1995 LECTURE SERIES

Making and Preserving Memories

Dr. James L. McGaugh
Director, Center for the Neurobiology of Learning and Memory
University of California, Irvine
May 10, 1995

Memory is quite possibly the most important and essential human property. It is an article of faith that everything that we do as human beings is based upon our memories. The very foundation of who we are is built upon a series of half second intervals that record where we have been and direct us to where we will go. Memory is the capacity to glue the world together. And it is that gluing process that enables us to be human. It is the machinery of our identity. We would be utterly lost without it.

But there are different views on the power and importance of memory. The novelist Doris Lesing wrote, "..It's extraordinary how little we do remember. It's almost as if memory is not considered useful by nature..." A good point, really, when you consider the totality of our experience and how little of it we actually remember. Think about all the things that have happened to you in your life that you don't think about and don't remember. What did you have for lunch three months ago on a Thursday? What year did your nephew graduate college? What about that foreign language you used to speak fluently? Sometimes memory is a sieve. Indeed, it often seems that the brain is designed precisely to get rid of information.

One of the first people to notice the self-editing features of memory was the psychologist William James. Back in 1890 James puzzled over the transience of some memories and the vivid power of others. Of particular interest to James were those memories that were so highly charged with emotion that they actually left some kind of a scar on the cerebral tissue. James postulated from this that emotion plays a role in memory and that profoundly emotional experiences affect a significant change in the brain.

This notion was humorously portrayed by Gary Larson, creator of "The Far Side" comic strip. In one of his more well known strips, Larson portrayed the community of forest animals as they recalled where they were when they learned Bambi's mother had been shot. This was a tragic and traumatic event in the forest. The rabbit recalled repairing his burrow when he heard, the Moose had been crossing the road, the snake was getting ready to shed. The murder of Bambi's mother, not unlike the assassination of JFK, was so emotionally devastating that it etched itself into everyone's memory. The event will be remembered forever.

But an event does not have to be negative to be ensconced in our memories. Happy events, too, provided they are highly emotional, will also stay with us. Weddings and other romantic events or the birth of a child all have the kind of emotional weight that leads to heightened, long term recall.

But why would the brain work this way? That was and still is one of the critical questions for brain researchers. From what we know about the nature of memories, it is clear that the brain engineers a consolidating process such that certain memories are encoded with more lasting impact than others. The brain does not act immediately to fix every experience as a strong, complete and durable memory.

Because the evidence suggests that memories are consolidated slowly over time, researchers began to design experiments to probe this reality. As we studied this question we began to focus on natural methods and pathways through which the brain could regulate the intensity of memory by somehow ranking the importance of events and experiences. Because adrenaline, or epinephrine, is released during periods of heightened excitation, we began to focus on this hormone and the role it might play in memory enhancement.

To test this theory Paul Gold and Rod Van Buskert designed the following experiment in which rats received punishment at a certain point in a controlled environment. When the rats had trained, Gold and Van Buskert injected the rats with either a saline solution or adrenaline. As an additional variable the injections were administered either immediately, 10 minutes, 30 minutes or 2 hours after training. The results showed conclusively that the rats injected with adrenaline immediately after training exhibited the most profound improvement to memory.

Having demonstrated a clear relationship between adrenaline and increased memory, we were then interested in mapping areas of the brain in which these pathways might be most evident. The most promising area is a small area of the brain called the amigdula. Our educated guess was that adrenaline may activate memory by turning on this particular area of the brain. Accordingly, we set about designing experiments to test the theory.

One of the critical experiments was designed by Ken Chang Leung. Leung implanted a hypodermic needle directly into the amigdula of a group of rats. When the animals were trained, a smaller needle was inserted and a small amount of epinephrine (which is, of course, another word for adrenaline) or saline solution was injected directly into individual amigdulas. The rats that received epinephrine showed dramatically enhanced memory while the animals receiving saline solution showed no improvement.

The next experiment was structured in exactly the same way except that a beta blocker, a compound that effectively blocks the effects of adrenaline, was injected in tandem with the epinephrine. Rats receiving amigdula injections of both adrenaline and beta blocker showed no improvement to memory. In effect, the beta blocker negated the already demonstrated memory enhancing effects of the adrenaline and it did it by selectively operating on the amigdula, the critical region of the brain for emotion.

Additional experiments have demonstrated that, under normal circumstances (i.e., without an adrenaline delivering needle inserted directly into the amigdula), epinephrine acts by acting on receptors that are located outside the brain along the vegas nerve. The vegas nerve, of course, leads into the brain and the pathway through which epinephrine stimulates memory is by stimulating receptors along the vegas nerve which then release norepinephrine or noradrenaline into the amigdula. This is why epinephrine stimulates memory. It is also why beta blockers interrupt memory enhancement because they block the pathways through which epinephrine and norepinephrine are carried to the amigdula.

Another interesting note about the effects of certain drugs on memory concerns the opiates. Opiates include drugs like morphine, endorphin and encaplin. It should be noted that endorphin and encaplin occur naturally in our bodies. These drugs have been shown to impair memory. Interestingly, beta blockers can also be used to enhance memory by blocking the natural pathway of these memory impairing compounds.

