 Thanks Robin It is recently published book synaptic self the neuroscientist Joseph Ladoo asserts that nature and nurture are different things But instead are different ways of doing the same thing wiring synapses in the brain Thus he reasoned the essence of self is a reflection of the pattern of interconnections in your brain and Those connections take place at the synapse The novelist Salman Rushdie has often been quoted to have said life teaches us who we are If we accept that we are our synapses as Ladoo suggests Then it is fitting that this conference's first speaker is dr. Eric Kandel Who has made one of the greatest contributions to our understanding of the biological answer to the question? How does life teach us who we are? Dr. Kandel has unraveled the key molecular events of how life's instructor experience Can alter a single gene whose activity leads to anatomical changes at the synapse? And it is those changes that enable a wide variety of organisms to acquire and retain a behavior Through an elegant sequence of experiments dr. Kandel has uncovered the genetic switch that converts the transient changes made to the proteins involved in short-term memory Into the lasting structural changes that occur at the synapse in establishing long-term memory In doing so dr. Kandel has demonstrated a new way of thinking about how to approach the problem of understanding the brain his laboratory has pioneered the now often traveled bridge between molecular biology and the quest to understand human cognition But it might come as a surprise for some to learn that a majority of the studies That led to the awarding of the Nobel Prize to professor Kandel were not performed in humans or monkeys or even mammals No, they were performed in an invertebrate a marine mollusk called a plesia, californica commonly known as the sea slug And I mentioned this because the excitement that lives in the details of his work May cause us to overlook its power as an example of the unity of life Life's instructor in shaping who we are Operates via a universal mechanism found throughout the animal kingdom Operating with little regard to an organisms presumed stature in that kingdom be you a fly a Sea slug a human being or the pinnacle of evolution the echo locating back So let us keep in mind the significance of professor Kandel scientific achievements as we learn and remember The words of the other gifted investigators who have been invited here to share their life's work with us To paraphrase ladoo learning and recording life's experiences is what enables us to rise above our genes Without the capacity to alter synapses and Stabilize those alterations Who we are becomes merely a reflection of our genetic constitution Impoverished and unaware of self Life without memory is no life at all Dr. Kandel is currently a university professor at Columbia University and a senior investigator for Columbia's Howard Hughes Medical Institute and Is a member of the National Academy of Sciences? His work has been recognized with numerous honors including the Albert Lasker Award the Wolf Prize of Israel the National Medal of Science and of course the Nobel Prize in Physiology and Medicine Award in the year 2000 his research has guided current thinking on the social and scientific aspects of human illnesses such as schizophrenia and depression as a teacher Dr. Kandel has trained many talented scientists and is co-editor of the landmark textbook principles of neuroscience a Book that seems to double in its physical dimension with each new addition Finally as a fellow teacher of neuroscience Neuroscience, I would like to extend my gratitude to dr. Kandel for providing us with a beautiful scientific story that inevitably Arouses a passion in our students We look forward to hearing more from that story today dr. Kandel I'd now like to ask the audience to please join me in welcoming dr. Eric Kandel Michael. Thank you for that extraordinary introduction Myself described in quite such glowing terms as you generously did today. I'm really sorry. I didn't tape it so I could Play it for my mother-in-law You know the old saw that behind every Nobel laureate. There's an utterly astonished mother-in-law This has been such a remarkable day for me at Gustavus Adolphus So I didn't tell anybody about this until just now, but at 5 15 this morning a very peculiar hour I got a telephone call from Stockholm And it was Michael Solman and he said Eric He said this is your second visit to Gustavus Adolphus And I said yes, sir, and he said I really want you to take very careful notes and please Report them back to me Because when December 10th comes around this year, we want to make sure we get it absolutely right It's really wonderful to participate in this Nobel symposium and I want to thank President Johnson and Michael Farragano And Tim Robinson and everyone else who is involved in making this possible As many of you know in the last five decades We've witnessed a remarkable increase in the explanatory in power of biology That is likely to have a broad impact on all aspects of modern thought Including how we think about the mind and therefore how we think about ourselves as Result when intellectual historians look back on this period They're likely to acknowledge that the deepest insight into the nature of metal processes will not have come from the disciplines Traditionally concerned with mind. They will not have come from philosophy from the arts or even from psychology or Psychoanalysis, but from biology This is because in the last two decades biology has participated not simply in one but in two major Unifications of thought that bear and our understanding of mind First there has been a remarkable Unification within biology itself This is brought together into a common molecular science the various sub-disciplines of biology Cell biology by chemistry developmental biology Immunology the biology of cancer and even the biology of nerve cells the building blocks of the brain This unification derives from the major advances in our understanding of the gene Which has revealed how its structure determines heredity and how its regulation determines cell development and function These remarkable insights combined with the ability to sequence genes have given us a Marvelous sense of the conservation between different cells in any one organism and of the remarkable Conservation across widely different organisms Second there's been a parallel Unification between the neural science the science of the brain and cognitive psychology the science of the mind This second unification is far less mature than that brought about by molecular biology But it's potentially equally profound perhaps even more so For it has already provided us with a new framework for understanding perception action and memory storage These two independent unifications Stand at the extremes of the biological sciences and raise the question to what degree can these two disparate strands be brought together Can molecular biology which provided the driving force for the unification of the biological sciences Enlightened the study of mental processes Can we participate in even broader synthesis in the 21st century a Synthesis ranging from molecules to mind a synthesis that would open up a new molecular therapeutics In my talk this morning I would like to outline the possibility of a new biology of mind a molecular biology of cognition and Suggest that it will occupy Center stage in the early part of the 21st century much as the biology the gene occupied center stage in the last half of the 20th century I Outline this development by using as an example the study of memory I focus on my me because the study of my me has occupied my own research interest for almost 50 years my aim over this time is to develop a Reductionist approach to learning and memory that would allow me to explore their underlying molecular mechanisms in detail Learning as you know is the process by which we acquire new knowledge about the world and memory is the process by which we retain that knowledge over time Learning and memory have proven to be endlessly fascinating mental processes for me Because they address one of the most remarkable aspects of human behavior our ability to acquire new ideas from experience Most of the ideas we have about the world and our civilization we have learned So that in good measure we are who we are because of we've learned and what we remember Conversely many psychological and emotional problems are thought to result at least in part from experience and specific disorders of learning and Disturbances of memory haunt the developing infant as well as the mature adults Down syndrome the normal weakening of memory with age the devastations of Alzheimer's disease Only the more familiar examples of a large number of diseases that affect memory I Initially became interested in the study of memory as an undergraduate at Harvard College Motivated my interest in psychoanalysis, but as it became immersed in biology during my medical training I began to find the analytic perspective limiting I began to think that during my lifetime The black