords while the perceptive area called Vera's area is in the back of the brain where sensory information comes into the brain but it raised the question whether memory which is such a complicated function has so many facets to it could also be localized to a specific region and there's several outstanding people including car Lashley professor of psychology at Harvard it's not Columbia but you got to get a job in Academia so he and ended up at Harvard and he was convinced that memory could not be localized to a specific function of the brain and the reason he argued this is because he used a particular complex maze task to test for memory and mice and rats subjects of his experiments are very smart if you deprive them of visual input they'll use tactile or factory information in order to find their way if you deprive them of tactile information they'll use Vision so they can compensate for one another but nonetheless he was not aware of this and he used this task and convinced many people things changed when wild the pfel came along the scene train is Columbia who is an outstanding neurosurgeon he went to the Montreal Neurological Institute and became interested in sort of higher mental functions and he wanted to explore that in a wake subject undergoing operation and he specialized in people who had epilepsies due to head trauma that left a scar tissue on their brain which produced the epilepsy but in order to make sure he doesn't damage broker's area veras area areas that are essential for the patient's function he developed a procedure whereby he could operate on unanesthetized patients he injected a local an anesthetic into the scalp open up the scalp open up the skull and knew that the brain itself doesn't have pain receptors so now he can work freely on the brain without having any worry so in order to make sure that the areas around the scar tissue were not critical for functioning he would stimulate different areas of the brain and see what he would elicit in the patient and it was marvelous he would stimulate one area patient would have visual experiences he stimulate another area he'd have motor experiences he wrote to sherington who' SP all of his career working on cats and he said imagine having a preparation that talks back to you and then he found all of a sudden when he stimulated certain areas he got hallucinations people remembered certain experiences you know bumping at the Charles zooker at the candy store uh meeting friends hearing a song that was played at their graduation and this was remarkable and they always found it in exactly the same area in the temporal lobe and a structure deep to it called the hippocampus and he studied this with his colleague Brenda Milner and they were really becoming convinced that this was important for memory storage but the really absolutely convincing evidence became when William Scoville operated in a patient that produced a very profound memory deficits and the way this happened is a very interesting situation the patient was known for many years as hm we now know it is Henry mullison he died a few years ago he was knocked over by somebody writing a bicycle and that gave him scars on both sides of the temporal lobe as result of this he had convulsions that initially were were very well controlled with anti-convulsive medication he was able to complete Elementary School go to high school get himself a job but with time the seizures get worse and worse and could no longer be controlled and he presented himself to scovel for surgical procedure to remove this scar tissue and the the tissue deep to it so Scoville operated on him and removed the hippocampus on both sides this had never been done before Penfield had only removed the hippocampus on one side as result of this bilateral removement of hippocampus hm was left with the most profound memory loss you could possibly imagine uh Scoville was besides himself extremely upset called a penil he said this is a tragedy this was just terrible what happened here uh and Penfield agreed he said look the most useful thing we could do is to study hm and see what we can learn from it why don't I ask Brenda Miller my colleague who's been studying these patients with me to come and visit you and study hm so she spent the next 15 years going back and forth between Montreal and New Haven to visit with hm and really found out an enormous about about it the first thing that struck her is how many memory functions he still retained despite the fact that he seemed in some ways to be so completely amnestic to have such a tremendous memory loss for example he could remember memories before the operation he remembered the awkwardness of his childhood you know his first dating experiences he remembered starting school he remembered to speak perfectly good English his IQ was unaltered so memories that occurred prior to the operation are not stored in the hippoc campus shortterm memory if you asked him repeat after me 884 5447 he could do this so you could give him new piece of information he could remember perfectly well for short periods of on what he could not do was to connect short-term memory to long-term memory he couldn't take new information and put it into new long-term memory for the longest time brender Miller thought this explained all of hm and then she made another fantastic Discovery she found that even though he could not convert new short-term memory into long-term memory he could learn