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Iván Izquierdo: Recollections and omissions

Neuroscientist talks about the importance of memories and also of forgetting

eduardo tavaresWith a thick accent that still betrays his native Buenos Aires, physician and neuroscientist Iván Izquierdo, 66 years old, from the Federal University of Rio Grande do Sul (UFRGS), is one of the greatest specialists in the physiology of the memory in the world. Productive as few, owner of a curriculum with over 500 scientific articles, which have now been cited almost 8,000 times in works of other researchers, Izquierdo has conducted studies that, in the last three decades, have helped to understand the role performed by chemical substances and brain structures in the formation, preservation, and loss of recollections and memories. One of his most important contributions was to demonstrate that there are two divisions of memory, the short term one and the long term, which are formed in parallel, but in a different way. “We are precisely what we remember, and we are also what we do not want to remember”, says this assiduous reader of his fellow countryman Jorge Luis Borges.

His wife was born in the state of Rio Grande do Sul, and with many friends on this side of the frontier, Izquierdo left Argentina in 1973, “when the political situation was very threatening”, and headed for the homeland of his wife. He lived three years in São Paulo, where he worked at the São Paulo Medicine School (today, the Federal University of São Paulo), before settling in Porto Alegre. He used to think that Brazil was just one stopping place in his life, but he was wrong. He ended up staying, because, amongst other reasons, here, the military dictatorship beckoned with the prospect of a slow and gradual opening up of the regime.

“And in Argentina, there came a sudden and total closure”, he explains. In 1981, when he felt himself to be “one more at home” in the new country, he was naturalized as a Brazilian. Today, he defines himself as a “Meligeni of science”, in a reference to tennis player Fernando Meligeni, born in Argentina and also naturalized Brazilian. Izquierdo, incidentally, frequently resorts to idols from sport – and from literature – to explain concepts of the neurosciences, as the reader will see in this interview. Formally retired since last year, he continues on active service, heading up the Biosciences Memory Center, at UFRGS.

Why did you decide to study the mechanisms of the memory?
Because I thought – and still do – that it is a mechanism that has something mysterious behind it, something to do with who we are. We are individuals because we have a memory. We are precisely that which we remember. Each one of us has a certain stock of memory that is peculiarly ours, which we do not share with anyone. All this seemed to me sufficiently interesting for me to dedicate the rest of my life to this theme.

How much is there today of a mystery for science on the question of memory?
Well, there will always be one mystery, which is the fact that memory involves, in a certain way, transformations of the reality that people see, or that people feel, into a neural code. And, afterwards, perhaps this neural code – which is both electrical and chemical – retransforms itself into memories, recollections. There will always be something that will make this be eternally mysterious.

What are the main contributions given by your research group for a better understanding of how memory is formed?
The first great contribution of ours, together with other groups, was determining the major brain mechanisms that modulate the memory, with various mechanisms mediated by neurotransmitters, such as serotonin, dopamine, and noradrenaline, or by hormones, like adrenaline, beta-endorphin, vasopressin, and the corticoids. This was in the 1970s. In this line of work, I would highlight the discoveries of the mechanisms of action of nicotine and amphetamine, and later on, of beta-endorphin on the memory. The modulation of the memory by all these substances makes the formation and recollection of the memory so sensitive to the emotions and states of spirit.

More recently, we identified which molecular substrates of the areas of the brain these substances act on, to form and recall memories, and in what way. The second important contribution was the study of the real molecular mechanisms of the memory, above all in the hippocampus. This started in the mid-1980s, when there began to be useful models on which one could work. This line of research allowed us to get to know in detail the molecular sequence of the processes of forming memory in the hippocampus and in other regions of the brain. The third major contribution was the division of the memory into short and long-term memory.

Contrary to what used to be thought, we demonstrated that the divisions of the memory are two parallel and differentiated processes. We demonstrated that the short-term memory was not the initial part of the other, the long term memory. This is of great importance in the pathology of the memory. The most recent contributions of ours consisted in identifying the mechanisms involved in recollection in several regions of the brain, the molecular mechanisms for extinguishing memories, and, recently, the mechanisms which proved to be a different kind of memory: memory for learning once again. It is different from the memory for learning more, and different from recollection.

