Toward Total Recall : UCI Researchers Hope Drug Can Improve Memory

You can recall everything that happened during prom night, but you can’t remember where you left your keys last night.

You check your watch. Fifteen seconds later you can’t remember the time.

The image of Grandma’s cute little white house is vivid in your memory--until you find a snapshot that shows it was yellow.

And just when you figure your memory is shot, you recall with ease where you put the lawn rake three years ago.

Human memory is a bewildering marvel, capable of miraculous feats and frustrating failures.

But now, after what UC Irvine professor Gary Lynch calls “a bona fide scientific revolution over the last 10 years,” brain researchers are beginning to understand some of memory’s most basic workings.

Lynch, a psychobiologist at UCI’s Center for the Neurobiology of Learning and Memory, is among the leading brain scientists. He and colleagues have discovered what they believe is the actual process by which memory is stored in the brain, and they have devised an experimental drug, Ampakine, which they say increases learning speed and retention in rats.

The university has licensed an Irvine pharmaceuticals firm to develop Ampakine as a possible prescription drug, hoping it will increase memory in mild cases of dementia, stroke and Alzheimer’s disease. So far, its effect in human beings is untested.

But it’s only the latest development in brain research, Lynch says. A decade of discoveries now allows science to describe “with some degree of confidence things that would have sounded like science fiction 10 years ago. What we know now compared to just five years ago is incredible.”

Why is it you can remember the prom but not where you put keys?

The reason is that you are using two physically separate kinds of memory, Lynch says. The prom is engraved in your “episodic memory,” a very powerful system for preserving the rich details of events. The hormones released when you feel strong emotions intensifies these memories, and your hormones really pumped on prom night.

But the location of your keys was recorded in your “scratch-pad memory,” which is notable for two qualities: You can’t store much information there, and the information evaporates fast, usually in a few hours. This is inconvenient if you don’t retrieve the keys before the memory about them goes blank, but in the long run the system is a boon. Who wants to remember where his keys were five years ago?

This also explains why you don’t remember the time only seconds after looking at your watch. As soon as the need for the information is gone, scratch-pad memory tosses it overboard.

But how could the memory of Grandma’s white house be so vivid yet so wrong?

Lynch says it is not known exactly how this happens. There is evidence that new memories can partially override old ones, so that seeing a white house similar to Grandma’s yellow one might unconsciously tint the original memory.

It is also known that newly formed memories are, like unset concrete, vulnerable for a few hours. During that time, the brain can send a code that erases the new memory.

Lynch’s goal during his two decades of research has been to discover how memory works at its most basic level--in the individual brain cell or neuron.

He thinks he has not only succeeded but also has discovered how the process can be intensified by drugs. The National Academy of Sciences will publish the latest link of his theory later this year.

ROAD MAP FOR YOUR LIFE

All this is more important than most people realize, Lynch says. Most people think of memory only as remembering to pick up milk on the way home. In reality, you use memory constantly. You leave work and recognize your car among the hundreds in the parking lot. You remember how to open the door, how to start the engine, how to drive home. You hear a song on the radio and remember the emotions you felt when you first heard it. You see a red light and unconsciously remember that you’re supposed to stop.

“Memory is the device that organizes the world for you,” Lynch says. “Whatever you encounter, you will relate it to something in your experience--that is, to something you remember. You have to, because your brain’s just built that way.”

The brain sizes of all mammals, from white mice to blue whales, follows the same formula. Tell a brain scientist the mammal’s weight and he can tell you what the brain weighs.

But there is a startling exception to the rule: Us. If human beings adhered to the formula, our brains would be about the size of softballs. In reality, they are roughly four times larger.

All this extra mass is in the cortex, the crinkly surfaced dome of the brain. “And the cortex,” says Lynch, “is Memoryland.”

It is an unimaginable jumble of electrical circuits. Each of 10 billion brain cells connects with 50,000 others. One square millimeter of cortex contains 80,000 brain cells, making the cortex the most complex electronic circuit board on Earth.

This means the brain’s memory storage capacity is effectively unlimited. You’d need many more than one lifetime to fill it up.

THE LEARNING CODE

But no matter how full it becomes, the process of summoning a specific memory does not become slower. Experiments have tried to saturate memory but have failed. In one classic experiment, students were shown photographic slides, three seconds per picture, five seconds between pictures. One group of students was shown 100 slides, another 1,000 slides, another 10,000 slides. Afterward, all three groups could instantly recognize about 90% of the slides they had seen.