new motor tasks this is the way Brenda M discovered that she hat she had hm do a mirror drawing task whereby he drew the outlines of a star not by looking at his hand or at the pencil but by looking in the mirror leard D Vin like this is difficult to do when you and I do that we make a lot of mistakes the first trial and the first day doing 10 trials we get progressively better the second day we start off with a few mistakes we get better and better third day we're perfect this is not just you and me this is also hm he does as well as you and I do but if you ask him hm how come you're doing so much better on Wednesday than you did on Monday he would say what are you talking about I've never done this before in my life seeing a dissociation between the conscious awareness of something and the motor skill and we see this in Clive wearing Clive wearing has one of the worst cases of Amnesia in the world I know it's like we did now day and night the same blank no difference between dreams or anything like that no sens at the brain has been totally inactive no dreams and no thoughts of any kind whatever Clive was a renowned conductor living in London when he was struck down by a virus in 1985 parts of his brain were completely destroyed including his memory however his ability to play music is unaffected do you feel different when you play music I've never heard a note since I've been y I don't know what it's like to play music and you're unconscious you played us some music about two minutes ago not known to me tot un man I've never heard of not yet just amazing he plays as well as he ever played he conducts as well as he ever conducted completely unaware that he's done it a minute or two afterwards the cooning when had Advanced dementia Chuck Close describes this very well would go into studio and be a different person all of the sudden he would start to paint Major Works not exactly of the quality of his early ones but still extremely interesting despite the fact that when he left the studio he was essentially inarticulate so this made one realize that memory is not a unitary faculty of mind it exists in two very different forms implicit and explicit explicit is what you normally think of memory it's the conscious recall of facts and events about people places and objects and this involves the medial temporal lob and the hippocampus and this was recognized in the Nobel Prize given out yesterday and this requires conscious attention implicit memory procedural memory is memory for skills and habits for non-associative and associative learning and involves different structures the amigdala the cerebellum and the simplest cases The Reflex Pathways themselves this does not require conscious attention so when you first learn how to ride a bicycle you say to yourself put your left foot forward put your right foot forward and you teach yourself how to ride the bicycle with the parents help after a while if you talk to yourself you fall off the bicycle you don't want conscious attention you do this automatically so I'm going to focus primarily on explicit memory storage and going to discuss with you what are the molecular underpinnings of this we know from the work of the Moses and o'keef that the hippocampus which store's memory is importantly concerned with space now you couldn't tell this by a New York taxi driver because if you ask him to go from 116 street to 165th Street he would get lost but if you ask a London cabie about this they have to take tests in order to qualify and in order to qualify they do this training for some time their hippocampus actually gets larger as a result of this experience so if you ask him the route a cab driver in London from High Park to Primrose Road the hippocampus lights up an Imaging experiments and the longer you drive the cab the larger the hippocampus becomes so there's an important lesson there don't ever stop driving your taxi now information about space in fact information about anything you to learn comes into what are called Association cor Dees that leads into the ananal cortex which is the input phase into the hippocampus which has both the Dente gyrus and the hippocampus proper we can study the same thing in mice because they have an exactly similar structure to the hippocampus the interal cortex and the association cortex and we can use spatial tasks you put a mouse onto a round platform that has 40 holes and you shine light and you play classical music the mice hate classical music they hate the light they're dying to get away from it and the only way they can get away from it is to find one out of 40 that leads to an escape hatch that allows him get away and after first they do randomly they go to any hole they see this is a mistake uh then they become more systematic they start with one hole and go systematically till they find the right one and after a while they eyes aha this is related to some particular marking in the wall they pick out the marking on the wall and they go to it and if you watch what happens with time you see that with time there's a strengthening of certain critical synaptic Connections in the brain you can actually see a growth of new synaptic Connections in the brain so let me just show you roughly what this looks like in Baseline you have synapses ending on a neuron so this is a press synaptic neuron this is the target cell in shortterm memory remember when you just repeat something for a brief period of time you get a