2000 LECTURE SERIES

Critical Issues in Brain and Memory

Dr. James L. McGaugh
Center for the Neurobiology of Learning and Memory
University of California, Irvine
April 4, 2000

You are now looking at what is known in the trade as Plan B. I'm Plan B. And I had a couple of choices, not a lot of choices could've been made, but I decided that we had delayed, we had found out this on short notice and so, I was going to put myself on the spot. And I had a choice between giving a lecture and talking with you and I thought since we've had almost six years of lectures it might be a little more fun to have some talking. And so that's what I would like to do.

Now, I'm not going to do this alone, however, I have some help. We have a number of the faculty members of the Center for the Neurobiology of Learning and Memory here tonight sitting in the front row. No, I'm not asking to be a millionaire, but I do have lifelines down here. And no telephone calls, but lifelines. And so, if things get tough, as I am sure they will because I already have some of the questions up here, I will ask for a lifeline. I'd like to introduce them if they would just stand up as I call their names and wait until they all stand up. Frank Laferle and Larry Cahill, Mike Leon, Norm Weinberger, and Dick Thompson. These are faculty of the Center for the Neurobiology of Learning and Memory. Each is a very distinguished scientist and I could have tried to put anyone of them on the spot for tonight and I decided not to do that, but I'd put myself on the spot and then ask for their help when I need that lifeline. And as I say, I know that I will need it.

Now, the plan is this, I'm going to talk for a few minutes to remind of the problem of memory. You may not be thinking about it at the moment, but you will be shortly because I want to remind you of it. And then after I reach a certain point and I don't know exactly when that point will be, then we're going to have questions. I have some cards up here. And if you would like to write down questions, there are cards available that can be passed out to you and in addition, we'll take questions from the floor. I only ask that you allow me to be the speaker and you the question asker. So keep your questions short and I'm also admonished by my staff no follow-up so that we can have other people ask questions as well. And we'll see how far we can get with that.

Now, you'll note that there is no program tonight. Actually there is a program, but it's going to be thrown away, because it was the program for tonight's speaker, it's not here and it was too late to make one. And in lieu of that, I tell you it was not my idea, the staff decided that they would make available an article of mine that was very recently published it the "Journal of Science" and I think it's out front. Some of you may have picked up a copy. Did some of you pick up a copy? Others of you may wish to do so. Others of you may wish not to do so. That is your right. It's your right not to pick it up and it's certainly your right not to read it. And some of what we will talk about tonight is most assuredly in that article, but much is not. You can take that as a souvenir. Or the next time you go out for dinner or if the table is wobbly, you can use it to settle a leg under the table. It's yours to do with what you like. Some of you might find it interesting. At least you can give it a try.

Let me see, I think that covers the ground rules. One more thing I want to say. Thank you very much for coming. And thank you very much, even much more for staying. The thought crossed my mind that we should fix the doors so that they would only swing in and not open until after you discovered that the speaker was not going to be here tonight and then you were stuck. Well, you're stuck for a while anyway. But we're going to try to make it as much fun as it can possibly be for you during the time that we're here. Now, it's also crossed my mind the reason that you haven't left is because you're waiting for the cookies. There will be cookies, but no questions, no cookies. All right? All right.

If you weren't thinking about memory, you should've been because you are your memory. Everything that you are, everything that you were, everything that you will be as a human being is your memory. If you don't have memory, then there's no need to worry about gallstones. If you don't have memory, there's no need to worry about your income or your income tax. Memory is what enables you to record the things that you've experienced during the course of your lifetime and to be able to use that information when it's appropriate to do so. Now, think with me for just a moment. I said just a moment and you remembered. You all remembered. I said just a moment. That moment is gone. And your knowledge about that is now memory. It's memory just as your memory of events of 50 years ago. It's memory.

Now, all of you have plans, well, some of you have plans for cookies. Some of you have plans for questions and some of you have plans to get in your car and drive home. And you have plans for tomorrow and the weekend and for this summer and maybe next year. And what are those? They haven't happened yet, have they? So those are memories. Those are your recollections of things that you have thought about and stored away and you think of them as being part of your lives. And they're not part of your lives, they haven't happened yet. They're only part of your lives in the sense that you made them up and they're your memory. And they're sitting there side by side with events of many, many years ago and the word moment and many years ago, all somewhere in your head up here to allow you to get along in life.