All of these experiments (and others) demonstrate that the amigdula is the locus of many of the neuromodulatory interactions that take place inside our bodies. It is a translation center for decoding the meaning of epinephrine and norepinephrine, the opiodes like endorphin and encaplin, and different amino acids. The effect of all this involves modulation of the release of norepinephrine within the amigdula and a colinary deactivation.

Hence, in asking the question why some memories are strong and others are weak, our bodies contain hormonal and neuronal machinery and pathways for doing just that. The modulation of memory occurs in various brain regions that regulate memory strength in relation to the significance of the experience as encoded through a complex dialogue between hormones, neurons and brain structures.

Attempting to validate these hypotheses with human subjects is a daunting challenge. We can't do to people what we do to rats but we have designed experiments to evaluate the pathways and structures through which humans encode memory at different strength levels. In one experiment we test memory by showing two groups of people the same set of 12 slides. The variable is the story that accompanies the slides. One group hears a neutral story and the other group hears a very tragic, hugely emotional tale about a child who is hit by a car and rushed to the hospital by his mother where he clings to life as his severed feet are reattached and his other injuries are triaged. A very powerful story.

Two weeks later we asked the participants to recall the story. Somewhat predictably, the group that heard the exciting story exhibited much greater recall than did the group that heard the neutral story. Following this, we then set out to discover if the enhanced memory was related to adrenaline.

To test this we conducted the same experiment with the exception that the subjects were first injected with a beta blocker. Same experiment. We monitored heart rate and blood pressure and after the story was completed we asked the subjects to judge the emotionality of the story. The group with the beta blockers thought the story was extremely sad and very emotional. But two weeks later, when we asked the beta blocker group to remember the story, they remembered it at the same level as the group that had heard the neutral story.

Hence, we showed that the beta blocker blocked the enhancing effects of emotion on memory in humans just as it had blocked the enhancing effects of emotion/adrenaline on laboratory animals.

To help confirm these results we conducted the same experiment on a patient with a rare disease which causes a naturally occurring brain lesion that eliminates the amigdula region. When told the emotional story, this patient did not display any memory enhancement from the adrenaline stimulating emotional component of the story. Just as rats with lesioned amigdulas did not show enhanced memory with increased adrenaline, the patient without an amigdula also did not show any memory benefit from adrenaline.

Tying this together, the basic assumption is that every experience leaves some kind of memory. If that didn't happen then we couldn't memorize a thing. For example, consider memorizing a poem. You go through it once and remember a few words. Next time through you pick up a few more. Read it again and now you've got the first few lines and you proceed until you memorize the whole poem. From this simple, everyday experience we can assume that every experience leaves at least a tad of memory and that memory storage occurs even under the most mundane or boring circumstances (like reading Faulkner).

However, if the experience is exciting then two things occur. One, hormonal systems of the adrenal gland and elsewhere are stimulated and these systems activate the amigdula. Second, neuronal systems will be triggered and they, too, will activate the amigdula. The active amigdula then instructs the regions of the brain responsible for memory storage to create space for a strong memory. This is why the forest animals remember where they were when they learned Bambi's mother had been shot and why we all have memories which we will never forget.

In considering these pathways and the experiments we have conducted it is tempting to think how we might come to use drugs to enhance memory. But there is a flip side with opposite therapeutic indications.

Many veterans of the Vietnam war and other armed conflicts suffer from painful memories of their experiences. These are memories that are intense and lasting. Drugs can also be important for decreasing the debilitating effects of these traumatic and often incapacitating memories.

Memories of this kind are typically created when the pathways of memory are overrun and overactivated. A veteran may have a horrible memory of his best friend's head being torn off before his eyes. A survivor of a plane crash or the Oklahoma City bombing may have a memory of equally gruesome clarity. And these debilitating memories are not the exclusive property of the direct victims. Rescue and recovery personnel who sift through wreckage for survivors and body parts are also traumatized by recollections of the horror they have experienced.

It is interesting to note that this phenomenon was described more than 300 years ago by Rene Descartes. Descartes said, "The usefulness of all the passions consist in their strengthening and prolonging in the soul thoughts which are good for it to conserve." That is, making memories strong. "And all the harm they can do consist in their strengthening and conserving these thoughts more than is necessary." It is amazing that Descartes had this figured out in the 1600's.

Now, we have shown that we have in our bodies a system that is designed to make memories strong or weak in relation to the importance of the experience as calculated by hormonal and neuronal responses. But with this system we run the risk of post-traumatic stress syndrome. As we have seen, this disorder is caused by overactivating our memory systems with experiences that fall so far outside of the normal range of activity.

In dealing with the post-traumatic stress disorder patient, every time the subject re-lives the painful memory the experience is so real that it is stored as a new experience. In this way the memory is intensified much the way we would memorize a poem. The trauma just gets stronger and stronger.

Research into possible drug therapies to combat post-traumatic stress disorder is focused on breaking the cycle of memory strengthening. If this can be done, the debilitating memory will start to fade. Other research is focusing on the use of beta blockers to post-traumatic stress disorder from taking root. Imagine a crew sent out to pick up after a fatal motorcycle crash. With beta blockers we know that normal behavior is not affected but that memory is somewhat impaired. Not a bad option under such grisly circumstances.

As memory research continues, we are getting closer to unlocking so many mysteries. However, with every door we close behind us, many more must be opened. We have learned a great deal about the neuronal and cranial pathways and structures that impact the magical mystery of memory. But we have a long road still to travel.