functional strengthening so it acts more effectively but there's no anatomical change but with long-term changes when you repeat something so it goes into long-term memory you have an alteration in the expression of genes and I'll come to that in a moment and actual growth of new synaptic connections so you now have additional synapses that you didn't have before what does that mean this means that if you walk out of this lecture remembering anything that you heard here and this is not something that I urge on you but if you insist in remembering anything it's because you're walking out of this with a different head than you walked into this lecture with so this is the plasticity of the human brain you find this in experimental animals as well what are the molecular underpinnings of this if you look at short-term memory it's a change in the functional strength of a synaptic connection the synapse in the hippocampus use glutamate as a transmitter and you insert new receptors called Amper receptors to strengthen the synapsis but if you give repeated stimulation interesting things happen you recruit a modulatory system which in the hippocampus is dopamine could be other modulatory systems serotonin acetylcholine and other regions of the brain this activates an enzyme that generates an intracellular messenger called cyclic a that recruits the cylic dependent protein kinas the translocates moves into the nucleus and there activates a gene that turns on long-term memory that's called kreb cyclic game pre-response element binding protein this is found in almost every memory storage both implicit and explicit and that gives rise by acting on Downstream targets to the growth of new synaptic connections now the nice thing about mice is we can do genetic experiments and we can test how important is this cyclic g p dependent protein kind is going into the nucleus preventing it from activating CB well if we do that and we do the same task we gave it before this is a normal Mouse and this is a mouse in which the cyclic g p system has been compromised the longterm memory has been severely compromised that puts one a position to begin to explore things about how memory varies as a function of age now I must tell you something very interesting when I was a medical student we never discussed Alzheimer's disease we never discussed age related memory loss it's not that we didn't know about Alois Alzheimer it's there were very few people who live that long one of the amazing things about the 20th century is that the age of people's life expectancy has increased dramatically in 1900 this is not when I to medical school I went in the early 1950s but still 19 I know you think that I went was born there um the average age life expectancy was 50 years now 76 years for the weaker sex 81 for women the stronger sex remarkable and many of these as a result of changes in life habits better died less smoking you know not eating fatty foods exercising etc etc etc but as a result of that we began to see really significant amounts of Alzheimer disease there is a genetic form of alimer disease which is very rare that has an early onset but the sporadic form the form that people commonly suffer from first makes itself manifest in the late 60s early 70s but really becomes significant in the ' 90s when half the population has it but with time people not only lived longer but they lived better and we began to see a weakening of memory that seemed to be slightly different from age related memory laws although it bore some similarities to it and it was called euphemistically benign senescent forgetfulness and some people considered this a legitimate separate category there wasn't any strong empirical evidence others thought that it was an early stage of Alzheimer's disease and this is a problem that's interested a number of people including my colleagues and myself to ask the question is normal aging a distinct entity or is it an early form of Alzheimer's disease so we carried out a series of comparisons we looked at the age of onset in the progression we looked at the anatomical localization of the two disorders and the defects involved let me take you through each of these we find it difficult to do age of onset um of age related memory loss uh alone in people because it's difficult to dissociate that from alim's disease we don't have excellent ways of diagnosing early stage of alim's disease um but in mice they don't have spontaneous alus disease but if you look at the mou mouse that I was showing you before a young Mouse does very well in this task but as it reaches midlife which is thought to be the onset of age related memory loss you begin to see a significant compromise in its ability to learn a spatial maze moreover we had known for years that all sum disease begins in the ental cortex as Scott small and others carried out Imaging experiments they found that there is a separate entity the so-called age related memory law that begins in the dyus a rather discrete region quite separate from the aninal cortex so we teamed up together to try to explore this in molecular terms to compare the dyus in the ental cortex in people who died without having any evidence of all disease and we carried out aphr metric chip experiments on postmortem material from people 38 to 90 years old in which we took the Dente jarus and compared it to the ananal cortex to see whether there were changes that were unique distinctive to the dent