Profile of Ivan Izquierdo

As a boy, Ivan Antonio Izquierdo, who was elected a foreign member of the National Academy of Sciences in May 2007, became fascinated by the concept of memory after reading the short story “Funes el Memorioso” or “Funes: The Memorious.” The story, written by Jorge Luis Borges, describes a young man who had a perfect memory: he could reconstruct an entire day of his life in full detail, but it took him a full day to do so. “It was a demonstration that a perfect memory is simply not possible,” remarks Izquierdo, who went on to become a neuroscientist and lay the foundation for understanding the molecular basis of short- and long-term memory. “But that made the field [of memory] interesting to many people.”

Izquierdo’s experiments have revealed how specific regions of the brain influence the consolidation of memories and how mood can affect memory retrieval. Some of his findings have influenced clinical therapies for posttraumatic stress disorder and improving memory retrieval in Alzheimer’s patients.

Born in Argentina and now a Brazilian citizen, Izquierdo has received more than 50 national and international honors and awards for his research, including election to the Brazilian Academy of Sciences in 1977, receipt of the two highest civilian badges of honor in Brazil in 1996 and 2007, and receipt of Brazil’s most prestigious science prize, the Conrado Wessel Award, in 2008.

In his PNAS Inaugural Article (1), Izquierdo seeks to identify molecular markers that may predict why some memories are better consolidated than others. His findings show that the hippocampus and amygdala work in parallel during memory consolidation, not in series as was thought.

Friendships Foster Learning

Izquierdo could not help but become interested in science. His father was a pharmacologist, and his mother had a background in pharmacy. Born in 1937, Izquierdo spent his youth in Buenos Aires attending school, learning to play the guitar, and spending time on his grandfather’s farm. In his teens, conversations about science with his uncle, a practicing doctor, pushed him to consider a career in science.

Izquierdo entered medical school at the University of Buenos Aires, Buenos Aires, Argentina, in 1955 and in 1959, decided to pursue his doctorate in pharmacology. While at school, he worked with histologist Roberto Mancini to study the effects of hyperglycemia on the testes. They discovered that hypoglycemia caused lesions in the testes that were not unlike those it produced in the brain.

By 1959, Izquierdo was transitioning from medicine to neuroscience. Working in his father’s lab, he began to study the pharmacology of learning in rats. He trained the rats, injected them with various drugs, measured how the drugs influenced learning, and then, based on what was known about the mechanisms of action of the drugs, made inferences about what was going on in the brain. These experiments provided the foundation for his lifelong interest in the molecular mechanisms of memory building.

During the same time, Izquierdo worked in the laboratory of distinguished neuroscientist Eduardo De Robertis, who is known for discovering neurotubules and synaptic vesicles. De Robertis proved an influential mentor, teaching Izquierdo about neuroscience as well as “life in general,” says Izquierdo.

Izquierdo’s transition from medicine to neuroscience was well timed. The late 1950s marked the birth of psychopharmacology and as a consequence, neurochemistry. Memory research was becoming more “scientific and less theoretical,” explains Izquierdo. The brain was no longer being regarded as a “black box. People were making measurements,” he says.

One of those people was James McGaugh, a neuroscientist then at the University of Oregon. He led this shift in the field after he showed that a variety of drugs could enhance a newly acquired memory. This finding established memory consolidation as a biochemical phenomenon and opened new pathways for memory research. Over the years, McGaugh and Izquierdo developed a tight friendship. In fact, Izquierdo credits McGaugh with teaching him how to think about memory.

“He used to say that the most salient aspect of memory is forgetting,” says Izquierdo. “And I started thinking about why. No one remembers what happened last afternoon, no one remembers the third word of my previous sentence. So, forgetting is a major thing. And memory consolidation is a multi-faceted process.” After he completed his doctorate in pharmacology in 1962, he moved to the University of California, Los Angeles, CA (UCLA) for postdoctoral training with neuroscientist Jose Segundo. There, Izquierdo added electrophysiology to his palette of techniques and explored whether it was possible to learn during sleeping, “something that is still impossible to prove,” he says.

