2002 LECTURE SERIES

The Magic of Memory: Peeking Behind the Brain's Curtain

Dr. James McGaugh
Director, Center for the Neurobiology of Learning and Memory and Research
Professor, Department of Neurobiology and Behavior, UC Irvine
May 22, 2002

Well, thank you for that splendid, extravagant introduction. I greatly appreciate it. Tom, it was over the top, but it's not bad to have something over the top once in a while. It's very pleasant to hear. Thank you. And thank you, Judge Sills, for the news about the continuing sponsorship of this program. We think that with you, it's a great thing to be able to bring this information and opportunity to the community and by that, I mean the broad community of all the citizens of this area who wish to come and learn more about the most important part of their body, the brain, and the most important thing that it does, which is to learn and remember. So thanks to the Irvine Health Foundation for this generous and continuing support.

Well, there is the topic of my talk, but you knew that already because it's in the program. So we'll go to the next part. Many of you have seen Aldridge Park. Those are mature trees, but when my wife, Becky and I, and our children, Doug and Jan, and later Linda came to this campus, there were no trees there. And somewhere between 1984 and 1985, we were invited, those few founding faculty members, to come and plant a seedling and we did and these are the seedlings that we ourselves planted at that time.

Now, I see these trees as a metaphor for the growth and achievement of the UCI campus. As these trees have grown, so has the quality and the breadth and all offerings of UCI. And so has my own research program. These are a metaphor for that also because most of what I'm going to talk about tonight started here at the same time that these trees were planted. There was a little background, but the research that you'll hear about came along as these trees were inching their way up to the heavens.

Now, I've had an awful lot of support from this campus, from the administration, from the School of Biological Sciences, from the Department of Neurobiology and Behavior. I have been supported and I have been honored. And I guess it's no secret that this is one of my favorite buildings on campus. But this is the home of the Department of Neurobiology and Behavior where I have had my main faculty appointment since I arrived here in 1964. And since 1981 or 1982 or 1983, depending upon whether you start with when we thought about it when we moved in and when we officially became a center, for approximately 20 years, I have done, conducted my research in the Center for the Neurobiology of Learning and Memory and the buildings collectively I'm happy to know are the Herklotz Research Facility -- and that's where the research is done that I'm going to report to you tonight.

Now, here are just a few of the people who have been helpful in this research effort over the years. Some of you who've been around a while, if you look carefully, will see some names that you know. These are all people who played a part in the research over a long period of time. Actually, I was in research for seven years before I moved here so I cheated a little bit and put a few of those people on as well, but they're adopted, UCI adoptees and that's fine as well.

And this is my current laboratory. They are seated over here in the dark some place. Would you stand, please? I can't see. Where's the folks from my laboratory now? They're not all here.

Later on at the coffee time, if you stare--this is part of the memory part of it. If you stare at these pictures and there'll be a test to see whether or not you can find these people afterwards. And most of them are at the workstation where they do most of their work and you can see the workstation where I do most of my work.

Now, tonight, we're going to talk a little bit about magic, so we have to have a little magic show here for you. Why magic? In Las Vegas and other places like that, some of you have probably seen a magician make a lion or tiger disappear before your very eyes or appear before your very eyes. Well, that's no trick at all and the reason it's no trick is because you can do that too. You can just think about it here for a moment and you can have a tiger dancing in your forehead right now. You don't need to go to Las Vegas to do that. You can even remember having seen a tiger or you can imagine a drawing of a tiger, if you wanted to. You can remember events long past and you can remember events recent past, and you can remember what you think is going to happen tomorrow and the next day and next year and you can put this all together and have a continuous experience of life all created out of your own magic time machine of memory. And while you're doing that, sitting in the background are all the things that you know how to do. And they're just sitting there so you're prepared, perhaps, to ride a bike or drive a car or play tennis or play golf and you're doing any of that right now so that's all in the background. That's part of the magic act. And the magic appears then when you go to the golf course or you get on the bicycle, you get in the car. All of the sudden, those memories are there and they get you through life.

So you don't need to go to Las Vegas to have the magic act. We have the magic act in our heads all the time. It's incredible. It's absolutely incredible. There's nothing like it. We are the only thing in the universe that can do what we're able to do. Just absolutely incredible.

Now, how do we think about it? Well, this has been thought about for a long time, I suppose since the dawn of time, people wondered, hey, ugh, how do you remember? Yeah. How does that happen? What goes on here? And that was thought about for a long time. Well, at least this thinker here has got it right and that's a very recent discovery and that is, the thinking and the learning goes on in that part of the body, the head, goes on in the brain. But that wasn't really decided for sure until the early 19th century. Up until that period of time, there was considerable argument about where the mental faculties of all kinds, including learning and memory resided. The Greeks, as you know, had it in the heart. The Egyptians not only had it in the heart, but had it in the kidney. That's an interesting thought. You can worry about that--you can wonder about that when you get up in the middle of the night. Say, hum, now I remember.