box of the brain will begin to be opened up And when we'll be able to explore directly many of the issues that really confront psychology and the last few years This has really begun to happen, and I would like to sort of outline Some of these issues for you using memory storage as an example But before I get into detail let me start by putting the study of memory storage into a bit of a context for you It is convenient to divide the study of memory storage into two parts the systems problem of memory and The molecular problem of memory I'm going to speak primarily on the molecular problem of memory But I want to begin by saying something about the systems problem of memory the systems problem of memory Ask the question where in the brain is memory stored while the molecular problem asks at each side in the brain Where storage occurs what of the molecular details whereby that memory is laid out? the systems problem dominated thinking in the early part of the field and It really had its origins at the beginning of the 18th century With the question I'm sorry the beginning of the 19th century with the question Is memory localized in the brain and before that could be addressed There was an even deeper question that had to be addressed and that is to what degree is any mental process localizable to a specific region of the brain and this was a Problem that was first addressed by a V&E's physician France Joseph Gould beginning in around 1810 and Gould made two seminal contributions to the study of the mind First is that he realized that all mental functions derived from the brain So he was really one of the first major forces to stake take a stand on dualism arguing that essentially every even the highest metaprocesses have localization within the brain and To he was the first one to argue that there must be localization of mental functions And he was therefore the first one to really be a localizationist in terms of thinking about the brain The way he thought about it was that he thought that there were about 35 major mental functions these he got from descriptive psychology at the time and he Assigned each of these areas to a different part of the brain. So he assigned sort of the Intellectual functions of the front of the brain and the more emotional functions to the back of the brain And he thought that even the most exquisite mental function such as imitation spirituality veneration firmness Benevolence could be localized to particular regions of the brain. I think it's going to work And Combattiveness amiciveness romantic love. He thought was localized to the back of the brain Now how did he arrive at this assignment? He had a very interesting approach to the problem. He didn't like doing experiments He thought they were bad for one's health And so he did most of his work through a theory and he had a specific idea of How these functions will be localized he thought that as One practice the particular function For example sublimity or hope or imitation that part of the brain That was concerned with that function would grow very much like a muscle grows with exercise and as it grow it would push on the skull and Cause the skull to bulge So if you went around and examined your friends who specialized in certain traits For example, if they were very smart the front part of the brain would bulge if they were very if they were a Very expert in romantic love. You would expect the back part of the brain to bulge and this way he was able to characterize and and assign every one of these functions to very specific areas of the brain this made an enormous impact on the Austrian scientific community and He was really regarded as a major pioneer in the study of mental function But the French were not as taken with it John Pierre Florence a great French neologist a contemporary of girls Really didn't believe that this was the case He thought that this was a very glib assignment to function really based upon superficial values And he really challenged a lot of these things. He was particularly concerned with the assignment by Girl of romantic love to the back of the brain Well, did this on a basis of knowing a several attractive Vinny's widows and he was struck with the fact that they had a very prominent Back of the brain and he therefore thought a motiveness romantic love would be localized There and what Florence that is he began to remove specific parts of the brain in experimental animals And he focused particularly on the back part of the brain And he removed this in dogs and in chickens and in cats and he found that it interfered with their motor function in some ways But in no way to feed with any aspect of the romantic aspirations or capabilities So he developed a very different view of how the brain works He developed the view that higher functions of the brain are not localized to any specific region but they diffusely distributed throughout the cerebral cortex and that in so far as You remove small pieces of the brain. You're not going to affect any specific function But as you remove significant parts of the brain you affect all of the higher cognitive functions in parallel their thing stood for a number of years until around 1860 when Pierre Paul Boca really returned to this problem and Began to open up sort of the modern localization of function in the brain and he did this through a series of brilliant investigations of aphasia this orders of language which occur following strokes occasionally following tumors and Boca began his investigation with the study of a particular patient whom he called tan who had a particular aphasia in which He could understand language perfectly well, but he could not articulate language. He could not speak This was not simply limited to the speech apparatus because he could hum a tune perfectly well Moreover, it wasn't just that he couldn't speak the language. He couldn't write the language and When he died and came to autopsy Boca found that he had a particular lesion in the front part of the brain which Boca Boca's area what else was the poor boy to do the region needed a name How great I am With time he collected eight patients Who had exactly the same kind of aphasia? inability to articulate speech even though they could comprehend speech perfectly well and When they died and came to autopsy the oil had lesions in the frontal lobe Moreover as he looked at all of these patients you realize that invariably for lesion is on the left side And this caused it to express one of the really great insights in neuropsychology He said we speak With our left hemisphere. It was really the first insight in the fact that Language is localized not only to specific regions, but to specific regions in most cases in the left hemisphere This was an enormous stimulus to students interested in localization of function a few years later fits and hits it began to explore the motor cortex I Can't quite get the added a focus in the motor cortex, but take my word. It's on the strip right here, and he stimulated Different regions in a motor cortex, and he found that as he stimulated different regions different parts of the body twitched And there was a tremendous localization of different muscle groups to different regions of what he called the motor cortex Other areas the visual part of the brain is localized to the back of the brain The auditory cortex to the middle of the brain many different functions were localized And this was really put together in a very coherent way by Karl Wernicke a neurologist working on 1870 In Breslau an extremely inferential source of great neurological thinking in Germany Wernicke encountered a patient that was the opposite if you will of focus patient focus patient could understand But he could not articulate speech Wernicke's patient could articulate speech, but could not understand When he died and came to autopsy Wernicke found that this patient had a lesion in the back of the brain at the point where the temporal comes together with the parietal lobe and the visual cortex And he realized that in fact there was a separate location to the comprehension of language Then there was to the articulation of language Over he realized that his region which he called furnacus area, you know Having followed Bokeh's example, he was given very little choice He called Wernicke's area and he realized that Wernicke's area connected to Bokeh's area through a pathway the archiophysiculus and These several insights allow him to formulate a theory of language which will go Extremely simplified still explains about 85 percent of the clinical phenomenon that one encounters with patients of aphasia It also is a theory of Speech if you will He said we obtain information By reading or listening to speech from the posterior part of the burning and these you notice I know these areas are located Right near Wernicke's area as if it's a funnel that collects information from these sources. We then process this Written or auditory information and translate it into a narrow code and Propagate that code by the archiophysiculus to Bokeh's area where the code for grammar is localized And we articulate that speech