HRS and if so that followed a systematic Trend we found 19 candidates as the first step we explored one of them rbab 48 because it really has such an interesting uh change a system systematic change is a function of age so this is the level of the messenger RNA for rbab 48 and this is the level of the protein it systematically declines the function of age and it declines in a very very specific region you only see the decline in the dentus you don't see in the aninal cortex you don't see in other regions of the campus which I'm not showing you what is rbab 48 turns out that it's an old friend I mentioned you before that long-term every gets triggered by cyclic a activating kreb one kreb one recruits a partner The kreb Binding protein but they don't really activate genes until they recruit rbab 48 which is a histone acetat it acetates lysine residues and that allows you to alter the chromatin to open it up so you can transcribe genes so it really throws this switch that allows you to turn a gene on so it's a very important component of this tripartite switch so in humans you can do these wonderful coalation experiments but you can't do causal experiments for causal experiments you have to turn to experimental animals and we turn to mice and we ask the question if humans show a systematic decline in rbab 48 do mice also show a systematic decline because we know they have an age related memory loss and if you look you see that in the Dente gyus there is in the normal Mouse as it ages this is a young Mouse this is an old mouse a deficit in rbab 48 moreover it's specific to the Dente jarus you don't see it in any other region of the hippocampus I only Show You ca3 ca1 by comparison now we can do something very nice we can express this Gene we can block the gene we can block the Gene and turn it off so let me show you what we did can you take I showed you that an old Mouse has a def in rbab 48 what happens if we take a young Mouse and shut off rbab 48 can we create in the young Mouse age related memory laws this is a young Mouse this is an old mouse this is a young Mouse in which rbab 48 is functioning but here we shut rbab 48 off of the genetic trick we then allow it to come back and memory comes back so we can recreate age related memory loss in a young Mouse by turning off this Gene that's pretty that's pretty effective here um can we restore memory in an old mouse by enhancing the expression of rbab 48 and the answer is yes this is an old mouse we now give it rbab 48 and boom restored the memory loss so we can now ask the question I told you before you can pick up I'm being carried away with myself here you you can pick up in humans a deficit in Aging in the Dente Jaris we cared out Scott small in our group out this experiment in mice and we saw with elderly mice you saw in fact this defect again quite specific in the Dente Jus if you inhibit rbab 48 so you inhibit this one gene you can recapitulate the Aging deficit this characterize characteristic of the old mouse and of old people the rest of the hippocampus you don't see this deficit so let me summarize what I've told you so far I think this provides the clearest evidence yet that there is a distinct entity age related memory loss that is separate from Alzheimer's disease its onset is earlier it begins in midlife contrast to Alzheimer's disease which sporadically begins much later the anatomic localization is different D Jaris versus ental cortex and it involves rbab 48 which is part of the CP system while there is no such abnomal ity um in alim's disease now the fact is you know we're all you know very athletic I mean look at the shape that zukan is in for God's sakes this guy works out he's got a trainer blah blah blah blah blah blah does this have any meaning does this affect any of these processes we're talking about can exercise help overcome age related memory loss everyone says it does is there any evidence for it so the last few months two new factors have emerged that I want to sort of finish my talk telling you about one is Young Blood which you're not going to get a transfusion of tonight uh and the other is Young bones young blood is a very kakami experiment that was carried out by a group that just published in nature medicine in which they cross beused an old mouse with the blood from a young Mouse old mouse had a cognitive deficit when they exchanged blood and gave it the blood from a young Mouse they improved this cognitive deficit and it functioned like a young Mouse so there's something in Young Blood that's good for you now we knew this all along my mother told me young blood is good here this is the final proof my mother was right she usually was but what are these factors that are carried by Blood we don't know but I'm going to indicate to you one candidates that comes from Young bones this is the work of Jared keni at Columbia chairman of the genetics department who's made a wonderful Discovery he's found that bone is an endocrine organ it relases a hormone called osteocalcin osteocalcin acts on the muscle it acts on the liver it acts on fatty tissue both white and and black fatty tissue it acts on test on the testes it acts on the pancreas but in addition to all of these visceral organs it acts on it acts on the mind it acts on the brain and Gerard has found that it increases the level of these modulatory transmitter that I was talking about dopamine serotonin it increases neurogenesis which we're not going to