Now, sitting there and staring at the head doesn't get the job done -- and so about 200 years ago, Franz Joseph Gall, a German who then moved to France, thought he had an insight about this and he was one of the people who helped to locate mental functioning up in the head once and for all. He had his insights early on in school when he looked around at his schoolmates and saw that they had different shaped heads. And he began to draw the conclusion that the kids that had different shaped heads also had different propensities, they had different tendencies to do things. And he thought about it a lot more and over the course of the next several years with a colleague named Spurzheim, they developed the field, which later became known as phrenology.

And this is a later day example of phrenology in which the skull is all marked off and if this were in--if I had put it in precise focus, you'd be able to see where immotativeness is, where propensity for--what--for touching. There's an area of touching, which is on the side of the head because people end to touch the side of their head. And the whole--every spot on the skull had a tendency and the larger that was, the greater the tendency. Now, the back of the skull in the very back region is an area that he identified as physical love, which was based on a widow that he had happened to know. Now, he didn't tell us--he knew--we know how he knew that there was a large protuberance on the back of her head. We have no idea how he found out the other part. I'll leave that to your imagination.

Now, Gall got it part right and a lot wrong. The part right was it's in the head and there must be--he thought there was a relationship between the skull and what was the size of what exists underneath. And he thought there might be some relationship between the size of different regions and the functioning. And in a way, that's not a bad hypothesis, and it turned out it could've turned out to be true. But as it turned out, if you look underneath the skull, you just see a brain and the brain doesn't conform to the size or the shape of the skull and so that part of the hypothesis was wrong.

The other part of the hypothesis was rejected a bit too soon and that was the idea that there probably are not a lot of propensities, that the brain works as a whole. No. There's increasing evidence that there are lots of different things that we do that may involve a different combination of brain systems. The brain doesn't work as a whole all the time; as a matter of fact, probably never works as a whole, but rather, the different parts have important roles to play. And a major effort of neuroscience these days is that of trying to understand how these different parts of the brain work to do this magic act.

So here's looking into the brain just to see a few of those parts that Gall could not have imagined because Gall didn't have the imaging techniques that we have today, did not have electro physiology, was unable to do the kind of anatomy that we do, certainly could not do pharmacology, molecular genetics, so on and so on and so on. All of the tools that we have available to us, he didn't have. And so now, we have the luxury of this magnificent armamentarium that we can use to investigate and ask what do the different parts of the brain do? How do they serve to perform this wonderful magic act? And I'm going to tell you a little bit about that.

But first, a little bit about a few pioneers in learning and memory research. The first one never gets enough credit for what he really did. Those of you who studied psychology know that he invented the nonsense syllable and that may be all that you've ever learned about him, that's consonant, vowel, consonant. But that's not what he really did. He was the first one to tell the world that the mental faculty of memory can be studied objectively, scientifically, just as anything else can be studied. Isn't that interesting that there was a science of the distant planets, of the distant stars long before there was a science of the thing that is closest to us, which is our own brain and our own memory. That didn't even begin until about 1800 and didn't begin to ramp up until this very century. But the early impetus came from Herman Ebbinghouse in 1885 who published a magnificent treatise on experimental studies of memory in a human, himself. And everything that he found is known to be true to this very day. Enormous impact. But it took the field out of philosophy and speculation and put it directly in the laboratory for investigation.

Another one is William James, who just five years later published--although probably was writing during the time that Ebbinghouse's volume was published--a book on psychology, which is one of the most wonderful pieces of literature that you could ever want to read. And in it, he made a number of distinctions, which we--which guide our thinking today. He was the first to make a clear distinction between an early stage of memory and a later stage of memory, long- and short-term memory. And he was the first to talk about, in a serious way, the difference between memory as we know it in declarative and in explicit ways and memory in the form of habits and skills. So there's two dichotomies there, which shape our thinking today, very importantly.

And then George Mueller and Alfonz Pilziger. George Mueller was a student of Herman Ebbinghouse. In the 1900s, they did some interesting experiments, which have guided my entire scientific life. They did experiments that showed that when material is newly learned that it is very labile, very subject to disruption and with time, it becomes less subject to disruption and they propose that the learning of new information first continues or perseverates and eventually, over time, consolidates. So they gave us the perseveration consolidation hypothesis of memory, which has turned out to be so important in my own thinking.