as language and notice he said that Bokeh's area is located right near the motor representation of the parts of the lungs that are concerned with speech But this was a remarkable set of insights because it would gave one a coherent theory And in fact, he was able to make powerful Predictions from this he said You know I could predict that you could suffer a loss of language and aphasia Without having any lesion in Wernicke's area or Bokeh's area. Can any of you think how this could come about? How would you get that? One way to get that is to have a lesion in the archiophysiculus that connects the two But we now call conduction aphasia and patients with conduction aphasia have been described These patients can understand language. They can articulate language, but there really is no connection between the two It's like a presidential press conference Information comes in and information comes out, but they're really not related to one another With this sort of a theory of one of the most complex of mental functions the The forefront of science began to move to memory storage and Scientists began to ask if all of these functions are localized is memory also localized but this was really a deep question because you have to realize that at the You know beginning of the 20th century the end of the 19th century It wasn't all clear that memory was a discrete function of mind But it was a separate mental process that could be separated from Perceptual and motor process of various kinds And the first person who really addressed this systematically was a Harvard professor called Carl Lashley And unlike the Harvard professors we have here he occasionally got things wrong and he How do I get myself out of this one? So he was interested in seeing whether memory was localized and he did this by Primarily using rats and having them perform various tasks and then seen to what degree memory the task was interfered with by surgical lesions of various parts of the cortex And he found very much like for arms In fact, he's sort of a modern student of Florence that memory could not be localized to any specific region Rather the severity of a memory defect produced by lesion was directly related to its size The more cortex you removed the more of it that memory deficit that you had and he formulated the law of mass action Saying it's the volume of the tissue that is important not the localization and this really Had a very powerful impact in the field because if that's so then the biology of memory storage will be very hard to To really make it advances on the two to progress and there this situation stood until around a 1950 maybe slightly earlier than that when Wilder-Pentfield got into the game I need to hardly tell you Wilder-Pentfield is a Columbia trained scientist Excuse me a student of Sherrington Wilder-Pentfield is a fantastically interesting guy. He was interested in Focal epilepsy epilepsy that it comes from just localized sites in the brain Usually the neocortex as a result of the deposition of scar tissue following trauma or injury of various kinds And he realized quite early on that the brain doesn't have any pain receptors So if you infiltrate a local anesthetic into the scalp You can remove the skull and expose the surface of the brain and stimulate various areas And have the patient tell you what the response what he feels when you stimulate those areas and all this in a situation Which the patient felt no pain whatsoever? And he did this in order to make sure that he was not going to damage either Vernica's or Broca's area some other area vital to function as he prepared to remove the particular scar tissue that was causing the epilepsy and As he was doing this he Stimulated the brain and asked the patient to tell him Whatever he was feeling or thinking or what was going through his mind And he found in a few patients under various select circumstances that if you stimulated certain regions in the medial temporal lobe He would be able to elicit memory-like phenomenon. Now. These were sort of vague Hypnagogic experiences patient would recall that he had been in a room or he would recall having heard a particular melody Occasionally recall seeing a particular face and this sort of convinced Penfield that he was in fact localizing in the temporal lobe aspects of an anatomical memory system Most neuroscientists were extremely skeptical They felt number one this was a very rare phenomenon He didn't see this in most patients almost all of his patients were suffering from focal epilepsy and Since this was in the temporal lobe Most scientists felt that he might be eliciting temporal obsesure, which is characterized by having hallucinatory-like phenomenon But within a few years very strong support for this notion came As a result of a series of studies carried out by Brenda Moomer Who was called in to examine a very famous patient called HM that many of you probably have heard of Who had been operated on by a surgeon by the name of Scoville HM was about 26 years old when he presented himself to Scoville When HM was now when he was a little kid He was knocked over by a bicycle and he sustained a bilateral concussion that affected the temporal lobe and Left him with seizures so periodically he would have a seizure now in the initial stages This was what quite well controlled with medication But with time as he graduated from high school and began to get a job in an assembly plant He found that this interfered quite dramatically with his work He had seizures more and more frequently and they could no longer be controlled by medication And so he presented himself to Scoville who was a student of Confield with the idea that perhaps an operation would help him and Scoville operated on him and removed the medial temporal lobe on Both sides. I'm showing it only in one side including a structure deep to it that I'm going to return to later on called the hippocampus and they did this on both sides Removing the medial temporal lobe which I'm outlining here and the structure deep to it the hippocampus This in case you're curious is a structure called the cibiculum the little shelf in which the hippocampus Which is only about the size of your thumb sits Now as a result of this HM's epilepsy was dramatically improved. He's still alive now He was just recently examined by a friend of mine. He practically never has a seizure He takes only low levels of medication, but he was left with the most profound memory deficit you could possibly imagine and This memory deficit was characterized by Brenda Milner who Scoville asked to come and examine HM Because he was struck with the fact that HM was not functioning well And Brenda Milner who is Penfield's colleague and was familiar with these early studies has carried out a brilliant series of investigations and HM that have opened up And codified if you will the systems problem of memory What struck her as she examined HM was not only that he had a profound memory deficit But that it was remarkably specific and that many areas of memory storage were completely intact For example HM could remember everything in detail of what had happened to him his life experiences before the operation He remembered the trauma of his childhood as well as you and I He remembered the awkwardness of adolescence. He remembered to speak English He remembered what he had learned in high school remembered absolutely everything Of significance that had happened to him the details of the apartment in which he lived Up to the time of the operation number one number two. He had a Perfectly good short-term memory So if you introduced him to Jerry Kagan He'd be able to greet Jerry Kagan and say hello to him if he then Introduced him to Judy Rappaport. He'd be able to converse with Judy Rappaport if you brought him back to Jerry Kagan He not only didn't know Jerry Kagan's name. He didn't remember him He had a short-term memory that functioned quite well as long as he focused in on the object That was the center of his attention So if you gave him a telephone number eight eight four five four seven He could perfectly well handle a telephone number if he kept repeating it if you distracted him he lost it so what was clear and what When the man that brought out so beautifully is that what HM's memory defect involves is not short-term memory or old long-term memory But rather specifically the ability to form new short-term memory He failed to be able to take new short-term memory and put it into long-term memory His difficulty was to form new long-term memories This was really remarkable because first of all it was the first Localization of a memory process and it showed you that short-term memory and long-term memory really quite distinct processes Short-term memory was functioning perfectly normal But the ability to put new short-term information into new long-term information was completely lacking When the man the thought that this defect in converting short-term to long-term memory Applied to all areas of knowledge for many years. She examined him and She was really struck with how profound it was for example She studied him on a monthly