go into so it also in so doing prevents some of the consequences of deficiencies in these modulatory transmitters like depression and anxiety it reduces an inhibitory transmitter called Gaba and it also favors hippocampal dependent spatial learning and memory so my colleagues and I began to speak to Gerard to see what happens in age related memory laws you know is osteocalcin helpful there so we looked at the candidate molecules that we'd identified the CYCC game p dependent protein kyes kreb and RBA before the8 we found that we gave osteocalcin we improved the level of each one of these candidates so you give this to an old mouse and upcome the level of each one of these if you knock out osteocalcin you reduce the levels of them what are the behavioral consequences of osteocalcin Novel object recognition task which is requires the hippocampus this is a young Mouse this is an old mouse this is the old mouse this is the old mouse with osteocalcin so this one substance causes a nice restoration of age related memory loss but it doesn't simply work in the agent which I showed you before you take a young Mouse and you improve their performance by giving him more osteocalcin so even the young people in this audience are probably not working on their maximal fun fun level this applies even to my young friend sitting in the first row if you look at the level of osteocalcin in the blood as a function of age you see it decreases progressively with age so what do you think is likely to bring that back exercise a simple running task begins to bring the level up this only stays up transiently because you're only doing it for a short period of time but certainly one possibility that we're now testing is if you now expose the mouse to long periods of running whether you can bring the level up in a more sustained fashion and have a significant staining effect on age related memory loss number one and number two even though it's a kakami experiment Gerard and I want to see whether or not this is one of the key factors in young blood that rescues the old mouse so let me simply summarize the second part which deals with these factors that osteocal released by bone amates age related memory loss and it does it through the players that are important in age related memory loss and because with aging there is a decrease in bone mass you are in fact releasing Less osteocalcin in the blood and exercise is one way of keeping the moment it's particularly true for women where bone mass decreases more significantly than with men that exercise allows you to keep that level high and both osteocalcin and the factors carried by Young Blood act through kreb one I didn't tell you that the factor that acts through Young Blood also acts through CB one and this I think provides additional evidence to the fact that one can separate age related memory loss from Alzheimer's disease as distinct entities and tells you as you probably know that a sound body helps assure A sound mind let me simply point out the colleagues in my lab that did this work and particularly uh selus cosmus who I think is here who's carried out the experiments on osteocalcin has made a wonderful contribution and of course the osteocalcin discovery itself is Gerard ceni need did a lot of the classic earlyer work and Frank ay and Laura Carman with whom we've had the privilege of collaborating here and I think Lor's also here have made wonderful contributions so I want to thank you for inviting me to give this lecture I'm just delighted to be here thank you very much uh I will be delighted to ask any easy questions save your hard questions for lat any questions please Charles okay Mt uh I think at any point in your life this can help but obviously earlier is better but I think if any one of us begin at this stage I think one can help so I think it's extremely important yes in fact if you if you look at just the the statistics why do people live so much longer until this recent obesity epidemic there was a general tendency for people to number one stop smoking which is dramatic because in this audience 25 years ago most people were going out having a smoke right away no longer happens although ecigarettes may bring that back uh and they do more exercise and they eat better so really Public Health measures have proven to be extremely important and my guess is they're also important for age related memory loss yes C do do you exercise yes what do you do I I am fortunate enough to work in a building that is next door to the student dormatory and it has a pool and I try and most days to get there and swim and when I travel I take my bathing suit with me and the rest of the you know doesn't take a lot of equipment to swim and I try to go to hotels where there's a pool I'm invariably the slowest person in the pool that's my claim to fame but I try to swim as often as possible and the weekends I play tennis I play singles I assure you you can beat me so don't worry about that but I do play s yes cardiovascular what's the what's the mechanism in order to get this effect of bone mass swimming is probably not the best exercise walking is a superb exercise in people my age walking is a superb exercise and I actually moving to Manhattan from Riverdale in Riverdale you drive every place in Manhattan you walk every place so one of the I'm sorry osteocal what's the mechanism the biochemical mechanism for producing osteocal it it is there is a Machinery in bone that