So I'm going to talk about that. We've already had an introduction given by Professor Karu who pointed out that early in my career, I started investigating this hypothesis. The hypothesis that they had was memories take time to store. Now, it--that hypothesis languished for about 50 years. Nobody paid much attention to it and in 1949, Carl Duncan at Northwestern University did a very interesting experiment and so did Ralph Gerard, who was then at the University of Chicago and spent the latter part of his career right here at UCI, did a very comparable experiment.

What they did was to train rats, in Duncan's case and hamsters in Gerard's case, on a little task. They had to jump from one side of a box to the other in order to avoid a shock and then they received an electric convulsive shock, that is electricity applied to the head, either immediately afterwards or at sometime there afterwards and then they were tested the next day. And when they were tested the next day, if they had received that treatment sometime after the training, it had no effect at all, this is no treatment, but if that treatment came immediately afterwards, there was amnesia for the learning.

Now, this, of course, fit with clinical evidence of amnesia that was well known, but not well understood, had never been brought into the laboratory. And for example, about 30 years ago, I took a group of graduate students up to Big Bear to go skiing. One of them took a--the kind of a flop that you save on a video, if we had had videos, and hit his head and got up and took one more ski run and said he didn't feel so hot and left and went home. Well, to this day, he has no memory of the entire day of skiing, has retrograde amnesia for that skiing trip, even though he was conscious or a period of time after having had the fall. That's retrograde amnesia.

Now, this is where I came in. I said, if this indicates that there is a period of susceptibility then why not look for retrograde enhancement? That is, is there something that can be done to the brains of humans and animals that will make memory stronger? And so I did experiments in which I injected animals with stimulant drugs, either immediately after training or at sometime afterwards and I got retrograde enhancement of memory. That's pretty exciting. I was a young graduate student that was almost--I hate to say it--almost 50 years ago that I made that discovery, but I can still remember the rush that I got from it and also I was so excited that I decided I couldn't believe it and I immediately built a completely automated maze so that the animals could be trained without my touching them or doing anything to do--doing anything to them so that the maze would automatically record what they did. And I got the same results and so--and other people did, I'm happy to say. So it lived.

Now, we thought a lot about why this is the case. Why do we have a memory system that stores memory slowly? And we thought about it. Say, what are the things that we remember best in life? What are the things that stand out in your own magic box, in your own magic lantern? The things that stand out at the things that are a little more emotionally exciting or a lot more emotionally exciting. I'm sure that Mark McGuire will never forget that homerun that he hit. Many of you remember the scene from the Vietnam days. You all remember this. A lot of you will remember this picture that was taken just before President Kennedy was shot. And many of you, many of you have experienced this. You remember your children when they were born and you remember them when they were young. And your young children who have grown up now remember you when you were young. Life is like that. And now, I dare say that many of you here will remember exactly where you were and what you were doing when you learned of the O.J. Simpson verdict. This has actually been studied and it turns out that the memory for this is very valid, has been studied for as long as 18 months. And even 18 months after the episode or the reporting of that, subjects were able to report reliably where they were and what they were doing.

Now, the interesting thing is that those studies that studied this phenomenon also showed that there was one thing that predicted how well they remembered where they were and what they were doing and that was the degree of emotional arousal at the time. That's the only thing that statistically predicted how well they remembered where they were when the verdict appeared.

Now, that happens with emotional arousal? You get excited about something. Somebody says, you got a raise or you're fired or that you won the lottery or is that your car out front and so on. And you have brain activation of a number of stress hormones--I'm only going to talk about two. One is the anterior pituitary adrenal cortex leading to cortisol in humans or corticosterone in the rat and on the other side, we have the activation of the autonomic nervous system, the adrenal medulla and epinephrine or adrenaline. Both of these are released from the adrenal glands, which are next to the kidneys. So the Egyptians were not far off. Some action starts down at that level.

Now, here is the summary for the midterm exam. The whole talk and everything I say is premised on this model. We have an experience and when we have an experience, even a mild experience, that is going to lead to some memory consolidation in different parts of the brain. To the extent that this experience is exciting, it's also going to activate the stress hormones that I just mentioned to you, plus some others that I won't talk about. And in addition, that's going to directly excite a region of the brain in the temporal lobes, the medial temporal lobes. The temporal lobes are right inside here and the amygdala is on the frontal part of that. And we have two of them, one on either side. That will get directly excited and there's one region within that, the basal lateral amygdala, but I can just use amygdala because in the human, amygdala is basically basal lateral amygdala. And then the stress hormones and the basal lateral amygdala then will modulate or influence the amount of storage that takes place over here. So you learn some information over here, somebody said you did a job and they said it was a lousy job, the lousy activates this part of it up here and you're inclined to remember that.