basis for over 10 years every time she walked into the room It was as if he had never seen her before He was a completely new event. He would sit down for dinner as soon as the dinner was over He thought he had not a meal. He was ready to start all over again Needless to say this was not great for his figure many things like this He would finish reading or a paragraph much less a page in a book and he had forgotten what he had read So Brenda Milner understandably thought that this applies to all areas of knowledge and Then one day she discovered that that's not correct In fact a large number of tasks that HM does perfectly well, and this is the way she found it. She had him do a Very drawing task in which he did the outline of the store By looking in the mirror Not looking at his hand Or the pencil looking only in the mirror no more to the than she liked and when you and I do this We make a number of hours the first thing how to get progressively better And we do this again. Let's say Tuesday We begin with for a few hours and we get better still and if we do this again a fair day in the rains day No worries at all. This little you know, I would do it and this is in fact HM He does as well as you know, we're doing the task like this if you were to ask him on Wednesday Look HM. How come you're doing so much better than you're doing on Monday. He would say what are you talking about? I've never done this has before in my life So it was clearly a disassociation between these kinds of tasks that involve motor and perceptual scares and The conscious recall of what he actually did and this course Brenda Menor and Larry Squire and Dan Schachter to realize That memory is not a unitary faculty of mind, but has at least two major forms explicit and declarative or implicit and procedural Explicit and declarative is what one commonly thinks of a memory It's a memory for facts and events It's a memory about people places and objects and it has as a defining feature the requirement for conscious attention and That it requires the medial temporal lobe and the structure deep to it called the hippocampus This is in parallel with a Completely different system implicit or procedural memory, which is an enemy for skills and habits motor and perceptual skills of various kinds and What the behavior study classical op-ed and commissioning and non-associative firms of learning such as abituation sensitization and classical conditioning these sharing common the fact that they are unconscious in their recall You don't need conscious efforts to recall it So let me give you an example if you ride a bicycle once you've learned how to do it You don't tell yourself now I'm putting my left foot forward now putting my right foot forward you make those movements automatically In fact, if you talk to yourself, you're going to fall off the bicycle So there are lots of things a lot of motor skills when you play tennis you don't tell yourself After you've gotten into the game how to position yourself you do this Reflects the automatically and all those tasks are largely if not completely unconscious. In fact, this is fascinating because this is the first biological evidence for an unconscious mental process and it's interesting for several reasons one is we realize How much of our life is unconscious? There was no surprise to me, but it may come as a surprise to you I'm out of it most of the time anyway But it was so big when the eyes that this is something that Freud had been talking about for years now This is not Freud's unconscious. He was talking about Sexual strivings conflicts things that ultimately and the consciousness none of this holds true for this But it holds out the possibility that there may be components of Freudian unconscious that some day We might be able to discover in the brain But it's systems in the brain that mediate some of these unconscious instinctual strivings that Freud was talking about But the existence of these two memory processes implicit and explicit with completely different logic One of the current requiring conscious recall the other being unconscious stirring different kinds of information and involving different anatomical Systems well this involves they have the campus in the media of temporal This involves a number of other structures deep in the brain like the amygdala for emotions the cerebellum Striatum and in very simple cases like those of invertebrates the sensory and motor systems themselves The reflex pathways themselves This made one begin to think gee if there were these two Different systems do they share any features in common? Can molecular biology with its ability to reveal analogy relationships? delineate features that are shared By these two processes and this of course brings me to the second part of my talk and that is the lack of problem of memory How is memory stored at each site? Now there was already you know in the early 1960s clothes particularly in the mid 1960s clothes that There might be some commonalities between explicit and an implicit memory in aspects of the storage mechanism One was when we realized that both explicit and implicit memory storage have stages in each case There's a short-term memory which last minutes long-term memory that can last days weeks of the lifetime of the organism number one Number two, we know how to convert short-term to long-term memory That conversion most of the time not invariably requires repetition practice makes perfect and Three we knew from the study of a flex there and Brahms and a number of other people Bernie agronov That long-term memory differed fundamentally from short-term memory in requiring the synthesis of new proteins That applied to both implicit and explicit memory and applied to implicit memory in vertebrates as well as invertebrates So this was highly conserved and it struck me that if in fact the requirement for a new protein synthesis is so Conserved for long-term memory perhaps the specific proteins that were required But also conserved and if that was so then Discovering those proteins in any one context no matter how simple might give you insights into proteins that are of general importance In converting short-term to long-term memory Now over if one could study this in two or three different systems Maybe one explicit system as well as a couple of implicit systems one might get an idea at least an outline For the general mechanism whereby a short-term memory has been converted to long-term memory and my colleagues And I set ourselves the task of trying to use a radical reductionist approach in order to study this So we focused first on a very simple form of implicit memory storage and tried so to speak to drive it into the ground and then Switch to mice to explore explicit memory storage To see whether or not different or similar mechanisms were involved Now I'm looking for a very simple animal to study memory storage I focused for reasons that must be immediately obvious to you on the Marines near Laplicea Now looking at this as a glance you can tell this is an extraordinarily intelligent animal This is the sort of animal anyone would use for study learning and memory Judy in case it isn't clear to you. This is the head of the animal And this is its tail What we're not going to think about this animal is not only very smart, but it's also highly It's also highly accomplished And it's been able to do this with a nervous system that is remarkably simple Now your brain and mine has a million million nerve cells and these are connected in all kinds of complicated ways But what nervous system of an invertebrate like the place it only has about 20,000 nerve cells and these are collected in ganglia There are about 10 of these and each contains only about 2,000 nerve cells and this thing about ganglion may control not one but a family of behaviors So that the number of cells committed to a very simple behavioral act can be quite small a hundred cells or less And whoops my colleagues and I have focused in the simple animal on the simplest behavior if the animal has a withdrawal reflex of the guilt to stimulation of the siphon So this is like the withdrawal of a hand from a hot object So if you apply a tactile stimulus to the siphon You get a brisk withdrawal of the gill, which is illustrated here So your price in the society and you get a brisk withdrawal of the gill the gill is a respiratory organ Which happens to be external in snails and it is covered by a sheet of skin Corpore model shelf which ends in a siphon Now this simple reflex surprisingly mediated by 70 cells or so Can be modified by a variety of different forms of learning a Bituations sensitization up and conditioning the class and commissioning and each has both a short-term and long-term memory Depending upon repetition. I'm going to focus on one Sensitization and describe it to you in some detail Sensitization is a form of learned fear It's a process in which an animal learns about the properties of an aggressive stimulus So if you give the animal a weak tactile stimulus and get a modest withdrawal of the gill And I'll give it a lactic stimulus to the tail the same weak