The brain can manage such an immense cargo of memories because it breaks the process into smaller jobs. What seems to you to be a single continuous action of remembering is actually many actions occurring in quick, seamless succession.

At the most basic level, the brain stores each memory in its own network of brain cells by changing how those cells behave. An electrical “learning code” is sent telling each cell to “remember” whatever immediately follows, such as the impulses from hearing a sound.

The cells “record” by turning themselves into more sensitive receivers. Now the cells have hair triggers, and when the brain goes looking for this memory, the network where it’s stored is much more likely to respond strongly.

The process is pure cause and effect--first comes the code, then the information to be remembered--and the process depends on a sense of time. Code pulses spaced too closely or too far apart will fail to turn on the memory apparatus.

Lynch suggests this is the basic reason we have a sense of cause and effect, that we recognize (or imagine) two things happening at different times can be related. “This is why when a door slams and the light goes out, you instantly assume the slam shut off the light. It’s inescapable, because it’s built right into our brain organization.

“Notice, by the way, that you don’t think the light going out caused the door to slam. For us, time only goes in one direction.”

Time has other effects on memory. Say “ought,” “toe” and “mobile” and they’re recognized as three words. But the same sounds without pauses are recognized as one word.

Show your baby a teddy bear and it will remember the visual image. Say “teddy” at the same time and the word association is recorded as well. Then the sound “teddy” will summon up a visual memory of the teddy bear itself, a phenomenon Lynch believes is unique to human beings.

ORGANIZING YOUR WORLD

On the next higher level of memory, the brain is organizing memories according to physical similarities. Lynch says the very design of brain circuits causes this to happen automatically, unconsciously and irresistibly. The process produces “phenomenally good categories,” much better than categories we could consciously devise, he says.

Until recently, brain scientists did not know this categorizing process was occurring, yet people use memory categories constantly, Lynch says.

Example: A friend asks, “What’s that on the limb?” You look, see an adolescent male English sparrow with a band around one leg and an insect in its beak, and you say, “It’s a bird.” Why are you withholding all that extra information?

Because at first glance, the brain goes only to the category it has made for such objects, Lynch says. The brain goes deeper for detail as a second step when detail is needed.

This makes more sense than you might think, Lynch says. “It’s an excellent survival technique. You walk out in the street and you see an object coming at you on four wheels with someone sitting in it. You’ve never seen this specific object before, but you instantly know it’s a car. You don’t stand there and say, ‘I believe that’s a ’37 Ford. Or perhaps a Chevy.’ You know it’s a car and you get out of the way.”

Yet consciously trying to define a car category is extremely difficult, Lynch says. Try it, then see whether it would exclude a bus, a truck, a golf cart and a wheelchair. Yet such a sophisticated category was created in your brain, by your brain, without you realizing it.

Not only is the human brain capable of forming these categories, it cannot avoid doing so, Lynch says. Every encounter with something new requires the brain to fit it into an existing memory category.

A young boy who has never seen a spider may cram it into the only animal category he has developed. Consequently when he remembers the spider, he may remember it with only four legs. But if he forces enough spider exceptions into that category, they will form the a new category for spiders only.

This happens with adults as well. A primitive adult seeing an airplane fly for the first time may remember it as having feathers. An urban adult may remember seeing a police car when it was merely a black car with a package strapped to the roof.

You can experience this process anytime you want. Stare at fleecy clouds or into a cottage-cheese ceiling and soon your mind perceives images forming among the random patterns. Your brain is trying to organize the information from your eyes into something that will fit into one of your memory categories.

MEMORIES AT WORK

At the next higher level of memory, the cortex reaches outside Memoryland to add emotional and muscular power to memory.

All parts of the cortex have electrical connections to other parts of the brain, but there are immense trunk lines running to specific regions.

One destination is the amygdala, which controls emotion. It doesn’t matter what you’re doing, smelling, seeing or thinking, if we stimulate one part of your amygdala, you’ll feel angry. Stimulate another and you’ll feel happy or sad or hungry or lustful.

The emotional effects of memory are stored here. Whenever you recognize or recall something, your cortex checks with the amygdala, which sets off whatever emotion has been earmarked for that memory or category, Lynch says. This is the reason that string quartets might make you cry and movie theaters might make you hungry.

Other connections reach a region known as the striatum, where we organize our movements. Here recognition can bring fast action.