So what are the data? Well, now I have to show you some experiments to indicate why I draw the conclusions that I did. First of all, we use in many of--actually, most of our experiments an--what's called and inhibitory avoidance task, in which a rat is placed here, simply allowed to walk into this part of the alley and about here, it gets a very mild foot shock and that's so they go ooch and that's it. They have been waiting all their lives for this experience. Then they--the next day or two days later or a month later, usually it's two days, we bring them back, put them in the apparatus and they sit in the first part of the box for a long time before they go into the other box. And this one is--this rat is saying, why am I here? You see that? That's another part of our magic act. We can read animals' minds, particularly if we have pets, we know that we can, for sure that we can.

All right. Now, in animals that--normal animals that are just trained and given an injection of physiological saline, just saline we have in our bodies and they're tested the next day with a low foot shock, they will remain outside for about a minute, whereas in the first day, they go in within 10 or 15 seconds. So the difference between 10 or 15 seconds and this is their indication that they remember where they were and what they doing when the shock came on and they don't want to go back.

Now, these other groups over here that I haven't shown you yet received an injection of adrenaline, or we call it epinephrine, either immediately, 10 minutes, or 30 minutes, or 2 hours afterwards. And the object of this experiment was to see if a stress hormone that we ordinarily release to ourselves and that animals release to themselves will influence the consolidation of the memory of that experience. And the answer is yes. That's what happens when the injection is given immediately after training. Remember, they're tested the next day or two days later so the effect of the adrenaline, the direct effect is long gone. What you're looking at is the memory effect. That's the memory effect. Well, what happens if the injection on the day of training, the injection after training was delayed? Well, if it's delayed 10 minutes, the enhancement is less, 30 minutes it's less and 2 hours, not at all. So that's the gradient of post-training enhancement of memory with a hormone that you and I secrete into our bloodstreams when we get excited.

So this is the beginning of why we think it is that our getting excited and the release of the hormone plays an important role in determining how well we're going to remember the events that led to the release of the hormone.

Now, even at the time that we were doing these experiments, we knew that the amygdala that I mentioned to you was an important part of the brain because we were actually studying the amygdala at that time for other reasons. But we made an inductive leap and we said is it possible that the adrenaline acts by turning on this region of the amygdala, which is, even then, was thought to be importantly involved in emotion and emotional arousal. So we put down canula directly into the amygdala of rats, there are the canulas going in, and we injected a beta blocker, a drug that blocks the action of the first cousin to epinephrine or first cousin to adrenaline, noradrenaline or norepinephrine, which is the transmitter or neuromodulator, which is like adrenaline, but is the one that is in the brain in large amounts. So we put a blocker of that directly into this region and then we did the experiment again. So here's the experiment with animals that just got saline and here are animals that got adrenaline immediately after training. So there, the effect replicates and it is replicable.

We then asked what happens with the propranolol, the beta blocker that we put in the amygdala? First, does it do anything to animals that only get saline? No. It does not impair memory by itself, but what it does is to block the effect of adrenaline that is injected. So we said, bingo, we have found at least one site in the brain, which appears to play an important role in signaling the importance of an event such that there will be a regulation of the strength of the memory for that event.

Now, if that's the case, it should be then that if adrenaline itself is administered into the amygdala, it should enhance memory. And here is work of Anne Power that shows that is the case. These animals were trained, but in place of giving epinephrine in the periphery, into the body, the noradrenaline or norepinephrine was infused directly into the basal lateral amygdala immediately after training. And there you see the--we call it inverted U memory enhancing effect, just by tweaking the adrenaline or the noradrenaline in that region of the brain.

Now, we use a variety of other tasks and I'm not going to tell you all that we do; I just have to tell you some that we do. One task we use is a Morris Water Maze task, named Morris Water Maze because Dr. Morris is the one who introduced it. This is a cattle-watering tank and it is filled with water up to a certain level. You will probably not able to see that, but the rat here is sitting on a loose-eyed platform, which--the surface of which is about one centimeter below the surface of the water. The animal is put in there from one of a four starting points in this round tank and is simply taught to swim to this invisible platform. So the animal has to do special learning, swim to a spot in the tank where there is safety with no internal queues, but there, as you see, are posters on the wall.