tactile stimulus We now produce a much more powerful withdrawal of the gill The animal will remember this insult as a function of number of repetitions If you give one training trial, it remembers it for minutes. This doesn't require a new protein synthesis If you give five training trials, it remembers it for days. This requires new protein synthesis If you give further training, it remembers it for weeks and this of course also requires new protein synthesis So I'm going to tell you the difference between one training trial and five training trials the minimal difference between a short-term memory That doesn't require protein synthesis and a long-term memory that does The first thing we did is to work out the more circuit of this reflex There are 24 sensory neurons that innovate the southern skin and these make direct connections to six Identified motor neurons that innovate the gill The sensory neurons also make connections through inhibitory and excitatory into neurons that modify the fine of the motor neurons Now one of the things that struck us about this elementary neural circuit and which is held up for all neural circuits that have looked at the invertebrates and now it turns out invertebrates as well is that they're pretty much invariant That is every animal that you look at has the same number of sensory neurons They connect to the same number of motor neurons and the same number of interneurons in a fairly precise way Well, this was almost Kantian pre-knowledge Specifically organized neural circuit that was determined by genetic and developmental process How do you reconcile this with the learning process in order to address that? We looked at learning and we found that when you stimulate the tail you activate a number of Modulatory systems in which I show you only the most important certain magic one these certain magic cells end on The sensory neurons including on their pre-synaptic terminals and they act there to strengthen the connections between the sensory neurons and the motor neurons If you stimulate once you get a transient strengthening of connections last minutes doesn't require protein synthesis If you do it five times you produce a strengthening at last for days. This does require new protein synthesis so the solution to the paradox of the invariance of Connections of a behavior is that what is not invariant is the strength of the connections Learning does is to modulate the strength of this connection So in so far as you remember anything about the symposium, and this is not something I urge on you You probably should forget it But in so far as you remember anything it is because learning is strengthening specific connections in your body In order to study this mode, we've studied the nanomaniatic animal But we've been able to study it in isolated Self-culture because we could take a single sensor neuron, a single motor neuron, and a single serotonergic cell and really replicate for learning system and the learning process in culture So if we stimulate the serotonergic cell and culture once or even just puffed on serotonin We would produce a transient facilitation which lasts for minutes Which didn't require a protein synthesis, but if we repeat it this far off times We produced a long-term facilitation of these connections that was Unhibited as new protein synthesis Notice that in these simple cases and this also holds for other cases as well What short-term and long-term are stored at the same set of synaptic connections So looking at the connection between the sensor neurons and the motor neurons You can really get an insight in how the short-term process is set up and how it's converted into the long-term process So this is really Imported matter from what we want on the stain. How do you set up the short-term and how do you convert it to the long-term? And I want to consider this with you by looking at the connections between the sensor neuron and motor neuron I'm going to show you a blow-up version of this So this is the sensor neuron. This is the motor neuron. This is a tail stimulus. This is a serotonergic set of cells You stimulate the tail to activate the serotonergic cells and they engage a Intracellular signal pathway within the cell called the cyclic AMP system Which acts on an enzyme called the cyclic AMP dependent protein kind of that details are of more importance The important thing is that an external signal activates an internal signaling system within the cell a second messenger appropriately named if you will With a single pulse This is active from a short period of time and acts in the presynaptic tunnel to enhance Transmitters and change in these strengthening these connections But if you give repeated training practice makes perfect You increase the level of the signaling process in the cell Activate it for a longer period of time so that it translocates to the nucleus and there it turns on gene activation By getting rid of an inhibitor a gene repressor and activating an activator Then activator then acts on other genes That ultimately devise to the growth of mucinactic connections This is proven to be extraordinarily general So let me emphasize three points of this for you The first is if to turn on a large anomaly You normally simply have to activate an activator. You have to get rid of an inhibitory constraint a gene repressor Now you would say that is the most ridiculous way to build a biological system I want to put everything into long term memory. Why do I have a memory suppressor gene built into the nervous system? And the fact is if you think about it, you don't want to remember everything There are a lot of miserable things that you experience in life and you want to forget about them as soon as possible There are a lot of lectures you go to. The best thing to do is to forget them And one of the reasons you have this repressor is to make a very high threshold for memory storage number one Number two once you remove the repressor you turn on genes Now people who don't know very much about genes think of genes as being the invariant controllers of behavior And what they may not realize is that genes in the brain as genes in the liver and the heart can be regulated by external events They can't be mutated And this regulation is not only germline. It doesn't pass on to your children So if you learn about neural biology, your children probably will go into electrical engineering or something completely different That's happened in my case But it is important to realize that environmental experiences like our interacting with one another Gives rise to alterations in gene expression So you are having as a result of this two-day symposium an explosion of gene activity in your brain And third One of the key functions of gene expression in memory storage is the device of the growth of mucinactic connections So in principle you're capable of growing new connections here This is so interesting that I just want to elaborate on it In the pizzeria there is a doubling of the number of synaptic connections with low-term memory You go from the 1200 to 2800 and you can see it in front of your eyes. You go from here to there Okay So people again worry about this They say gee if I listen to a lot of these lectures and I remember this stuff My head is going to be clogged up again. You're not to worry You won't forget a lot of this stuff and there's a regression as you forget Uh moreover in the mammalian brain the changes are more modest than that this dramatic But you're probably asking to what the greatest has happened to you And this is you This is what you look like to yourself. This is a pre-victorian version, but this is how you look like to yourself when nobody's looking and I was taught in medical school that this representation is fixed that it's invariant and we now know that this is not true that This was found by michael nosenich who explored the representation of the hand area in the monkey And the hand area each finger has its own representation I went with you for five and when he examined five monkeys He saw that each monkey had a different representation of the hand And he didn't know whether this is really genetic differences or what to do to experience And so he had these monkeys do a task in which he had them press a barrel With three fingers of one hand just the tips and after several weeks of gaining food only in this way He saw that that representation Expanded the expense of other areas This is a very profound insight and it indicates That if you look around this room, you realize that every person in this room has had somewhat different life experiences And as a result every single brain In this Auditorium is slightly different from the brain of every other person's auditorium This is a significant contributor to the biological basis of individuality This is not to say as you will hear from other speakers that genes are not important But it also indicates that the environment can have a very significant effect on the structure of the brain In fact, we now know that identical twins that have identical genomes Will have because of differences in their Life experiences