Could you explain in more detail the workings of these two divisions of the memory, the short- term memory and the long-term one?
They are two memories that are triggered at the same time, which are formed in the same nerve cells, but which use separate molecular mechanisms. You learn something, and the definitive memory of this thing that you (or any other animal) learned takes several hours to be formed. Even so, while this long-term memory has not been constructed, you manage to respond (to a question that involves this learning process). For us to be able to talk during this interview, you do not have to wait for the memory of the previous sentence to consolidate, which will take several hours. You don’t have to do this. You answer straight away to what I say, and I answer to what you say. For us to do this, we use a system that is parallel to the long term memory, a simpler system, a little more elementary and less stable, which is called short term memory. It is like the working memory (RAM) of a computer.

How long does this short term memory subsist for?
More or less from three to six hours. The best analogy that I know to differentiate these two memories is the situation of when we will live in a hotel while they are building our house. The hotel is the short term, provisional, memory, and the house will be the long term memory.

What is your main line of research today?
From the 1990s, more or less, we began to work in collaboration with Jorge Medina’s group, from the School of Medicine of the University of Buenos Aires, on the mechanisms that really take part in the memory. In those days, it began to become clear in the world that the main neurotransmitter is none of the ones I mentioned before, but glutamic acid. The great excitatory transmission in the brain is glutamatergic, and the great inhibitory transmission is by the amino acid called gamma-amino butyric acid. We then started to study the mechanisms that are spurred or put into action by these compounds. While Eric Kandel (Nobel Prize in Medicine in 2000), for example, was demonstrating the molecular mechanisms of neuron plasticity in mollusks, we went on to study the same processes, or others like them, in memories of mammals.

More specifically, what is the theme of your more recent works?
We have not yet finished writing the work, but we are demonstrating that when people learn twice, they use different mechanisms from those used to learn something once. Learning is different in one or two lessons. You use another place in the brain. To learn twice, you use the same mechanism that is involved in habits, located in the caudate nucleus. To learn once, whether you are learning a lot or a little, the hippocampus is used more. This may perhaps be very important, because the majority of things we don?t learn well straight off, but in several sessions.

Is this distinction valid for the process of learning concepts?
I don’t know. For the time being, we know that this difference appears in rats that learn not to come down from a platform to avoid getting a shock. It is the learning of an induced behavior, a conditioned reflex. But, look, all learning processes can be reduced to behaviors or sequences of behaviors. All of them.

Could you explain the two major types of memory, declarative memory and procedural memory?
In general, declarative memories are those that humans can express, can declare that they exist. For example, the memory of medicine. I can say and demonstrate that I remember things from medicine. In animals, it’s more difficult to identify this kind of memory. In them, we use memories that are similar to those that humans can declare. Declarative memories can be semantic or episodic. We remember episodes from our own lives, animals too. We remember concepts of big things, like medicine, and animals as well. The procedural memories are those that involve habits, like, for example, knowing how to use a keyboard, how to swim, ride a bike. These are procedures. It’s difficult to explain this kind of memory, to declare that it exists; it can only be demonstrated by practicing a procedure: using a keyboard, actually swimming, really riding a bicycle.

Why, with time, do people lose their memories, even the long term ones?
There are various ways of losing memories. One is actual loss, which occurs when a synapse atrophies for lack of use, or disappears from damage or cell death. This is forgetting properly speaking; here, the memories actually disappear, because the cells that contained them disappear. But there are other ways of losing memories, at least of apparently losing. One of them is extinction, in which the memories are not lost; they are hived off to a less accessible place of the brain. In some cranny, there they are. Their representation exists, but is annulled by imposing a new learning process over the old one. Animals learn literally not to respond as they used to respond, not think as they used to think, and not to do as they used to do.

Do you mean that extinct memories can be recovered?
In theory, yes. They can often be recovered, but not always. Suppose, for example, that you are used to going every day to a bank teller’s window to get money. One day you go there, and the window is closed. So, you then change your behavior. Instead of going to get money, you turn about when you see the window closed. You do this on three or four days. When you finally realize that the window is remaining closed, you stop going there. You extinguish this behavior. But, if one day, by chance, you pass by the window and notice that it is open, you go there and get your money. Extinction is one of the ways of sweeping a memory beneath the carpet. It’s useful, it’s necessary. Without it, people would have no physical space in the brain to think. It wouldn’t be possible to compare things, since we would always be remembering that they are similar and would never be able to notice the differences. Or that they are different and we would never notice the similarities.