Now, what's so interesting to me about this process is that it has the strong appearance of continuity. That is, you don't think that what happened five minutes ago is ancient history, you think of it as being now. And you don't think of your expectation that I'm going to continue talking for a little while, you don't think of that as being somewhere else, you think of that as being now. And when you think, you reminisce about people you knew decades ago, a month ago, you can bring that up and have that now and you can have all of those things together. And it's memory that provides the glue that enables all of that to happen. I mean, it's incredible. It's the most, most marvelous, most marvelous capacity and the things in the brain that allow that to happen are the most marvelous machinery known, or mainly unknown because we don't know most of that machinery, how that occurs. I mean, it's just incredible that we have this capacity that can do that.

Now, I want you to think with me for a moment. You all know what a car is. And you all can think of a particular car, I want you to think of a particular car. And you can think of an experience that you had in that particular car, don't tell me about it. You can just think about it, the experience that you had in a particular car. And you can think about having driven in a car today. And you can drive a car. Each of those is a different aspect of memory. You know what a car is. That's a generic thing. It's a car. Call it semantic knowledge. You know what a car is. And then you can think of an experience that you had in a car. Now, that's a particular car. Then you can think of having been in a car recently. And then also in your head you know how to drive a car. Most of you also plan to ride in a car a little bit later. Each of those is a very, very different aspect of memory, a generic knowledge of, a personal experience about, the ability, the skilled ability to do. Each of those is a different aspect of memory. Now, if I just said now, we're going to talk about a car and a particular car, your own car for example. And we're going to talk about an experience that you had in your own car and by the way, your ability to drive a car, you may have thought of this all being just the same concept and it's all the same memory. But those are very, very different aspects of memory. One of the things that we have learned, perhaps one of the most important things, among the most important things we've learned about brain and memory over the past several decades, is that these are not only different aspects of memory that we can talk about, these are handled by the brain in different ways. Doesn't seem like that to us, does it? It just doesn't. It just doesn't. Now, think about it again using the car. I said car. Now, you remember I said car. You had to know what a car was. You had to dredge up in your brain your knowledge about a car so that even your immediate, or your short-term, or your recent memory takes full advantage of and is completely dependent upon your old, long-term, stored memories. You see you don't have short-term memory, which sits all by itself. The short-term memory is a process, which accesses memory that you already have. So if I say to you I want you to do this with me now, quietly please, six, seven, three, four, two, one, nine. You remember that? How many of you think you remember it? All right.

Now, that's not a, anybody have that a telephone number, a zip code, or anything? No. All right. So that's a new sequence of numbers. In order to have that in your recent memory, in your short-term memory, you had to call upon ancient memory that exists there already and you had to do it instantly. Now, people sitting here in the front row and I are arrogant. We're arrogant and maybe stupid, as well. Maybe both. Because we have this strange belief that we have the capacity to figure out how that machinery works. You know, we don't get up in the morning and say, it's so complicated, we're not going to do anything, you know, we'll go to the beach. You know we get up in the morning and say we're going to do one more experiment to crack this thing open and try to find out how this thing works. But we have to do it with full knowledge that there are these many aspects of memory and that they are inextricably linked to each other. You can't pull out short-term memory and hold it here like this and look at it because dangling at the end of it is old memory, because that's what it's all about. And I can't pull out car for you. If I pull out car out of your brain and dangling there is your skill of driving a car, your knowledge that you have a car, your memory of an old car, your memory of things you did in a car, your memory of car accident. They're all dangling, they're all interconnected, all interconnected. So you can't just reach in and shake gently, you know, like pulling some spaghetti out so you can eat some spaghetti. So you're going to have a bite and then you've got the spaghetti, you can't do that, because it's all in there. And yet we know that in the brain these things, each of these memories, typed, has a different job to do. And yet it has to interface with all of the others.