slightly different structures to their brain Not surprisingly The ability to change your brain so to speak Varies as a function of age as your mother told you and the trouble is you'd never listened to her But as she told you You should start early in life doing the things that are really important This endures from a very interesting study on Vile string instrument players Exploring the representation of both the left and the right hand Now as you know the right hand of string instrument players Handles the bow in which the fingers are not individuated and the representation of the right hand of string instrument players Is no different from that of people in the street But if you look at the left hand you'll find that string instrument players have a much larger representation Than do people who don't play a string instrument player And if you start at the play before puberty Your representation is much larger than if you started later on even though you may have reached a high level of expertise I so I think this is really quite important because it makes us realize that people like Michael Jordan or Mozart Or Jordan and Mozart not simply because the genes or Lord God knows they have marvelous genes But also because they came from environments in which they were really exposed as Mozart was to music all of his life And were surrounded and embedded In the beauty of music and therefore picked it up for early and was able to use it Well, this is a background to implicit memory storage It really seemed appropriate to begin to explore to what the weekend we get inside into explicit memory storage and in around 1990 It became possible to really begin to do experiments in mice of the kind that we've been doing in emplasia And the reason it became possible to do this in mice is because Kapicki and Smiley's had developed techniques for knocking out individual genes in mice Uh and earlier people had developed techniques for expressing individual genes in mice So that made it clear that the mouse was a superb system for studying explicit memory storage Mice have explicit memory. They have a very good memory for space and for objects They have a very well-developed hippocampus And one can use genes to manipulate the hippocampus and then you can explore in a genetically modified mice How do you fact synaptic plasticity the alteration of of synapses in the brain on the one hand? And how do you affect behavior because you have other little mates that you have not done an experiment on And you can use them to explore behavior Moreover We knew the structure of the hippocampus Uh, we knew that it consisted of a series of synaptic connections And this and Loma had shown that if you stimulate any one of these pathways in the hippocampus and the names are unimportant You produce a change in synaptic strength very similar to one of encountered emplasia So if you give a single burst of activity to one of these pathways You produce a strict transient strengthening of connections And if you do this repeatedly you produce a persistent change The transient change does not require new protein synthesis. The more persistent change with repetition does So here as an aplasia there is a cellular representation of both the short term and the long term memory We could work out The molecular architecture of this for a number of pathways. I show it to you only for one And what we found was that the mechanism for short term memory was formally similar to that Which we had seen in the plesia although the details were different There was an NVA receptor that was involved calcium influx was critical So the specific molecules involved were different, but the principle covalent modification was the same a transient change Long term memory was amazingly similar. It required a modulatory input not certain. It required dopamine It led to an increase in the sinus signaling system. It led to the activation of genes And it turned or led to the growth of new synaptic connections I have not indicated it here, but it also led to inhibitory constraints of the kind that I illustrated to before So now we could do something very beautiful We could manipulate any one of these genes and I've shown you a very simplified view And see how does this affect synaptic pasticity and how does it affect behavior? I'm going to show you one experiment experiment, which essentially wipes out genetically the signaling system That is responsible for long term memory. The cyclic ampedepenepotene kinase And what happens when you do that is you don't interfere at all with the short term process because that involves another Cyclic signaling system in the hippocampus, but you selectively compromise The right term process produced with repeated trainers So this is the wild type mouse up here, and this is the mutant mice. These are two lines of mutant mice These are group data showing you that you've severely compromised the late phase So this is wonderful. You have a group of mice. They're completely intact. They have a normal phase of Early phase of LTP and they have a selectively compromised late phase and from this you could see Well, how do they behave? Do they learn? Do they have short term memory? Do they have long term memory? So we explored these mice in a contextual Conditioning task that he got by name of fans that developed at UCLA, which allows you very good temporal resolution You put a mouse in sort of a skinner box The animal works around becomes familiar with this space and then you sound a tone And you electrify the grid and you shock the animal and you get scared And it learns that this space is bad news Anytime you put it in the space it freezes anticipating a shock And you can now test it in that space at different times and we tested it one hour short term memory and 24 hours long term memory And what we found was this is the mutant This is the wild type that the animals learn perfectly well They have perfectly good short term memory, but they have selectively impaired long term memory just like h.m And this is exactly what you see with inhibitors of protein synthesis So here as an applause you we see that protein synthesis is necessary to turn on the genes To give me the growth of nerve synaptic connections So that makes is only one final point and I want to complete with a recent series of studies because they're really so interesting I've told you that what is special about explicit memory storage is consciousness The big problem for the 21st century and nothing I've said about consciousness has entered the picture so far In fact, I said nothing about consciousness Thank God because I don't know much about consciousness But Francis Crick first pointed out to us that a nice handle on consciousness Come into the picture Through the study of selective attention and recently by accident We made some progress in studying selective attention and then I put this into context for you The first thing we wanted to do is ask What is this late phase of LTP that is important for memory storage? And what is this protein synthesis really due to the animal? How does it affect how the animal represents space inside its brain? Now I showed you the body surface before how there's a beautiful map In 1971 John O'Keefe made a fantastic discovery that there is in fact a map of space It's more dynamic. It's more complicated. But in your hippocampus is a map a detailed map of space So if you put electrodes into a mouse's brain and the core from the hippocampus and have a tv camera Plotting the movement while the animal moves around in his space Different cells in the hippocampus the same cells that give rise to LTP Fire when the animal assumes different positions in space So some cells will fire when the animal is at six o'clock some cells will fire when the animal is at nine o'clock Some cells will fire when the animal is here. So as the animal walks around in fact as you walk around in a place Different cells in hippocampus fire at different positions in space And with time as you become familiar with space They will invariably fire there So you can take the animal out and bring it back a week later The same cells will fire in the same positions in space You put in a new space. It forms a new map. You bring it back to the old space. It keeps the old map So this is very interesting. It struck me. This is like a learning task. And how does it work? Well, we found that if you use the mouse That has the defect in cyclic ampere signaling This animal forms a good map. It has a perfectly good shorter memory, but it cannot maintain that map So the reason you need the late phase of LTP because it's important for stabilizing the long-term Security of that map and that's exactly what inhibitors of protein synthesis do So the signaling molecular signaling process in the formation and stabilization of the map on fact The same signaling mechanism that you use for synaptic plasticity. So that was quite encouraging, but where does Attention come in Well, a lot of this stuff was carried out originally in the rat When we first moved to the mouse we made a very very interesting finding We found that in the rat The