What are the other forms of losing memories?
Another interesting form is Freudian repression, which nobody has talked about in 70 or 80 years, except the Freudians. But now it has come back onto the scene as a fundamental process. An American group found the mechanism of Freudian repression, which is different from extinction. The group led by John Gabrieli (from Stanford University) discovered that the prefrontal area of the brain, right at the tip of the frontal lobe, has the hippocampus inhibited, the region that is most involved in recalling memory. It has the brakes put on the recollection, for example, of a certain word. This can be done until the hippocampus finally learns not to respond any more. In practice, it is as if the repressed memory were absent, although it is not and may always come back. Freudian repression and extinction of the memory are two fundamental weapons for us to be able to survive. I have just written a book A arte de esquecer [The art of forgetting], in which I say that to forget is something good, necessary. We are what we remember – and we are also what we do not want to remember.

But we do not have total control over this process. In other words, we often remember things we wanted to forget, and we forget others that we wanted to remember.
We aren’t perfect. As the years go by, the number of memories we have gets bigger and bigger. So, some we extinguish or repress. Depression is the most frequent cause, but less serious than amnesia, which is the failure or lack in general of declarative memory. In real forgetting, as we have seen, the bases of the memory get lost from the inactivity of the nerve circuits involved in one or other memory, or by the real loss of neurons, which happens with age, with degenerative diseases, etc. In Alzheimer’s disease, for example, neurons die, synapses die – as do the memories that were contained in them.

Is there today any effective treatment against memory problems? Against Alzheimer’s, for example?
There is still no treatment for Alzheimer. In this case, there is neuron death, and the lost neurons cannot be replaced with the original information.

Could the way out be to replace these neurons?
To recover a general function, yes; but not to recover each memory, of course. In the last few years, it has been discovered that some places in the brain have the capacity for neuron replacement, amongst them the hippocampus. But, from what has been seen up until now, this capacity is never going to reintegrate a memory that has disappeared. It may make it possible for the machine to be set up again, so as to be able to make a new memory.

And for lesser losses of memory and in younger people, are there treatments?
Yes, but there are no medicines. What there are forms of training the memory, usually based on reading. Medicines are no use, because the brain, at every particular moment, is already doing all it can, given the circumstances of feelings and emotions inherent in every moment. And the memories that have been learnt or recalled at previous moments.

Why do you usually say that forgetting is necessary for man?
It’s fundamental, because otherwise there would, literally, be no room in the brain for so much information. There are several recent studies to which little importance has been paid, but which are fundamental for understanding this. A Norwegian group, in collaboration with an English researcher, has shown that the hippocampus is the main region of the brain that makes and recalls declarative memories. An animal uses 40% of the total structure of the hippocampus to learn a given spatial notion. To recall this learning, it uses 60% of the hippocampus. During the time that it is learning or recalling this spatial learning, the animal cannot do anything else. It cannot, for example, do a good long-term potentiation or recognize a novelty, which are other things that the hippocampus does. So this means that the capacity installed in the brain is not infinite, it’s not so big as all that. It is quickly saturated in rats, and in humans for sure. We even have physical experiences of this saturation. We goto a congress, we listen to two or three talks running, and we get impression that there is no more room in the brain for anything else. At that moment, there really is no room. So we go out of the room, take a break, have a cup of coffee. After the dust has settled a bit, and the hippocampus has gone back to be used less, we can return to the room and listen to another talk.

That popular saying that knowledge does not take up any space makes no sense, then?
It does take up space. Acquiring knowledge and recalling knowledge occupies a lot of space. Generally speaking, the brain tends to use all the available resources for this task.

Do you mean that that story that humans use only a small percentage of the brain is a lot of nonsense?
To tell the truth, it’s not possible to say whether this is right or not. This is because we do not know how many neurons and synapses we have. Until twenty years ago, it used to be thought that we had, I believe, 10 billion neurons. Today, we know that there are at least 200 billion, perhaps 300 billion. And between these two estimates there is a difference of 100 billion neurons.

Is it possible to train the brain to forget traumas or passages of life that one would no longer like to recall?
Sometimes, the brain does this automatically. When it fails, we have what is called precisely posttraumatic stress or phobias. But there are therapies which use precisely extinction and which are applied for an individual to extinguish stress. The country where this has been studied most, odd though it may seem, is Turkey.