“Let’s say in comes a sound, and the cortex instantly recognizes it by its category. It’s a growl. You haven’t heard that growl before, but it fits the growl category,” Lynch says.

“The cortex sends it down to the amygdala, which says, ‘Uh oh, bad sound, dangerous sound. Switch on fear!’ And before you can think, you’re scared and moving.

“Now, if I shout ‘Duck!’ and you’re 1 year old, it doesn’t mean anything to you. But once you’ve learned what duck! means, you make that certain movement without thinking. This memory circuit has a direct line to the striatum and the amygdala and out come movement and emotion.”

THE HUMAN DIFFERENCE

So far, we could be talking about a man or a mouse, Lynch said. “We’re talking about circuitry that’s universal to mammals. It’s just as well developed in a rat’s brain as in yours.”

But a third region, the hippocampus, is much more developed in human beings.

“You don’t want to lose your hippocampus, and tragically enough, it’s probably the most vulnerable part of your brain,” Lynch says. “You have a heart attack, a stroke, and you can wipe it out. Then you can’t form any new memories--or very few.

“Actually, you could learn to ride a bicycle, but you’d never remember where you put it. We still don’t know why the hippocampus does that.”

But Lynch has formally published a hypothesis that the hippocampus adds additional kinds of memory seemingly needed to form ordinary memories in the cortex.

The first, which he calls “recency memory,” records the passage of time. “You run into someone, it’s Charlie, and you say, ‘Hey, Charlie, haven’t seen you in years.’ What happened was you recognized this person to be Charlie and then you checked the hippocampus to see how long it’s been since you saw him. That’s a powerful effect, and you know it immediately.

“What good is it? The only thing we’ve been able to come up with is there may be some evolutionary value to being cautious around things you haven’t seen for a while.”

The second powerful effect is knowledge of whether you’ve already been here and already done this. This is the scratch-pad memory at work, recording, for a short while only, routine matters that you’re not going to want to remember tomorrow. It’s where did I park my car or have I already checked the mail or what’s the phone number I just looked up?

“Everybody complains about this memory,” Lynch says. “This is a highly specialized piece of wiring, and it works differently than anything we’ve talked about. People who don’t have a hippocampus don’t have it. They park their car and they might as well have dumped it in the Pacific. They don’t know where it is.

“This is a very imperfect device, and it may be because its memory is actually meant to be thrown away. The trick is to stay away from it when you need long-term memory.”

People who never forget where they put their keys are using tricks, consciously or unconsciously, such as always putting them in the same place, Lynch says. They depend on remembering a procedure, a ritual, which is a different, very stable form of memory outside the hippocampus.

“Rats do this,” Lynch says. “We put eight Froot Loops in a maze--rats love Froot Loops--and they can get one by going through any of eight doors arranged in a circle. They’ll forget about one time in six whether they’ve already been through a particular door. So pretty soon they all adopt some sort of a system, like always turning right.”

The hippocampus’ third powerful effect is expectation or anticipation--memory of what the proper sequence of events should be. You meet Charlie and say you haven’t seen him in years. If instead of returning your greeting Charlie starts tap-dancing and yodeling, you will immediately know something’s screwy. “You instantly detect this prior to making any intellectual judgments or analysis,” Lynch says. “You instantly have a sense that something’s wrong, and it’s full stop, freeze, back up and what’s going on?”

The reaction in unavoidable, Lynch says. If you open your refrigerator and see piles of cash instead of food, your first reaction will be wariness, not joy.

“At this point, I suggest you now pretty much have the complete rat brain system,” Lynch says. “You’re not any better at this stuff than he is.”

THINKING IN MEMORYLAND

The difference between people and rats is that people have a huge cortex to store memories and unique ways of handling them.

“We are now going much deeper into the land of hypothesis,” Lynch says. “Now we’re into an area that is a little embarrassing for us brain scientists, because what I’m telling you is this: We don’t have much of an idea at all about what’s going on in 85% of your brain.”

The vast majority of the brain cells in Memoryland do not connect to anything outside, Lynch says. In effect, the cortex spends most of its time talking to itself, he says.

“This seems insane. Where’s all the real-world stuff--information from the eyes and the ears? That’s still going to small parts of the cortex, but the rest of the cortex is just hooked up to itself. It’s like a huge city where none of the streets leads to the outside.

“Now, we do not have a theory of this thing. That’s why we really don’t have a theory of behavior. We’re not going to stop, of course. This is the great, final mystery of all biology: What is this thing doing? Because whatever it is, that’s you. It’s the only thing that separates us from the great world of animals. But if this thing had plopped down from another planet, we wouldn’t know much less about how it works.”