generates osteocalcin and it is released with exercise and probably with other things there are other things that act on bone do this a question there well hi my name is shington thank you for your um so I was thinking that it would be a very interesting study if you looked at those who are paralyzed and um those who are paralyzed and what would be their um I guess their rate of age related um memory loss I didn't hear the the group of people you referring to those who are paralyzed those who are paralyzed yes you know I don't know the answer to that question it's a very good question uh Tom do you know do you know the answer to that whether there's an increase in age related memory loss in people who are paralyzed yeah it's an excellent question I just don't know the answer to that it's probably known Dr kandell I was wondering her do you know that I see you know yeah uh I can't quite repeat because didn't get all of it but I think you said what is my recommendation I say what would your recommendations be if you wanted to optimize these new Notions in order to give it the greatest critical utility I that probably the best thing and the easiest thing to recommend is walking and walking at a Brisk clip and they've actually defined the amount of walking they have to do sort of let's say half an hour minimal every day I mean it's got to be a serious workout it can't be just going you know to the grocery store and back if that's around the corner um and I think this would be extremely beneficial and obviously one needs to do outcome studies and there is actually a group in Columbia Ursula stabing is involved in that I'm actually helping her a little bit with that that is systematically studying the Aging population also being intellectually involved um that you know one has done studies that has shown if you take a group of women 70 years old and you divide them into two you ask one group to go into Elementary School class and help the kids that have difficulty with reading so these women have had no teaching experience but they all know how to read so they work with these kids and help them with their reading the other 70 the other half of the population age 70 doesn't do anything they go along as a control if you do cognitive tests six 12 months later you find that the women who are involved in remedial teaching function better on a variety of cognitive tasks there is now great interest I'm actually I'm going to do a program with Charlie Rose on this in cognitive enhancement through video games Mort will tell you the world is being changed by access to this and it's addictive for many people particularly young people but older people also enjoy playing video games and the issue that is now the concern is people can improve quite dramatically in the video games but the question is is it specific to the particular video game or does it generalized to cognitive embellishment as a whole do you see what I mean there is some sports you become very good at but doesn't help you with other sports so there's some tasks that you can become very good with a video game but it may not generalize to broader knowledge ofm that needs to be explored but all of these things are opening up and this is why I think the zukam and mind brain Behavior Institute has a future there are many unsolved questions in this one area alone D I was I was wondering to what extent is the effective exercise I'm over here can I ask my question to what extent is the effective exercise truly protective so if so if a patient exercises most of his life and then then stops exercising does his age related memory decline go back to where it it might have been early or does it does it advance we don't know the answer to that because you need to do systematic epidemiological studies in order to show that you can't use a single patient as an example uh I must tell you that's unusual most people who do exercise in a fairly systematic and religious way become addicted to it they feel lousy when they don't do it so I think it's a rare case but I don't know the answer to this I'm sorry I didn't hear the last part what happens in the case of what what happens if if a patient has a stroke or breaks a hip it falls down and they can't exercise you know to the extent to which then people don't peret are wonderful questions look I'm outlining for you a set of questions that are just emerging right we didn't have good evidence until a couple of years ago that age related memory loss is in fact a distinct entity different from Alzheimer's disease so now we have a distinct entity we have reason to believe from animal models and from preliminary human uh experience that this is a more reversible age- related memory deficit and preventable As you move along but we're at an early stage we need to do large scale clinical trials which would be easy to do on this yes you described one you've described one physiological pathway and presented wonderful evidence for it I'm wondering if there might be other Pathways of I should have said that so it's more complicated I don't mean to say that osteocalcin is the only Magic Bullet out there okay I'm saying it's encouraging to think that there is a significant factor out there there are others probably that are also important I completely agree with you so do you know the effect size or that there's no way of really estimating effect size no no thank you Dr Kendal I have a question over here to your left your left