So what do we do? Well, we get up in the morning and Professor Thompson decides that he's going to record electrically from a region of the brain and then he's going to remove that region of the brain and figure out what that region of the brain, what role that has in a particular kind of learning. And Dr. Weinberger gets up in the morning and he goes to his lab and he gets out the electrodes and he puts the electrodes in the animal and he says I'm going wiretap and I'm going to figure out what happens to the firing of the cells of these brains without intervention. I'm going to try to figure out if I can't crack this code by putting electrical wires down and wiretapping. And Mike Leon does wiretapping, but he also says I'm going to slice up the brain and I'm going to find out by looking at the sliced brain what part of the brain gets activated by certain kinds of stimulation, particularly olfactory stimulation. So he puts olfactory stimulation in and then he figures out how the olfactory system works and uses memory to remember odors. Larry Cahill, sitting next to him, says that's okay, but I want to do it with a human and so, he will give a human certain kinds of information to learn and then with colleagues, including Rich Hire and others, go to the brain imaging center on campus and do imaging of the brain and find out how information that's given to a subject will activate different regions of the brain so that they can get a handle on that.

Frank Laferle says well, we can do a little bit better than that because we can look at the cells themselves and we can look at the genes within the cells. And we can find out how these genes get turned on and turned off. And we can find out how this regulates such things as the development of Alzheimer's Disease. So you have just sitting in the front row, just think of all the different approaches that can be taken. And my own approach is an interventionist approach. I am impatient. I don't like to sit and wait for things to happen. And so, I put micro-quantities, tiny, tiny amounts of drugs and hormones into very, very specific regions of the brain to turn on or shut off those regions of the brain and discover the roles that those regions of the brain have in the memory process. So you can see the variety of things that we do to try to crack this complicated problem.

Now, in doing it we're not, I said we're stupid, but we're not really stupid, we know that memory is complicated. We know we each only have a piece of the problem. And we know that we're working on different aspects of memory. For example, most of the work that I do has to do with understanding the systems that regulate the storage of information. It has nothing to do with where memory changes are located in the brain. In contrast, Dr. Thompson is interested in the direct question of where are those memories located in the brain? So although some of our experiments may look alike, we're actually asking different questions about brain function. So you can have a region of the brain that's involved primarily in learning a kind of a motor skill. I say involved because we don't always know exactly how involved. And we can have another region of the brain, which is more importantly involved in holding information for short periods of time, the pre-funnel cortex plays a very important role in bringing that information out of long-term memory so that it's there, available for use. And we can have a brain region like my favorite brain region, the medulla, which is involved in regulating how strongly information is stored anyway. And then with Norm Weinberger's work actually measuring changes that take place in the, where we think ultimately many memories are stored, in the cerebral cortex, the outer bark of the brain. So what we have to do is to fractionate our research methods and try to make our research methods somehow match what it is that the brain is trying to do so we can pull it apart, not like spaghetti, but a little more delicately where we keep the right parts together and the right concepts together, and begin to understand how this thing all works little by little.

Now, we had a lot of talks here over the past almost six years and I want to remind you of some of these to jog your memory. You learned from Dan Schacter about the fragile power of memory and he talked about different forms of memory, explicit and implicit memory. We learned how important learning is for drug addiction from Sheb Siegel. I talked about the role of drugs and hormones in memory. Larry Squire from UC San Diego talked also about different forms of memory. Robert Zipalski from Stanford talked about stress. Bill Greenoe talked about how it's important to continue to use the brain throughout the life span, because the more you use it, the less you lose it, and also the vascular system goes along with it. Dr. Cotman talked about the aging brain and disorders of the brain. Dr. Pittman talked about post traumatic stress disorder, what happens when memories are too strong and take over our lives. Barbara Sherwin from McGill University talked about the influence of estrogen on memory in women. Her title was "Can Estrogen Keep You Smart? A Role for Estrogen and Preserving Memory." Some of you may be interested in that topic. Patricia Cool from the University of Washington talked about early experience and the perception of speech and told us how it is that by the time a child is nine months of age that child has already settled in on discriminating the vowel sounds that are used by the adults around it, and has lost the ability to discriminate vowel sounds not used. Early as nine months that's pre-verbal, that's already happened. Yelli Yollis from Holland gave us the, well, the good news and the bad news, first the bad news. We have to distinguish pathological memory loss, which is terrible, but the good news is there's also non-pathological memory loss, which is just the normal wear and tear over the life span. And he pointed out that we begin to lose memory ability, particularly as it relates to our speed of processing information, after the age of 25. So a 30-year-old already is worried and 35, and 40, and so on. Thank you Dr. Yollis, we needed to know that. Beth Loftis talked about the myth of repressed memory and pushed some hot buttons. The issue of whether people really do have memories that are repressed and then are recovered under some circumstances. And you may have opinions about that. Dr. Weinberger talked about his work on how it is that experiences alters how the brain works, the cortex in particular, and suggesting that the brain gets rewired during the course of learning. Dr. Steven Pinker took a bigger topic and he told us in 45 minutes how the brain works. Our last speaker, Dennis Selkoe, asked is Alzheimer's a reward for living longer? And he gave us a mixed message, he said, well, the mechanisms are there to make that possible, but I don't think that's really true. So forget my title and, you know, be happy, live long. And now, we're down to me.