Yes. It’s because in recent years they have had two tremendous earthquakes there. And in one of them, tens of thousands of people died, a very high number. After the catastrophes, Turkish neurologists and psychiatrists saw that there were loads of patients with posttraumatic stress, of people who had been in the places of the earthquakes but had survived. They put into practice whatever they could to treat them and saw that extinction discovered by Pavlov and prescribed by Freud could be used. Some of them supplemented the sessions of extinction with anxiolytic drugs, but this is not usually necessary. After the attack of September 11, 2001, a bit by influence from the Turks, the Americans started using more the technique for extinction, which was even somewhat forgotten in the United States.

What is the explanation for the so-called “memory going blank”? Forgetting the home telephone number, for example?
It can be many things, but usually it is absent-mindedness. When it is a more serious forgetfulness, like a student who studied for the university entrance exam and, on the day of the exam, remembers nothing, this blank is caused by stress. With stress, large quantities of corticoids are released, secreted by the suprarenal gland; they inhibit recollection, acting on the hippocampus and on the tonsils. With me, or with other people who once in a while are surrounded by students or reporters, the blank happens when I am submitted to questions from a lot of people at the same time. Then I go blank. It’s a defensive act.

Why do some people have, or say they have, a better memory for faces, and others for names or numbers?
This is usually due to practice. Bank clerks are good at numbers, men of letters at words, doctors are good with faces and for names. Musicians are good with music. This is not to mention the situation of people who present some congenital defects. Those who are born with eyesight that is not very good are going to be worse in acquiring visual memories, compared to a person without this limitation. But there is a certain system of compensation in these cases. The blind develop their olfactory memory more, for example.

I would like you to talk a bit about the question of the elderly recalling their memories in a romanticized way, and, often, centered on the best days of their youth.
There are several points in this question. The elderly keep losing memories, because neurons die as the years go by – and the memories they carry die too. But, at the same time, they go on forming a lot more memories. Every day that a person remains alive, the more memories he will try to have. So he is going to lose many memories, but he is going to gain others. There may be some muddle, which is proper to those who have a lot of information to handle, in some cases more and in others less. This is one aspect of the question. Another is that people, as years go by, begin to change their memories, begin to falsify them. There’s a fantastic book written by a great American psychologist, Daniel Schacter, which is called The Seven Sins of Memory. It tells how memory is falsified. People do this a lot.

But almost always in an unconscious way?
Yes, yes, generally in an unconscious way. My mother used to mix me up with a brother of hers, who looked vaguely like me. The two were men from the family, one was a brother, the other a son – So she would attribute to me things that my uncle had done. This is very common with people in general, and very common in the elderly in particular. To tell the truth, everyone does this.

Did you say in an interview that the very act of recalling memory ends up leading to a certain loss of detail?
Maybe this is due to the fact that the way for extinguishing memories is by recalling them. Recalling without reinforcing the recollection. I go back to that story of the bank teller’s window and the money. You recall the situation and you go there, to the window. Now, when you go there and don’t get the money, because the window is closed, it’s the moment you start extinguishing this memory. To extinguish, you have to recall.

Is this a paradox?
It is. You need to recall and see that the information you had is useless. Without carrying out this experience, it’s difficult to extinguish memory.

Is reading the best way of preserving the memory?
It is by far and away the best way. There’s nothing that approaches it. By reading, you exercise the visual memory, the verbal memory, the memory of other languages you perhaps know, the memory of synonyms, the memory of images. You read the word tree and an infinity of images of trees passes by in your head. It is reading that recalls most kinds of memory, most forms of memory. Reading a lot and having a good level of schooling also helps to prevent or to minimize the symptoms of Alzheimer’s disease. For those who do not the eyesight to read, listening to someone telling a story is excellent for the memory. Famous blind writers have done this, and it has worked very well, like the Argentinean Jorge Luis Borges and England’s John Milton.

You must be a great reader of Borges, because you always mention him in your interviews.
I read Borges a lot. He called a lot of attention to memory. Borges wrote a tale that is definitive on the question that we need to forget to be able to learn. The tale is called Funes the memorious. Funes was an individual who had a perfect memory, probably deriving from an accident. Funes could remember a whole day of his life, during which he could do nothing else. This situation, of course, was an impossibility, a demonstration by the absurd that the brain gets saturated.

What assessment do you make of the studies of the memory done in Brazil and abroad?
Here, there are few groups, but those that exist are good, of an international level. Besides my group studying the memory, perhaps the largest in Brazil in this field of work, there are several others in Curitiba, São Paulo, Ribeirão Preto, Rio de Janeiro, Fortaleza etc. There is now a new nucleus being set up in Natal. This group will be headed up in part by researcher Sidarta Ribeiro (from Duke University), who is in the United States at the moment, but is coming back.