here um I'm just curious if um either in Mouse models or in human models if there's been any studies on gender differences because I know that um females are more likely to have osteoporosis in different bone issues so I'm wondering if like that would like then have a large larger memory loss to just age related stuff for female either mice or patients is your question whether people with osteoporosis have a greater memory loss than those who don't basically yeah one one doesn't really know this this is again this is a question one can really look at because there is in a great Hospital like you know New York Presbyterian you know a lot of data on people with osteoporosis and one can begin to do cognitive tests on them you see when a patient comes into a hospital with osteoporosis he doesn't routinely get cognitive examination at all but this is something that probably will be part just like taking a blood pressure and taking EKG COG exams will become routine as we realize that this is a a variable that can be can be manipulated therapeutically yes Bo what about diet I think in I we don't know in terms of osteocalcin I've given you all the data we have so far but certainly everyone has the feeling that diet you know leads to Healthy Living leads to encouraging people to go so I think it's very important this is why the OB obesity epidemic in the United States is frightening uh now it's spreading into Europe as well it's just really terrible um hi Dr candel uh here waving right in front of yes that was your Tom um so I apologize because this may not be an easy question but I will hopefully it is sure so when you give with the exercise right with a one bat of exercise you have a transient increase in osteocalcin and then you have a transient Improvement in memory and then it goes back to normal when you do the blood transfusion from The Young mice that effect in the older mice persists even though it's just one sort of dose of blood so doesn't that no the the the cross profusion experiment but it's a relatively acute experiment they didn't carry these mice for very long periods of time okay so one doesn't know whe When osteocalcin is metabolized whether they go back this needs to be done this is a field that is just emerging and you're asking extremely good sophisticated questions that have not yet been explored I laid it on the table because of that very fact I think it's interesting this is a literature we want to follow and work we want to encourage because it can really affect large number of people yes function I'm asking about the recent research showing that drink in Coco leads to improved cognitive function there are there are 400 claims of this sort with different kinds of you know pills vitamins Etc none of them are really very very convincing uh one really needs to do very systematic trials in order to make claims like that it may be right but at the moment is not convincing Dr this gentleman he has a I'm sorry so yes so we we have a large patient cohort that's been on bis phosphinates for some time including ibus phosphinates which block uh know osteoclastic activity there are new drugs that are coming along that may increase osteoblastic but is there any information are there any data on the patients who have been on these for quite some time as to whether they might have we're waiting for to do that study I think it's a great we need we need funding as we all too Dr Kendell Dr Kendell on your left on your left um so osteocalcin uh seems to be inversely correlated with with memory at least in aging is there any other cognitive effect of osteocalcin that um perhaps there's a reason for it decreasing over time that would give older people some advantage or is is it for now thought to be just involved in memory well from it's involved in other things besides memory I think I pointed out to you that it's also affects modulatory systems in the brain that are important for anxiety and for depression in a beneficial way this may also account for the fact that elderly people have a greater tendency for depression that may be related to it but I'm just guessing here uh so you know when it's just beginning to explore this um it does other things besides memory a long large number of effects besides memory first of all I've only been speaking about things that affect the brain it also affects many other organs in the body is one of my slides Illustrated is there any hope for the Alzheimer's patient except for loving care yes I think there is great hope for Al uh I think the issue right now is there are probably several this is I don't work in this area I'm passing on to you what is contemporary thought that there are several one has the feeling that from a scientific point of view the understanding we have of the pathogenesis of Alzheimer's is probably pretty Advanced uh there are several treatments out there that according to our current understanding of pathogenesis should be effective they have not proven to be effective by and large and the reason that is thought to be the case is by the time a patient presents with sign significant symptoms so it's obvious that he has Alzheimer's disease or even you know earlier than that the patient has had the disease for some time and if you've had any disease for five to 10 years difficult to reverse it so the effort now is to try to stop people earlier to try to use diagnostic ways of Imaging plaque formation maybe even get through cereal