rat Is lazy Simply does not move when you put in a closure like that So the only way you can get it to move is to throw food pellets in which is what a key for everybody else including ourselves did And when we first began to work with mice we did essentially the same thing Only with time we realized that this might be an attention grabbing motivating stimuli And we found to our surprise that mice are different than rats They don't run around for nothing if you just put them around They will scamp around about in the reward and they said gee, that's pretty hefty You know, we can vary the degree of attention perhaps So we have three situations one of which the animal just runs around One of which the animal runs around for food and one let's make it even more attention grabbing We'll have the animal do a spatial task an up and conditioning task Periodically, we'll make it miserable. We'll turn on lights and sounds. They don't like this kind of stuff They're not into rock music as yet Then the only way they can turn that off is to find a unmarked space and sit on it for a couple seconds and most rats I'm sorry most mice learned that very well So this was very nice. We have three degrees of attention we can ask How does place field stability vary as a function of attention? And we found to amazement that there is a direct relationship between the degree of attention And the stability of the place field map. This is about a solid a place field map as you can get This is good, but not great and if the animal pays no attention at all, it's like you and me It's in a base Works and you walk into the same place the second time. They don't know where the height you are So this feeling was very interesting and causes to ask the final question How do you move from here to here? What sort of system There's a tension recruit in order to stabilize memory. Can you guess what we would look for? In the busy we were so impressed with modulatory systems And I told you that the mouse also has a modulatory system a dopaminergic system So we begin to explore whether the dopaminergic system that comes from the midbrain might in fact be important for tensioner processes And we found that if we gave a particular kind of dopamine receptors activated in hippocampus One that activates an animal cyclase is called the d1d5 receptor And we found that if the animal is not doing any task and we gave it a d1d5 agonist we could enhance modestly The stability of your map and if we had the animal doing a foraging task and intermediate A type of stability and gave it an inhibit of the d1d5 agonist We could really reduce the stability of the task dramatically This is not a complete recapitulation of what we see with the tensioner phenomena We think it's quite likely that a number of other modulatory components contribute But this is the first handle we've had in the mouse on the biochemical mechanisms whereby An attentional process Is mediated So let me simply conclude By pointing out that molecular biology is opening up here as it has in so many areas of biology the opportunity to see Universal truths if you were that's an overstatement to see generality In otherwise disparate processes Explicit and implicit memory storage have a completely different logic. They have different anatomical distributions But if you look at the storage mechanism per se the way the information is stored in each area You find that although it's not identical. There are major features of conservation The short-term mechanisms tend to be pleiotropic But the long-term mechanism is amazingly conserved in each case It involves the recruitment of a modulatory system that in turn turns on an intracellular signaling system That turns on both activators and represses gets rid of the represses and ultimately leads to growth And you see this not only in implicit memory in both the plizia and in the mouse But you see it also with explicit memory in the mouse What I think is interesting and this is more a suggestion Rather than a fact is that one of the fundamental differences between implicit explicit memory on this level Is how the modulatory system is recruited In implicit memory the modulatory system is recruited in a bottom up fashion if you will The serotonergic system is recruited by the tail stimuli by sensory neurons in the tail That connect directly to the serotonergic cells They're recruited in a reflex-like fashion While in the hippocampus it is very likely that the modulatory system is recruited in a top-down fashion That these neurons in the midbrain are recruited by influences from on high From the posterior parotal cortex and the prefrontal cortex areas that we know are also involved In mediating attention phenomena areas that involve for example and working memory But I think the encouraging thing is that molecular biology is really reaching age And is now being able to tackle progressively more complex problems and even beginning to get a little bit of insight Into attentional processes and I should simply conclude that insights into the basic processes of memory Have not only been useful in their own rights, but they've also been able to give us insight in how memory goes awry For example, we found that this conversion from short term to long term in the hippocampus is extremely sensitive to age And all the mice have a difficulty with spatial memory because this system is compromised And if you enhance the signaling system with d1 d5 agonists or with drugs that increase cyclical gain p You can enhance memory in the mouse My colleagues and I recently started a company on this modestly entitled memory pharmaceuticals And it's based on what we have in the mouse. So if you're a mouse, we can do a lot for you For humans, we're not so sure as yet. Thank you very much. These are my colleagues who did the work I'd like to invite the rest of the panelists to uh come up and take a seat the table in front here Our ushers will be distributing tickets dot tickets, but Cards on which you can write questions We encourage you to submit those and we'll see if we have time for a few here from the audience like to begin by Asking members of the panels if they have any questions for Dr. Candell or any observations to me Dr. Kagan Well, I I just I obviously congratulated Professor Candell. I was an exquisite talk, but then I said to him And I'm going to mention this at one A characteristic of both the infant monkey and the human infant in the opening weeks of life. It is There's no long term memory. It is very difficult That is it's like h.m. The infant could remember for a few seconds And then loses it And and I and I never thought of it in the way Professor Candell brought it on in it That would be a wonderful thing to study in the monkey Whether the genes that are responsible for the mechanism he described Turn on during for the first it's the first uh two months in the monkey in the first seven months in the infant Eric, what do you think? I think it's it's a very nice insight My guess is there may be additional processes because you're dealing with development per se. So I'm not Sure, I mean the facts are probably known how much were the hippocampuses at that particular point So the probably the right developmental processes going on that may also contribute But I think power pursue. I think this is what's going on And I think it's certainly an extremely doable thing now um I couldn't help overhearing Bob Plumman Discussing chip methodology as we were marching in in the procession and that kind of methodology is going to be extremely Useful and commonly used to look at gene expression in specific areas of the brain and I think that would allow one to test these problems Um, I actually was one time interested in because you know fraud makes a big point Of infantile amnesia And I have been interested although I've never explored it Uh, there is evidence for the fact that in rodents this also exists And what aspect of the immaturity of the nervous system is responsible for that is an interesting question Any other panelists with observations or questions? Not at this time. Let me ask you a question here from the audience then What about the effect of trauma on long-term memory? We have a hen who refuses to sleep in the chicken house after a raccoon attack On another hen in the hen house very smart Um, well, I mean there are many kinds of consequences from trauma first of all There's the immediate consequence of the concussion per se and I guess that's been best studied in football players Who get hit very hard in a football game and come out and Can remember details of what happened them right after that or right up to that moment But really don't remember anything afterwards. So it's like an epileptic seizure It's a little bit like giving an inhibitive protein synthesis It blocks any new information from going into long-term memory So one thing of trauma is to dissociate the immediate phenomenon from the ability to destroy it But there are also affective consequences of a traumatic experience that have nothing to do with that process per se but just Ranging from, you know, intelligent avoidance to