With that warning, Lynch offers his educated guesses.

At the front of the cortex is an area involved in coordinating physical movement, from climbing a tree to speaking a language. It must remember incredibly complicated instructions to accomplish these tasks.

At the back of the cortex are individual areas involved with vision, smell, sound and other perception.

Connections allow these two areas to talk to one another and form associations. Consequently, hearing the word dog can summon up a mental picture of a dog, and you can scan it as you would an actual picture. These connections allowed Beethoven, though deaf, to compose music by remembering the sounds of notes and instruments.

Lynch says no other mammal has anywhere near as many front-to-back connections. In a human being, they are gathered in immense bundles, trunk lines “as big around as your finger,” Lynch says. He guesses that communication along these trunk lines was the ultimate evolution of the human brain.

Once this link existed, the complicated programs at the front that had been controlling movement could now communicate with the huge store of memories at the rear. The brain no longer needed the eyes to create vision. The memory of images could be coordinated in the same way. You could experience a walk to the store entirely within your imagination, arranging memories of what you saw, smelled, felt and heard on previous trips.

There could be language, because the memory of word sounds stored at the back could be arranged by programs at the front into phrases and sentences.

There could be foresight and planning, because remembered images, stored at the back, could be arranged into sequences, allowing the brain to preview actions. This is what high-divers are doing when they seemingly go into a trance just before their dives. This is what novelists are doing as they devise a plot.

“I suspect it was the growth of this front-to-back thing that led to what we experience as thinking,” Lynch says. “You took those motor programs meant to help you climb trees, but you used it to organize the memory of climbing trees. You turned it inward. Of course, once this thing is clocking along, it never needs to do anything. It can go on forever.

“And here’s the irony to this argument. You tell me something, and I say to you, what are the rules of grammar you just used? I mean, you just used them. You changed the pronunciation of this word because it followed that word, you had this sequence, you used this exception--what did you experience as you were doing it?

“You’d have to sit down and think, but all you can do is analyze it. Because you didn’t actually experience anything. You just did it.

“So why are we so screwed up? Because in order to think, we run these programs, but our consciousness has no access to those programs. They’re organizing your memory and coordinating your thinking, but you have no conscious access to them.

“People have this wonderful idea that evolution makes things perfect for our environment. Nothing could be further from the truth.”

Memory at Its Most Basic Level

To store one memory, the brain sets aside a network of hundreds or thousands of brain cells, called neurons, which communicate electrically: A. Eye: Sees object and sends electrical impulses to brain. B. Visual cortex: Receives impulses, sends them to be recognized or recorded. C. Neocortex: Stores most memories. At 10 billion brain cells, the capacity is so large you can’t fill it in a lifetime. D. Amygdala: Adds emotional meaning to memories. Remembers how you react to spiders or kittens. E: Hippocampus: Remembers time (“I haven’t seen you in years”), recognizes incongruities (“There’s something different about you”) and temporarily remembers routine details (“We parked in the third row”). F. Striatum: Remembers that action is required, such as the necessity to duck away from a bee.

* 1. Above, a sending neuron transmits a voltage along its axon to the dendrites of the receiving neuron. 2. The gap or synapse between sending and receiving neurons is so small it can be seen only with an electron microscope. Electrical impulses are sent by squirting a chemical called a neurotransmitter across the synapse. 3. If enough neurotransmitter sticks to the receptor, the receptor opens. Salty brain fluid and its sodium ions flow through the channel. When enough ions enter through enough receptors, the receiving neuron fires its electrical impulse to another neuron down the network. This occurs throughout the memory network, recalling the memory as quickly as one-fifth of a second.

*

Getting a Quick Reaction

The memory system is so finely tuned that sensing an object, sound or circumstance can make you move faster than you can think.

* 1. You see a multicolored long coiled object. 2. Visual cortex queries the neocortex (“Have you seen anything like this?”) and the neocortex replies (“It looks like a snake”). 3. Hippocampus remembers a snake isn’t normally there. 4. Amygdala remembers you hate snakes and switches on fear. 5. Striatum remembers that when startled by a snake, you are supposed to jump back. This message is relayed to your muscles, and you jump.

* Source: Center for the Neurobiology of Learning and Memory, UC Irvine; Researched by STEVE EMMONS/Los Angeles Times