Now, first time the animal swims in this, this is a rough estimate of what the animal does, swimming quasi-randomly first around the edge and finally, he finds it. After about six trials or eight trials, the animal will swim within a short period of time, perhaps 35 seconds or so to the platform. Then the animal receives an injection of norepinephrine or propranolol into the basal lateral amygdala. So here are controls. These animals receive a controlled solution into the B.L.A., is basal lateral amygdala immediately after training. On the first day, it took them about 60 seconds 'til they get to the platform, the next day about 35. This is the improvement, which is just normal. Now, we have some animals down here who immediately after the training received norepinephrine. It took them, it looks like, about ten seconds to find the platform on the second day.

So there's an enhancement of memory for this very different kind of learning task. And as with the other task, a higher dose is not so good and propranolol completely prevents the learning. So these results are, with a very, very different kind of learning task, produce conceptually the same results. Activate the basal lateral amygdala with norepinephrine. There will be memory enhancing. Prevent the activation of the receptors by putting in a beta blocker and there will be impairment.

Now, we can look at this more directly--and Christa McEntire in the laboratory does that by putting down a little probe into the rat's brain, a micro dialysis probe so that it can sample the fluid, which is being released from this region of the brain. This is a cross-section showing where the basal lateral amygdala is a rat brain. It's right here. And the animal lives with this with a canula at the end in it and a probe is put in and this probe goes up through this little tube and the contents that--of the fluid that is being released by the animal can then be subjected to chromatography, high-performance liquid chromatography and we can get a measure then of the amount of norepinephrine that the animal is releasing to itself.

So here's an experiment. Here's an animal trained in an inhibitory avoidance task. Then immediately after, there's a group of animals. The norepinephrine in the amygdala is sampled, using the procedure I showed you. Here is the baseline before and it--I is inhibitory avoidance here. Oops. Up it goes. And it's--there are 15-minute period here, staying up for a long period of time. This is the enhanced release of norepinephrine in the amygdala, which is induced by this mild foot shock training that the animal had, just as would have--as was predicted from the pharmacological studies using the hormones and the drugs.

Now, this is--this group is composed of a number of animals so let's take a look at the individual animals here. And as you can see, there's quite a bit of variability. Here's an animal that released a whole lot and here's some animals that release hardly any at all. Did that make any difference? Well, over here, what Christa has plotted are the retention latencies. How long did the animal stay out in the starting chamber on the retention test day? And the cutoff is ten minutes because graduate students and post-docs don't like to sit and watch animals doing nothing for a long period of time. So Christa watched this animal do nothing for ten minutes on the retention test and this is an animal that released an enormous amount of norepinephrine, showed good retention. This animal released enormous amount, good retention. This animal released enormous amount, good retention. Let's come down here. This animal stepped through on the retention test in ten seconds. It hardly showed a blip at all of release. To make a long story short, there's a correlation of about plus .80 between the amount of norepinephrine released and the retention performance tested later.

So here is a neurobiological measure, a fluid taken from a small region of the animal's brain, which predicts precisely at, with a correlation of .8 or higher, the performance of this animal at a later time. So this is not a drug; this is what the animal is releasing to itself. It's what you release to yourself when you get emotionally excited and you remember.

Now, the other side of this was the cortisol side and I'll briefly describe some work by Benno Rosendall who's done a ton of work in the laboratory and I'll only mention a few of the studies. Here is using a drug that RU28362, a synthetic drug, which activates the receptors in the brain that normally are activate by cortisol so that when you release cortisol or when you take cortisone then these receptors in your brain will be activated. Now, this is a synthetic drug, which is very specific for that. So these animals were trained at the inhibitory avoidance task, user controlled, got a saline injection or a--yes. Saline injection. Then these animals got the glucocorticoid agonist in different doses. And there's the dose response effect of putting this glucocorticoid drug directly into the basal lateral amygdala. Very nice memory-enhancing effect, just like norepinephrine.

Now, we know that we can block the epinephrine effect by putting in a beta blocker. So he put in a beta blocker, a different on, atenolol in this case, and the question is, will it do anything to this enhancement? And the answer is it doesn't do anything to controls, but it blocks the enhancement. So it says this noreginergic activation, activate, activating of the receptors in this tiny region of the brain that use norepinephrine, which animals release to themselves, but blocking those receptors prevents the action on memory of both of these stress hormones. They converge in their influences right at this spot.

So here is a summary in case you haven't followed every single bit of that. Here is a schematic of the adrenal gland, adrenal medulla is--secretes the adrenaline, the adrenal cortex re--secretes the cortisol. So epinephrine goes up by activating the vagas nerve and goes into the brain stem and eventually releases norepinephrine. So here's epinephrine or adrenaline up here, norepinephrine in the basal lateral amygdala. That effect can be blocked by blockers of, like, propranolol and, like, atenolol.