So where are we now? I've told you about, I reminded you of all of those topics. And I've reminded you of how critically important memory is for our lives. And I've reminded you that memory is not a thing, it's a whole set of processes that our brain does for us. I just want to add one thing to that before we start the question and answer. One question, which I'll probably get, but I'm going to answer it before I get it is, is it true that we only use ten percent of our brain capacity? How many of you have heard that? How many of you were going to ask that? Thank you. I didn't ask it quickly enough. Well, my own view is that it's a very high percent of the capacity used all the time and we just don't know that.

Now, there's no way to measure it. I mean, first make that very clear. There's no way to measure it. But I want you to think about the job that our brain has to do. I mean, you wouldn't want the job. You would not want it. First of all, you've got to automatically take care of all the housekeeping chores, your breathing, your coughing, your sneezing, your maintaining blood pressure, your maintaining posture. You're not thinking about those things. Those are just going on all the time and the brain is huffing and puffing, making sure that all of those things are taken care of. At the same time, it's got to sense the environment. So it's sensing it all the time. You're hearing things, you're seeing things, you're touching things, you didn't know it, but if you think about it there are muscles on your posterior that are becoming increasingly sensitive as this talk goes on. It's got to monitor the environment all the time. It's got to be prepared to do things. So it's got to be prepared to spring into action at any time. So it's sitting there, ready to go into gear, while it's sensing all this stuff, taking care of all of these functions. And at the same time, it's storing all of the new information that's coming in. It's keeping alive all of the old information that was there to put it next to it, and it's enabling you to plan ahead using information that is coming in at the present time, combined with the old stuff, all your breathing, and all your coughing, and all your sneezing. It says, hey, you wouldn't want the job. It's a terrible job doing all of those things. Now, the job of the scientist is to say forget about the breathing, forget it, for memory, forget about the breathing, forget about the sneezing, forget about the sensation on parts of your body and so on. Get right to it and try to figure out how the brain works, how it does it, what goes wrong, and so on. And that's what we do. All right.

Now, we're going to turn to the question and answer period part of this. And I'll start with a question that I have here while you are all getting your machinery going. Remember the brain prepares us for action. Right? All getting prepared. So here's the first question and I will take this one myself. Does the brain store all of our experiences? How many of you think it does? How many of you think it does not? How many of you decidedly do not know? Well, I don't know and I don't think anybody knows, but we can make a good guess that it stores an awful lot of information. It has to store a lot of information. Information you don't even know about. Think of what has to be learned when you're learning how to ride a bicycle. You can't even talk about it. The only way you can do it is ride the bicycle. And it's got to store all of the information about the relationship between your balance and where your feet are and all of that. All of that has to be maintained, calibrated, calculated, and kept there so that each time you get on a bike you're better, and better, and better. You can't even talk about it. Same thing when you're playing tennis except the problem is you tend not to get better and better. Or you may try. Or golf. You may get worse, and worse, and worse. But my vote on that is probably not all, but an awful lot, because if it wasn't an awful lot of information that we get, then you couldn't build on experience. See? Because you never know what's going to be important coming down the street. And so our brains probably store an awful lot of information that we don't even know about, just in case it's going to be repeated and it can be added. If it didn't store a lot of information with every experience, then repetition would not be beneficial. So that's my vote. It's an empirical vote. How does the front row vote on this? How many of you think it stores everything? Nothing? All right. They agree with me. It stores something. All right. Do we have a question from the audience?

Dr. Cahill: Can I throw in two cents on that last?

Yes, you may. Dr. Cahill.