During his second year at UCLA, he worked with John Green, a neuroscientist who taught him intracellular physiology. Izquierdo implanted glass microelectrodes into neurons in the hippocampus or spinal cord and stimulated afferent pathways to the cell from which he was recording. He and Green were measuring “postsynaptic potentiation,” a phenomenon in which repetitive stimulation of axons enhances the response of the neurons innervated by those axons for a few minutes. They hypothesized that postsynaptic potentiation would be a basis for events that are crucial to learning and memory-making.

“We thought that this was the thing,” says Izquierdo, “until 9 years later, a Briton called Tim Bliss, presently a good friend of mine, discovered a similar process that could last hours or days and called it long-term potentiation. That ended up being the real thing.”

Izquierdo credits Green with having the greatest influence on both his scientific career and life in general. “He taught me how to live a paper, which is much more than just writing it.”

Setting Up Shop

By 1964, Izquierdo returned to Argentina where, in 1966, he became a full professor at the University of Cordoba. For a few years, he continued the electrophysiology work that he had done in Green’s lab, but his efforts were swiftly thwarted. In Argentina, he says, money was tight, and it was “practically impossible” to do the type of intracellular recordings that other scientists were doing in the United States, Britain, Australia, Japan, and Sweden.

“It was kind of frustrating, because technically, we were falling behind,” says Izquierdo. “We couldn’t keep up.”

Assessing his resources, he shifted back to neurochemistry, conducting behavioral studies while studying and fiddling with the chemistry within the brain.

“We went on to discover a lot of mechanisms that modulate memories while they are being made and eventually, when they are retrieved,” he says.

He focused on this work for 7 years until he had to leave Cordoba in 1973 when political turmoil erupted in Argentina. “There were bombings every day and then, police repression after that every night, and so, it was really a messy place to live,” he recalls. “We had two children, they were small, and so we decided to leave.”

They settled in his wife’s hometown of Porto Alegre, Brazil, where Izquierdo set up shop in the Pharmacology Department at the Federal University of Rio Grande do Sul. There, he continued using pharmacological means to probe the biochemical mechanisms behind learning.

He soon shifted his focus from modulating memory to understanding the mechanisms behind it. For that, he measured RNA synthesis and neurotransmitter levels in brain regions, such as the hippocampus, suspected to be involved with making memories.

One can effectively block short-term memory without affecting the long-term form.

For this work, Izquierdo used an aversive conditioning model. He and his colleagues would place an animal on a platform, and if it stepped off, it got a shock. The procedure is the animal equivalent of learning to look left when crossing a street, says Izquierdo. The shock instills a powerful memory in the rat that can last more than 2 years, depending on the strength of the shock. This was a potent research tool, because “you could do a lot of things to that memory right at the time when it was being consolidated, seconds after training had been completed,” says Izquierdo.

Izquierdo’s team generally gave the rats a very mild shock, because they did not want to create a lifelong memory, just one that could be modified with drugs, hormones, or other treatments. By the late 1970s and early 1980s, they began studying the effects of drugs delivered directly into restricted regions of the brain.

In fact, they successfully used this technique to test the findings of other researchers, including Eric Kandel of Columbia University, New York, NY, who was exploring the effects of drug treatments on neurons and the long-term potentiation that had been discovered by Tim Bliss.

“The pioneers in the field were not actually using even rats,” explains Izquierdo. Instead, they used slices of tissue to investigate not learning but long-term potentiation.

“We tested all the things that Kandel and others were trying in hippocampal slices so successfully in the hippocampus of conscious animals and found them all to be essentially correct. We ended up being some of the strongest advocates of a role of long-term potentiation in memory consolidation,” says Izquierdo.

From these experiments, Izquierdo developed a thorough understanding of the biochemical events needed to make a memory. Using the single-trial platform-learning test, he discovered that in the first several hours after training, the memory is stored in the hippocampus and several other areas of the brain (2). Recently, these findings were found to apply to other nonaversive and different forms of learning (3).

“That gave us a good picture of what memory-making is all about,” he says.