He recently published a scientific article about the importance of sleep for the formation of memory.
If anyone has formulated a really interesting hypothesis on this theme, it’s probably Sidarta. There are also several persons and many Brazilian groups, of psychiatry or neuropsychology, who are doing very good studies of memory. 15 or 20 years ago, this discipline was practically nonexistent in Brazil. Now, every day, a new group appears. The quantity and the quality of these groups are surprising me.

Are the other areas of the neurosciences doing in Brazil?
They are doing very well. Among the sciences in Brazil, neurosciences are one of the branches that worked out well. In São Paulo, there is an extremely interesting group at the Ludwig Cancer Research Institute, with which we are collaborating. They are studying neurochemistry. With them, we are doing a lot in common about memory. This group started its work much later than the others, but is now one of the groups in the vanguard. There are several large neurochemistry groups of the very highest level in Rio de Janeiro. My group itself is diversifying. There are now several persons who are independent researchers. There is Frederico Graeff, from USP in Ribeirão Preto, who has a big team working eagerly. There are many groups, I wouldn’t like to mention names, because the list is long and I would run the risk of forgetting some, as there are so many.

Why have neurosciences been a success?
Because… Perhaps because we neuroscientists were full of enthusiasm and encouraged each other (he laughs). I, Esper Cavalheiro, Cícero Coimbra (both from the Federal University of São Paulo), Roberto Lent, Rafael Linden (both from the Federal University of Rio de Janeiro), Luiz Roberto Giorgetti de Britto, Menna Barreto (from the University of São Paulo) have always got on very well.

You mentioned Natal. Are you in favor of the project for the International Neurosciences Institute in the capital of Rio Grande do Norte?
If they manage to turn the institute into a reality, it can be a magnificent enterprise. It is going to bring people of an excellent level, and they are all going to be together, which would be very good. Now, I get a bit apprehensive because Brazil is the country of the great projects that afterwards are not taken forward. I like to say that science in Brazil is more or less like Ayrton Senna at the beginning of his career: he would set out in the lead, leaving everyone behind him, but he wouldn’t finish the race. We have had great projects in Brazil. The largest of them not to have been taken forward is Pronex (The National Centers of Excellence Program).

It lasted two tenders. And it was going to be annual. It had two tenders in the first year, after that never again. Now, Pronex has come back, but in an extraordinarily reduced form. It has come back with one tenth of the original amount. And some states are outside the tender, like Rio Grande do Sul. The project for the institute in Natal is a challenge. I think they are going to get something of what they have set out to. But I don’t know if it will be all. Anything they achieve is going to be more than welcome, it’s going to be an important increase. They are proposing integration with private enterprise in support of the sciences. Private enterprise in Brazil does not have a habit of contributing to science.

Why did you become naturalized?
Why did I become naturalized? Because I felt more like one of the family. That was in 1981.

But do you see yourself more as an Argentinean or a Brazilian?
It’s difficult to define, because you never lose your roots, but a long time later they get transformed, because of what has grown on top of them. I must be a mixture, a sort of (laughs) Meligeni of science (the former tennis player Fernando Meligeni was born in Argentina and was naturalized a Brazilian).

Going back to talking about memory, but in another sense, people are used to saying that Brazil is a country without a memory, with a social amnesia. Do you agree with this statement?
This is an enormous Brazilian characteristic, and a grave defect. Nobody remembers the candidate for which they voted for state deputy in the last election. Nobody. This was less than two years ago, and no one remembers. It is a trait that, I think, makes it possible to lead a lighter life, apparently easier. But, actually, it is more difficult, because one tends to fall into the same errors and not give due importance to things. Brazilians tend to take everything with a touch of superficiality, which is good sometimes. But in real life. Look, we have 33% of the country who are wretched, according to what has just been made public. People who earn less that R$ 79 a month. Ask what is superficial and fun for these people. Nothing. Nothing is happy or fun in the lives of these folks, because they don’t eat enough, they don’t have enough to clothe themselves. So this air of lightness is very good for some things, but it is not good for them all. And, when you get to the level of serious things, likedoing science and feeding the people, I think it is better to have seriousness than lightness. The lightness of being, as writer Milan Kundera said, ends up being unbearable.