Corticosterone in the rat or cortisol in the human is permissive. It can go any place it wants to. It acts at a number of different places, but its effects also are blocked by preventing noreginergic activation, that little tiny spot in the brain, the basal lateral amygdala and then it influences memory by the projections to other brain structures.

So what other brain structures? Well, Gall was right. There are probably many places in the brain. He didn't know what they were or where they were. We know a lot more about that. But here are some of the major players that we work with, in any case, they're all listed up there. And as it happens, they are all directly activated by the basal lateral amygdala. Anatomically, they are connected. They directly--are directly influenced by the basal lateral amygdala and they are all candidate sites for consolidation of recently acquired memory. Let's take a look.

Now, here is a very interesting thought that was proposed by Ralph Gerard. Ralph Gerard was the founding dean of the graduate division here at UCI. He came here from--well, he spent most of his time at the University of Chicago, he spent a few years at the University of Illinois before he came here. And he didn't have a laboratory here, but he was still writing. He came here about 1962 and I actually knew him quite well. He met me at the heliport when I was hired. Many of you don't know this, but at the John Wayne Tennis Courts, that used to be a heliport. That's how we got here in those days because there was no 405. So I met Ralph Gerard there, but unfortunately, he didn't tell me about this paper. I only discovered this last year. If I'd only discovered this last year, it would've saved me about 20 years of work.

What does he say? He says, the amygdala may act directly on cortical neurons to alter their responsiveness to the discrete impulses that reach the cortex. These deep nuclei could easily modify the ease and completeness of experience fixation, that is consolidation, even if these nuclei were not themselves the loci of ingram. So he's saying the amygdala could be a modulating structure to make memory consolidation work. He said this in 1961 and nobody that I know of paid any attention to it. So here is this little gem sitting there, which now I can say has guided my research in retrospect.

So let's take a look and see if it's true. We're going to talk about hippocampally based memory, caudate nucleus based memory. Now, we have a different task. In that water maze, the cattle tank, the animals can learn lots of different things, but here's another standard task that's used. A visible hue--and in this case, the animals have to learn to swim to a visible--notice there's a little thing here. Actually, what it is, is a tennis ball that is painted in stripes and it moves around from place to place. So it's here and then it's here and the animal has to follow the visual queue. It turns out that if you remove the caudate nucleus from animals, they cannot learn this task and they cannot remember it. They can do spatial learning quite well. On the contrary, if you remove the hippocampus, the animals learn this task quite well, but they can't do the spatial learning. So here we have two brain structures that, on the face of it, play quite different roles.

So let's take a look at these interaction and let's put some canulas down into the hippocampus and some--in other experiments down into the caudate nucleus and let's see what happens. So here's the experiment done by Mark Packard, Larry Cahill back in 1994. The animals are going to get post-training injections into the amygdala and the drug used is diamphetamine, which acts both on another transmitter, dopamine, and on norepinephrine. Going to get it in the amygdala. Immediately in one of several brain regions immediately after they're trained on one of two kinds of tasks. So here, they're trained, they're given injections into the hippocampus immediately after they are trained. If they are trained on a spatial task, that enhances their memory as seen in performance the next day. If they are trained on a queued task, it has no effect. So it says the hippocampus cares about the spatial task and if the hippocampus can be activated, the memory will be stronger for that spatial task.

What about the caudate nucleus? The caudate nucleus. Training on a spatial task and injecting into the caudate nucleus after training has no effect, but training on a queued task and injected into the caudate nucleus enhances memory. The caudate nucleus cares about the task in which the animals have to swim to a visibly queued object, which is moving around to different places in the world.

What does the amygdala do? The amygdala is promiscuous. It doesn't care what kind of learning is taking place. It says, if learning has occurred and I'm injected, I'll make it stronger for both kinds of learning.

Now, is the memory in the amygdala? Not for this kind of learning because if we infuse a local anesthetic, lidocaine, directly into the amygdala before the animals are tested the next day, there is no impairment. So the amygdala can be inactivated at the time that the animals are tested and it has no effect at all.

So now we're able to do something fancier. We're going to look at the interaction between the amygdala and the hippocampus by making lesions of the basal lateral amygdala and infusing the hippocampus in inhibitory avoidance and what happens.

So here, we have post-training injections, but this, for the first time that I've shown you data, the injections are into the hippocampus immediately after training on inhibitory avoidance learning. And this is the--those response effect here and the injection is the glucocorticoid receptor activator. So there's the memory enhancement.