You know, neurotically induced fears both of which occur. I mean you can in a mouse make a mouse frightened into a completely neutral stimulus Learned fee is an extremely well studied phenomenon. In fact shoulder dude who is who Mike earlier cited has been one of the pioneers in working out in detail the role of the amygdala In learned fear and we've recently looked at the amygdala because it's such a beautiful structure to work on and it's got Exactly the same set of storage effect. It looks exactly like the Like a pussy. It's more so than the hippocampus It uses psychic ampy for short-term memory as well And then I think it's going to be a wonderful Structure for sort of understanding how genes come into play other genes come into play for long-term memory and also using it as a model for Phophobia and various kinds of pathological states I think there's only one other point that I would make on that which is interesting because I'm curious to get the panel's Comments on this to Primitive reductionist like myself it looks like The mouse is just going to be fantastic in the next years for studying all kinds of psychiatric problems That is one the number one to make mass models For a number of mental disorders. For example age related memory loss learned fear, but also Insofar as most genes that you isolate related with human illnesses You don't really understand when you first isolate the gene You may not understand its function what signaling system it belongs to You need then to spend, you know a decade Often finding out what it does and one key step is to pop it into a mouse And I would argue that even if something like schizophrenia, which we know we can model in the mouse And no model is going to hallucinate no mouse is going to hallucinate for you or make you aware that it's hallucinating But nonetheless the genes may have function Who's signaling purposes or it's who's affecting synaptic transmission? You could characterize in the mouse and I wonder what some of our humanoid colleagues would comment on that well certainly The fact that the mouse for Reasons you understand better than I you can uniquely use conditional knockouts also Seems particularly appropriate because the big puzzle of schizophrenia Is the way you are presumably born with the genes that make you susceptible to schizophrenia And yet it doesn't manifest itself till early adulthood late at late adolescence So the notion of the ability in the mouse to handle gene action at different times in development Would be particularly crucial because you could solve two problems at once I'd like to just like to add to that More particularly I think the mouse is going to be important for all of functional genomics work I don't think we'll find genes in mice for schizophrenia or reading disability But you could actually have a mouse model of reading disability If you find human genes and you want to understand how they work The mouse brain is the place to look so that you can study the brain related processes in the mouse Given knockouts and all of the other amazing things genetically and environmentally We can do with mice to understand how that gene for reading disability Works in the mouse brain even though obviously you're not going to test them on reading A bomb makes a point which is so Obvious but so important that it's I think it's important to restate it again and that is what Is essential to do is to take a human gene and express it in the mouse In order to get a better understanding of what its function is Even though you may not be studying it quite in the context from which you took it What does that mean that speaks to the universality of biological processes That has been a really extraordinary achievement of biology of the last 50 years the realization that Genes are similar in different organisms although The context in which it works may restrict the action in a variety of ways So it is almost essential for the human genome To carry with it of the model organisms that the worm or the fly And the mouse in order to make sense of it It would be impossible to understand the consequences of the human genome If we didn't have these other experimental systems and it really I think illustrates in the most dramatic way How biology has become of one cloth And I continue to be so amazed by that I mean I think that when historians look upon this period They're going to consider this the most fantastic intellectual contribution Uh of the 20th century to see the unity when I entered biology It was an unbelievably fragmented field and it now is in a level of chemistry and physics in having a unified Substructure Which we hope in the next decades will extend with equal rigor to the mind A question from the audience here Do people with photographic memories lack that genetic memory inhibitor? Who asked that question? Well, it says That is a brilliant question Uh and you know I went over as I have a tendency to but I have a joke built into this Which I'll pull on Judy LeVanne Rappaport And that is that I used to think Judy LeVanne Rappaport is just a very smart woman We've known each other through our much of our training and now I realize that she's probably just a mutant She lacks crypto She lacks that inhibitory constraint, but in all seriousness, um I used to be very envious of people that have fantastic memories until I read about them Laurie has described the famous memoirs There are several other cases that are recorded and the fact is in broad your the novelist has written a wonderful short story Uh on the person that you knew had a perfect memory. The fact is they're miserable. I'm really delighted to know Uh They feel their head is filled with garbage and I meant when I said that it's really important Uh to put things into long term memory sparing Uh because otherwise You lose discrimination and you see these people are not terribly creative So that it really inhibits your ability to think freely about things There's another question from the audience Training motor skills in sport or musical instrument performance begins with explicit memory Success or accomplishment is measured by implicit memory performance Is there a specific signal and synthesis system for converting explicit to implicit memory? That's fine. These are wonderful questions. Uh I haven't uh Thought that much about it. I can tell you we don't know If one thought about it, you could think of various transitional systems that could help But it is a fact that many things that end up as being automatic started off as explicit memory And you could see why this would be from a sort of a biological homeostatic mechanism efficient That requires much less effort, you know, once you don't have to think about it and can do it reflexly Um, but how that conversion occurs Uh, we don't really know My guess is it's occurring in parallel. But as you're learning it as an explicit task, you're also picking it up reflexly Why you then turn off the explicit conscious process? I don't know Maybe one last question here For those of us who went to graduate school in the Jurassic era We learned that the brain never grew in new neurons Uh in Or the adult mature brain anyway in recent years We've heard stories of neuro synthesis where new cells are being formed in the hippocampus and in the olfactory And actually there's some studies in claims primates in the frontal lobe Are we going to see evidence of this in humans as well? And is this going to be related to perhaps Alzheimer's disease or other degenerative disorders? Uh, well there are sort of two components of the question one is to what degree is cell proliferation And the nervous system Continue into adulthood. I don't think the evidence That this occurs in the granular cells of the hippocampus and the olfactory bulb is incontrovertible And I would be astonished if this was not the case in humans the evidence that occurs in Neocortase Gould's evidence Is not completely compelling and pasco archaic who is extremely reliable Has repeated those experiments very carefully in the monkey and doesn't see it So I would think that the cautious answer at this particular point is it certainly occurs in a limited number of regions It's going to be very interesting to see what role it has Uh Well If it occurs in the neocortex, it probably does not have a dramatically important role I would guess that that's the safest thing to say at this point Uh, and that stem cells of this kind can be tremendously important Uh for treating disease. I think most biologists firmly believe and certainly will encourage Investigations of those problems Any other panelists have any closing comments? All right, I think what we'll do is we will adjourn then until one o'clock Thank you very much. Dr. Campbell At this time we will invite members of the press to come up front And we'll have dr. Kagan here for about another 10 minutes and they can ask questions As they'd like and if you'd like to remain to hear these answers, you're welcome to do so So that would be a good thing to just I can find out Push that like away This might and so I thought we should check it out to see if it sounds on