Dr. Cahill: There's another way to look at the question that Dr. McGaugh just raised about how much our brains store. And it comes from considering a famous case from the early part of the 1900's. A fellow from Russia who became known as Lorius the Modest, who was a fellow who essentially remembered everything. And the story is a truly amazing one, which you can actually read about. Books were published on this fellow. But here's a guy who, just to give you one example, when given say a row of numbers, ten, a matrix of numbers, ten rows, ten columns, on a piece of paper, looked at it, read it for a few minutes, then they took it away from him. And they asked him, can you read the numbers? He could read the matrix off perfectly, all the numbers that he had been given. You could ask him, remember the matrix I gave you this morning, the one that was ten rows, ten columns of letters? Could you read column seven, row three, the letter. And he'd give it to you. You could ask him do you remember the one I gave you 20 years ago on August 2nd in the morning? Can you read column seven backwards? And he would do it just like that. But the reason I'm saying all of this is here's a case of a fellow whose brain appeared to remember everything and it was incredibly bad for him, he went crazy, ultimately. And so I take that as an example that probably our brains, on some level, remember a great deal of things, but on another level must be very, very efficient in what they decide to store and how well, because if they didn't we'd end up like this poor, crazy, Russian fellow.

Yeah, so he had a very sad ending to his life. Just let me add to that the point that I think that brings us together is that we don't know, we may not be able to remember something and yet we can benefit from that experience and see it at a later time. Poor Mr. "S" remembered everything. We're lucky. We have highly selective memories, even though we may be storing at a very low level lots of information. Do we have a question?

Female: Okay. How important do you think environment is for the early years of development and memory, for instance, in a newborn?

Dr. McGaugh: Michael Leon do you want to take that?

Dr. Leon: All right. There is wonderful information about learning, not only in newborns, but even in the fetus. There is information showing that the fetal baby who hears its mother read to it every day will recognize the mother's voice and prefer it to a strange mother reading the same passage. All this is going on in utero. You can show that animals can learn in utero as well and very sophisticated things. So learning is going on right away. Learning also does things that are quite remarkable early in life. One of the things that it does is it forms the way the brain works for the rest of the life of the individual. If you give early learning to an individual, it actually can save cells from dying early in life. So those cells remain there where they wouldn't have remained there had you not had that kind of learning. So definitely it plays an enormous role. Infants are learning from the moment they come out. And it irreparably changes their brain. That's how individuals are formed in large part. There are many kinds of normal brains. A large part of the reason why there are many kinds is that the early experience that people have are different and it forms different kinds of brains in these individuals, and you have to live with those brains for the rest of your lives.

Dr. McGaugh: Yes?

Male: On that note, how does music influence neural tracks or the brain?

Dr. McGaugh: Music?

Male: Yes.

Dr. McGaugh: Well, it soothes the savage beast. That's what it does. And the expert on the soothing of savage beasts is Dr. Weinberger.

Dr. Weinberger: Could I get that question again? What was the exact question?

Dr. McGaugh: Tell us about music and the brain. Was that it?

Dr. Weinberger: That's too big. That's too big a question.

Dr. McGaugh: What was the question? Oh, in infants.

Dr. Weinberger: That's you, Gus. I see you. Couple things. First of all, the evidence is very strong now that music is part of human nature. It's part of our natural heritage. It is not an entertainment add-on. Mike Leon talked about learning about the mother's voice. This is mainly third trimester. The auditory system really starts operating about the 26th week. And a child or a fetus who hears music actually can show memory of that music after birth for at least at some time. What's interesting is that as early as you can test a human infant you find that it has tremendous capacities for dealing with music. For example, its ability to detect the difference between two notes is just as good at birth as it is any other time in its life. So it has the acuity to make sense of that world. An infant, very few weeks old, can detect very subtle changes in rhythm, very subtle changes in memory. It can follow the up and down, the high and low note pattern, which is called contour. For those of you in music, it can not do transposition, that is a song sung in one key, moved to another key will be a different song for that child. It doesn't have object permanence at that age. That comes several years later. So it has these tremendous possibilities and abilities. Now, what's important is we all know that instinctively because there is a language that's usually called motherese and I think we all know how we talk to infants. We don't talk this way. They don't understand what we're saying. And I'm not going to do motherese here. And motherese is universal, which is that all cultures have it and we all address, and by the way I think we do that with pets as well, and we lose the motherese at the age at which a child can understand language. We talk to them in a musical, melodic kind of way and they respond to that. So that's where our heritage is. And if I had another three hours we would talk about maybe the evolution of music. But, it's there. It's part of us. Enjoy music. Play musical instruments. Interact with your kids and loved ones, etc., etc.