This group of animals I'm going to show you have lesions at the basal lateral amygdala, our friendly structure. There's the controls. There's no impairing effect. And there are the animals that get the glucocorticoid injected into the hippocampus. It's important to get this experiment. The drug is injected into the hippocampus. If the animals do not have a basal lateral amygdala, the drug cannot act. The basal lateral amygdala is a co-requirement in order for the hippocampus to do its job.

What about the cortex? Well, in this experiment, a drug, which is activated normally by norepinephrine, a synthetic cyclic A.M.P., a first messenger, the details are not important. This drug is injected into the cortex, into the interrenal cortex in the back of the brain immediately after training and here is enhancement of memory. So we can enhance memory by injecting a drug directly into the cortex. Is the basal lateral amygdala involved in this? Well, basal lateral amygdala lesions don't prevent that learning, but they completely prevent the effect of the drug that is administered into a very distant region of the brain, the interrenal cortex. So it's a switch area. It's an enabler area. It's a modulating area that allows things to happen for memory in other regions of the brain.

So here's a summary of that. We have an experience. We have the basal lateral amygdala activated and we have a lot of different brain regions over here, which might get turned on. And when an experience occurs, some consolidation begins to occur in these regions, the basal lateral amygdala is activated, the adrenal gland is activated and viola, they turn on and they exert their modulatory influences so that they can influence the changes here, but this output from the basal lateral amygdala is critical in enabling the enhanced consolidation to occur in the other brain region. This is a, like, a train station controller that enables this to happen.

…And first, I'll talk about an experiment done by Larry Cahill here a few years ago. This is now a very famous experiment that has been replicated many times throughout the world. It's a very simple experiment in which in place of giving human subjects a foot shock in an alley, which I thought was a reasonable thing to do, but Larry thought that wasn't a good idea, the human subjects were told a story and I'm going to tell you briefly the story of these subjects. There's three story phases.

A boy and a mother leave home, they cross a street, they see a damaged car, they go to the hospital to visit their father who works there. They see some makeup that's been put on people to make it look like they've been injured because this is disaster preparedness day. The mother makes a telephone call, goes to the bus station. That's it. There are three parts to the story, leaving home, seeing a car, being in the hospital then afterwards. And then the subjects got a surprise test several weeks later saying, what do you remember--oh, I forgot to tell you--with every part of that, a picture is shown. Boy and mother leave home, picture, car, there's a picture. And a few weeks later, they're asked, tell me what you saw in that pictures, not what story did you hear, but what was in the picture, what details did you see in the picture? And it turns out that these subjects and the controls remembered the same amount of information from each phase of the story.

Other subjects got another story. Boy and mother leave home, they cross the street, the boy is hit by the car, he's badly injured, his legs are severed. He's rushed to the hospital, the surgeons rush frantically to save the boy's life, reattach the leg, legs. The mother makes a telephone call and goes to the bus station. So several weeks later, these subjects were asked what pictures--tell us what you saw. And this is what they remembered. About the same at the beginning of the story, exactly the same at the end, but grossly different in the middle of the story where the gory stuff happens. There's actually a picture of awful looking legs, terrible looking legs. And that's the effect of emotional arousal.

Now, the question is, is this--does this effect depend upon the kind of systems that we've been talking about based on animal research?

So here we have a replication, this is another experiment. Subjects get the neutral steering wheel, we're only looking at the middle section where the bad either boring stuff or bad stuff happens and here is the enhanced memory induced by the arousal when the subjects are tested several weeks later for the memory of the pictures. Does propranolol impair memory if it's a neutral story, a boring story? No, it does not. What happens is propranolol is given to subjects, a beta blocker, before they are given the arousal story? It blocks the enhanced effect of arousal just as we had predicted from the animal experiments.

Now, there are some recent experiments that have followed up on that. If human subjects are given an agonist, that is a drug that turns on this same system, the adronergic system, it has a reverse effect: it enhances memory in humans just as it does in rats. And this is really something that is quite remarkable. Shelling and Kaputo, two different investigators, studied human subjects in the emergency room and they measured in detail--because they always do--the amount of adrenaline that they received and the amount in the blood stream and the amount of cortisol they received for treatment of inflammation and the amount that was in the bloodstreams. They recorded that and then weeks later, they studied the subjects' memory of their emergency room or traumatic care experiences. And it turned out that the only thing of all of the variables that they had in their study that predicted the long-term retention of the memory of their care in the hospital was the amount of epinephrine that they received and the amount of glucocortisol that they received. That's what predicted their long-term memory. So those fit very well with our rat experiments.