spinal fluids levels of a beta to be able to detect these things at an earlier point so one can Institute therapy earlier as well as looking for new therapeutic approaches but I I think most people working in the area feel that even though it's been disappointing so far we're in a verge of significant advance in all timeas disease also there's a question there on thealony hi um I was wondering if it you could answer the question is it possible to synthetically produce this substance and so do you think it could be beneficial in the prevention or treatment of learning disabilities in young children that impair memory you I didn't we neither of us heard you sorry um I was wondering is this okay please I was wondering if it was possible to synthetically produce the substance in order to prevent or treat uh learning disabilities that impair memory in young children or in adolesence learning impairment I I I don't want you to get a simple idea that all learning impairments is osteocal that that just nonsense there are many reasons for having learning impairments for example there could be some developmental abnormality that leads to learning impairment we know that there are a number of these that happen uh those would not be helped by these approaches but you know these things again in principle are amable to analysis and understanding it's a more difficult problem but there no reason one couldn't get at that but there are many many reasons for cognitive impairment particularly in young people um also is it able to be produced synthetically the osteocalcin can it be produced synthetically could one could osteocal be produced synthetically yes there is no reason why that couldn't be used but there's no reason to believe that this would be helpful in young kids with cognitive impairment see because as far as one knows or we can measure this their their blood osteocalcin level is probably reasonable they have young bones but I don't want you to walk away thinking that this osteocalcin thing which you have throwing out as an initial clue as a contributing factor potentially to age related memory loss is the Panacea you know the brain is extremely complicated there are many things they can go wrong and produce cognitive impairment that are that are not related to ocalin two more questions one is in the back here thank you so much for being here and for inviting the alumite to listen to you it's been we're delighted that you're here I am delighted that I am here um you I've read a few of your books um I study um contemplative sciences and I'm interested to know what your um understanding or um connection that you might have with monks who have been studied that they've had they done a lot of research science on the effects of meditation and I'm wondering if in that population as the Elders of these Tibetan Monks primarily who've been studied um do you see the effects of meditation having um very positive effects towards cognition and memory I'm neither a monk nor a meditator but I have several friends who get enormous benefit out of meditation uh and I would not be surprised um also I think for example um if you're depressed and you respond effectively to cognitive behavior therapy or to Dynamic Psychotherapy I think the chance chances are this not only will improve the quality of life but longevity to just give you an absurd example if you're not depressed you're less likely to do harm to yourself okay but there are other reasons probably you know your lifestyle is more Dynamic if you're not depressed many other things change so in so far as meditation helps people it probably has you know a variety of of offsprings I just have no direct experience with that but there are people who have experience with that one final question at the back there micone um Dr kandell um I believe that in some of the Scandinavian countries they have wonderful epidemiological studies going back do you think there's any possibility that data mining of that you're absolutely stud no no we uh Gerard and I have actually talked about this we're doing this in another case we've identified in a completely different context a gene that is involved in post-traumatic stress disorder it's called Tia and we're now looking at Scandinavian populations to see where there's also a marker for other anxiety States it's a fantastic population it's been used for schizophrenia studies for depression studies it's it's a very valuable resource the question was whether it might have hidden in it the effects of what you're talking about here that nobody seen before I think it's worthwhile looking into you're absolutely right so I just want to end with two comments yes one is that Eric is being a little modest and selfin facing he he has held his own with Tina Turner in hours of German television and so issues of transcendental states are not new to Eric the second point is that in science there is a Continuum between the audacity of bold hypothesis and the pursuit of the frankly absurd with a fine margin and Eric for 50 years as I think you've heard this evening has found this way of choosing bold hypothesis that quickly transformed into the accepted Cannon of neural science and we've been treated to a master class in that this evening and Eric we're all very much in your great

Channel: Columbia University

Views: 13,286

Keywords: eric Kandel, Memory, Brain

Id: IV4nDxG-nfc

Length: 70min 8sec (4208 seconds)

Published: Tue Jan 13 2015