Dr. McGaugh: I have a couple of questions up here about Alzheimer's Disease and Frank Laferle, I'm going to toss these at you. I need another lifeline here. Two questions and you can take them both. Why is it that Alzheimer's patients can draw a picture of an event that happened a long time ago, but can't verbalize it? And then secondly, do you think that there will be a vaccine for Alzheimer's Disease?

Dr. Laferle: It is peculiar that Alzheimer's patients are quite efficient at drawing. I was recently at this black tie affair that was given by the Alzheimer's Association of Orange County and part of the festivities for that evening was an art auction that was a situation here where they were going to auction off art that Alzheimer's patients had drawn. And it was amazing how intricate and detailed this work was. I was very surprised because I, you know, I was a little surprised when I got this invitation, art auction, and I went in there with my own bias and expected little stick diagrams to be drawn and I was astounded by the intricacy of the art. Why is that? Well, we know and we have known for some time that certain functions are localized to particular areas in the brain. And we happen to know that language and disorientation and lack of communication skills is one of the early hallmark features of Alzheimer's Disease. And somehow that manifests itself as a loss of verbal skills, but yet the patients have no problem in terms of expressing themselves in an artistic form. Now, for the second question, that's a little bit easier for me to answer. And based on some animal model work, it turns out that if you develop an animal model that develops some of the pathological features of Alzheimer's Disease you can reverse that by giving the animal a vaccine. There are a lot of questions about the efficacy and whether or not that will work in a human context, in a developing organism that does not over-express a particular protein. Now, you have to remember this, when we develop these animal models generally we do that by causing the animal to express a lot more of a particular protein. That's not the normal physiological avenue by which one develops Alzheimer's Disease. And so while these vaccines show some promise in an invivo animal model, it's still unclear whether or not it will work in a human situation and worse yet, it's not clear how the human immune system is going to tolerate that kind of vaccine at the present time. But it nevertheless, I think represents a very promising avenue for research.

Dr. McGaugh: I have a follow-up, Frank, a related question. Is there any research being done that will enable scientists and doctors to know if a person may get Alzheimer's Disease before the symptoms appear, such as in the Huntingtons?

Dr. Laferle: Yeah. Well, people are working on trying to biopsy different areas of Alzheimer's patients, including skin, and recently there's been a report that you can find some evidence of Alzheimer's Disease occurring in people's muscles. And that's kind of a peculiar phenomenon. And but one that would be very easy to do. And take out a small sliver of a person's muscle, check it out under the microscope and provide a conclusive diagnosis before the person dies, which right now is the only way to diagnose Alzheimer's Disease. That is something that we are currently investigating in our laboratory too, because it turns out there is a very peculiar muscle disease, which is the most common, age related muscle disease in people over the age of 50 and it's called Inclusion Body Myocitis. And it's interesting to people who study Alzheimer's Disease because within the skeletal muscle fibers of these patients they have accumulated all of the proteins that one normally has accumulated in an Alzheimer's Disease brain. They don't have Alzheimer's Disease. They have the consequences of muscle disease, mainly muscle weakness and paralysis. But yet for some reason they develop the complete complement of proteins that one sees in an Alzheimer's brain. So that's one avenue that potentially may hold out to be a diagnostic, you know, way of telling whether or not someone has it before they actually die. It's not clear what the value of that is at the present time because even if you know, there really are not effective treatments to cure Alzheimer's Disease. So a lot of people feel as though by just telling someone that you will develop Alzheimer's Disease, or you're on your way to it, that you're just going to add a lot of stress and reduce the quality of their life. And that it's not really a fair way, or a fair piece of advice to tell someone unless you have some way of offering them some hope.

Dr. McGaugh: Question right here.

Female: Just to go back to the children for a minute. With the extreme influence of early, early effects on childhood, has anybody ever done any studies on some of the more heinous criminals we've had in our society as to what happened in their early, early childhood? Have they ever drawn any conclusions from that sort of thing?