And now, one final set of experiments. Amygdala activation during learning correlated with long-term retention as measured by brain imaging. And the lead work on this also was done by Cahill, but has been replicated by two published studies and one study I know of that's in press, using somewhat different techniques, but always with the same result. So here is the experiment. Subjects were, um, injected with [inaudible] glucose and then they were shown a series of two-minute film clips for about 30 minutes while their brains were being scanned using positron emission tomography. So they're looking at film clips. And I'm only showing you one set of data for subjects that looked at very exciting film clips, the kind of film clips that, should you rent at a store, they would take down your name, address, and call the police. These are awful, awful film clips that these subjects were watching.

So they watched them and their brain was being assessed using brain scanning. And then several weeks later, the subjects were given a surprise memory test and plotted here is a number of films recalled and plotted over here is the amygdala, right amygdala glucose, which means by inference, the activity of the amygdala at the time that the subjects were viewing these films and the correlation is plus .93, which is about as high as you get. This says that if you only knew one thing about these subjects--and that is what their right amygdala was doing when they viewed the films, you'd have probably the best possible predictor of how well those films would be removed--would be remembered several weeks later. So it's like the norepinephrine story with the rats. If you only knew one thing about our rats and that is how much norepinephrine was released in the amygdala, that would be sufficient to enable you to predict what they would do in that task at a later time on retention testing.

I'll just--as a footnote here, it turns out that all of these subjects were males, all males. This has now been studied in two different groups here and Dr. Gabrieli, who was our last speaker, also reported this same finding, he was one of the subsequent investigators, using females and the correlation is just as good with females. It happens to be with the left amygdala. So the brains of--I'm bringing you new information. The brains of men and women are different. It's very important to give these gems of truth to a public audience so that you can take away this latest information. That is, by the way, a serious subject of investigation, why is it that the brains of men and women differ with respect to this and that a lot of work will be done on that by Dr. Cahill and others.

So here's a summary of the story. I'm not quite finished, but I want to summarize what I've said so far. The important thing for creating this effect, these effects I've described, is that experience has to induce the release of adrenal stress hormones. There has to be an activation of norepinephrine in the amygdala, in particular, the basal lateral amygdala. This has the effect of regulating the storage of information in several other brain regions, probably lots of them that currently my laboratory is working--investigating many other regions of the brain. That's our current intense focus of investigation. And all of this is to create a correlation between the significance of our experiences and our remembrance of those experiences. This is the--part of the machinery, the magic machinery that we have that automatically generates this relationship between the importance of experiences that we have and then how well we remember those experiences at a later time. And it doesn't take any work on your part to do this job; the machinery is there. The magic behind the curtain is doing its job.

Now, here's another bit of truth that we discovered not too long ago. I mentioned the Ralph Gerard in 1961. Everything that we have said, but not in detail was also said by Descartes in 1650. The usefulness of all the passions consist in their strengthening and prolonging in the soul thoughts which are good for it to conserve. So the usefulness of emotion is to strengthen and prolong in our minds and brains memories, which are important to keep. And Descartes knew that, unfortunately, and I didn't know that or I wasted maybe 40 years if I'd had only known that.

Now, he said something else. This is not the entire quote. And all the harm they can do consists in their strengthening and conserving these thoughts more than is necessary. More than is necessary. What does that mean? Well, a biological psychiatrist that we know looked at that and said, there we are, that's post-traumatic stress syndrome, P.T.S.D. And this led to the hypothesis that possibly, the over-activation of this system that I've described as being so wonderful may lead to the making of very strong memories, which can, if they are bad memories, take over people's lives and at worst case, incapacitate them for years and decades, that's the post-traumatic stress syndrome that is suffered by people who've been in terrible experiences, such as the awful wars that we have as plagues and bring upon ourselves.

So is there anything to that? Well, yes, there is. There is now the first study and there's another one in press. And this one was by Roger Pitman and Larry Cahill is the co-author on it in which they got a hold of subjects that had been subjected to trauma, but not seriously, physically damaged, and they started putting them on beta blockers within six hours after the experience and kept them on them four times a day for ten days. And then later on, many weeks later, they studied their traumatic memories. And what they found was that the subjects that were given the beta blockers had significantly fewer traumatic memories than the control group that were given a placebo.

Now, this is only a first publication and one other is on its way, but if these hold up, this will not constitute the very first treatment for the prevention of development of a debilitating disorder. So some good may come out of this, which was totally unexpected and that is looking at the Descartian side of the, of this system, which ordinarily does a good job, even in post-traumatic syndrome, it does a very good job of creating a correlation between the importance of events and its remembrance and that's the problem. They are too important and they're remembered too strongly. And there's a way to back that down, according to this publication and one other.

So now we have come to the end. I've told you a little bit about a portion of the magic act of the brain and with that, let me close and thank you.