Clinical Implications

In the early 1980s, Izquierdo began to test a theory known as “state dependency,” postulated by Steven Zornetzer, a close friend of Izquierdo’s who worked at the US Office of Naval Research, Arlington, VA. Zornetzer suggested that memories are best retrieved when the brain’s chemical state at the time of retrieval matches the one present at the time of consolidation.

“If you are frightened and your brain releases a lot of noradrenaline and dopamine, then you are more likely to remember other fearful memories, rather than happy or sexual ones, in which the brain’s chemical brew is probably different,” says Izquierdo. “We tested this hypothesis, and we found that to be true” (4).

The finding went largely unnoticed until recently, says Izquierdo. Now, state dependency has come into vogue because of links to mental disease, such as depression and drug addiction.

“When a person is depressed, their brain goes into a specific neurochemical state and begins to remember bad memories and sad things,” he says. “That’s why depression is so dangerous.”

That is not the only finding that has had medical implications. Some of Izquierdo’s memory biochemistry studies led to the observation that simple exposure to novelty—new surroundings, a new task, a change of task—triggers a series of molecular events in the hippocampus that enhances information retrieval. Clinicians have used this finding to help patients with Alzheimer’s disease, mild cognitive impairment, and even the despondency that arises from chronic disease in a hospital ward (5, 6).

In addition, Izquierdo’s research influenced a technique routinely used by mental health providers to treat learned fear syndromes, including phobias and posttraumatic stress disorder. Called “extinction” by researchers and “exposure therapy” by clinicians, this technique relies on repetition of a conditioned stimulus without traumatic consequences. Izquierdo showed that prolonged exposure to the platform without the foot shock accelerated and deepened fear extinction (7).

Mining Memory’s Secrets

Since 1988, much of Izquierdo’s research has been a collaboration with Jorge H. Medina at the University of Buenos Aires. Theirs is “the longest lasting and most productive association between scientific labs in the history of Latin America,” says Izquierdo. “Our joint work is the most cited in the continent.”

That work includes what Izquierdo considers his most important paper. In 1997, his team began studying the separation of short-term memory, which lasts a few hours, and long-term memory, which can last for 1 day or a lifetime. Contrary to what researchers at the time believed, he showed that there was not one short-term memory pathway that then led to long-term memory. Instead, the two processes happened in parallel. One can effectively block short-term memory without affecting the long-term form (8). “It is not my most cited paper but probably is my most important paper,” he says.

In 2004, Izquierdo established what would rapidly become the most cited research lab in Brazil: the Memory Center at the Pontifical Catholic University of Porto Alegre, Porto Alegre, Brazil. There, in collaboration with Medina in Buenos Aires, the researchers combine precise biochemical assays with drug-infusion procedures. Using these techniques, Izquierdo, Medina, and coworkers discovered another phase of memory, something they call “memory persistence.” This is a mechanism that begins ∼12 h after the brain creates a memory and determines whether it will stay in the brain or not (9).

Izquierdo and his colleagues are now looking for molecular markers that may predict why some memories are better consolidated than others. This work is the subject of his Inaugural Article (1), which shows that the hippocampus and amygdala work in parallel during memory consolidation, not in series as researchers previously thought. Immediately after an event, during the first few hours of memory formation, the hippocampus and amygdala both contribute to memory consolidation, each using its own specific set of enzymes. Then, days after that, memories are no longer controlled by these two areas but rather by cortical regions.

Indeed, Izquierdo believes that there are probably copies of a single memory scattered around the brain. This diversification protects against lesions that we experience every day as little arteries in the brain clog.

“When I remember the face of my mother,” he says, “I tend to remember the faces of other people in her family or things she did. There are lots of overlaps. We probably keep many copies of many memories, some more exact than others, some with certain sorts of overlaps, some with others.”

Izquierdo keeps his memory sharp outside of the lab by writing short stories. He has published 50–60 stories, penned usually during late-night bursts of creativity. The stories generally take place around the time of World War II or in the backdrop of cities he has lived in, and they feature important events from his childhood and adolescence.

At 72, Izquierdo has no immediate plans to retire. He simply wants to continue his research on memory consolidation and would like to understand how memories persist. From his vivid descriptions of events 50 years ago, it is clear that his memories do persist. Now, he wants to figure out why.

Ivan Izquierdo.