Dr. Leon: It's interesting that kind, those kinds of analyses really fall to people who are interested in criminology. And the ability to work with these people is not something that most neuroscientists are particularly interested in doing. It's actually a big process asking people for their brains and talking to their family. So the answer is no. But it's the kind of thing that is interesting people more and more with the use of modern day imaging techniques. So they're able to see things in these people's brains that suggest some kind of injury or deficit. But going back to where they were, you don't know where that happened or when that happened within their lives. They could've been taking high levels of drugs. They could've had some sort of an accident. You wouldn't be able to tell early on what happened in order to produce something like that. So there's a possibility that exists that early kinds of experience can twist someone into someone who you wouldn't want to even ask for their brain.

Dr. McGaugh: I want to echo that last point because I think we want to be concerned not to over-use the ideas of biological determinism in terms of the choices that people make in their lives. And that's why you'd need to a very large field study of this kind, because you can always look in retrospect and find something that happened in the childhood of a terrible criminal. Now, what you need to know is whether or not that same kind of thing happened in the wonderful person right next door. And the only way you can do that is with very large-scale studies. Once somebody made a prediction to predict that you could always tell what was going to happen eight days from now. And the reason they knew that because if you looked eight days back in anyone's life, you could find that there was something unpleasant that happened. Well, if you look back yesterday something unpleasant happened, and the day before, and the day before. So retrospective research of that kind has to be done extremely carefully with the broad scale vision that Dr. Leon was talking about. Another question? Over here. Yes.

Male: Yes. I'd like to know what the mechanisms are by which the brain actually physically stores memories at the cellular or biochemical, biomolecular level, and are there differences in these mechanisms for short-term versus long-term memory?

Dr. McGaugh: All right. Let me. I'm going to take a stab at the second question. Everybody down here has strong views on this. The answer is yes to the second one. There are different mechanisms underlying short-term and long-term memory. And I think that that is not disputed by anybody that I know of, unless somebody in the front row wants to stand up. For example, I'll just give you one illustration among many. If you give an animal a protein synthesis inhibitor, a drug that will prevent proteins from being synthesized, the animals will learn perfectly well, they just won't remember. That is, long-term memory is not made, short-term memory is. The same thing happens by the way with a heavy dose of a drug that you are all familiar with, Valium with Benzodiazapens. They do the same thing. You can learn and perform perfectly well on the short-term, but you don't make strong long-term memories. So there is a clear separation between the two.

Now, with regard to what is the fundamental molecular, cellular basis of memory, we know what the dominant view is. And I'll tell you and then I'll throw out my lifeline here so that all my folks can help me. The dominant view is that when nerve cells talk to each other, one nerve cell talks to the other nerve cell, a change is induced at the synapse, that is in the connection between the two, such that it takes less stimulation of the first cell to fire the second one later on. And that is known in the field as long-term potentiation so that the cells get potentiated and so there is a cellular model that does appear to match what happens in real life. Now, the other thing that's interesting about that is that just as with real learning, protein synthesis inhibitors do not prevent the establishment of long-term memory, but they prevent its formation on a long-term basis. So you can have short-term, long-term potentiation with protein synthesis inhibitors. Now, there are reviews that we could refer you to, including one very good one by Tracy Shores, a student of Dick Thompson's, arguing and it's a little bit like the fiddler on the roof. On the one hand, and on the other hand, and on the one hand, on the other hand. Bottom line is I think if you took a vote of all the neuroscientists who've worried about this problem and say raise your hand if you think that the cellular basis, a cellular basis of long-term memory is this synaptic change, long-term potentiation, raise your hand if you think that's the case. My view is that the hands are going to go up like this. Most of them are going to go up, most of them are going to go up. But they're hedging it because there's lots of forms of plasticity in the brain, including doubtlessly many forms that we have never investigated, don't know anything about, because we don't yet have the tools to investigate. And so, all we can say is that on the basis of what we know now, there is a reasonably good relationship between long-term potentiation and long-term depression, these synaptic changes, and what we know as long-term memory. Who wants to give me a lifeline? Dr. Thompson.

Dr. Thompson: This is a good model for memory storage. However, we're only now beginning to realize the number of gene processes that are involved in the formation of long-term memory. The development of these new techniques with chip technology, for example, a simple experience that can cause a change in plasticity of the nervous system may cause changes in the expression of 500 or 600 genes. So we're only at the beginning in terms of the detailed biochemical mechanisms that underlie memory storage.

With that once again, let me thank my faculty colleagues for their wonderful assistance with the lifeline and thank all of you for coming tonight. And now it's cookie time.