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Profile of Ivan Izquierdo

s a boy, Ivan Antonio Izquierdo, who was elected a foreign mem- A ber of the National Academy of Sciences in May 2007, became fascinated by the concept of after reading the short story “Funes el Memo- rioso” or “Funes: The Memorious.” The story, written by Jorge Luis Borges, de- scribes 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 pos- sible,” remarks Izquierdo, who went on to become a neuroscientist and lay the foun- dation for understanding the molecular basis of short- and long-term memory. “But that made the field [of memory] in- teresting to many people.” Izquierdo’s experiments have revealed how specific regions of the brain influence the consolidation of 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’spatients. 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 re- ceiptofBrazil’s most prestigious science prize, the Conrado Wessel Award, in 2008. In his PNAS Inaugural Article (1), Ivan Izquierdo. Izquierdo seeks to identify molecular markers that may predict why some mem- ories are better consolidated than others. By 1959, Izquierdo was transitioning more “scientific and less theoretical,” ex- His findings show that the hippocampus from medicine to . Working plains Izquierdo. The brain was no longer and amygdala work in parallel during in his father’s lab, he began to study the being regarded as a “black box. People , not in series as of learning in rats. He were making measurements,” he says. was thought. trained the rats, injected them with vari- One of those people was James ous drugs, measured how the drugs in- McGaugh, a neuroscientist then at the Friendships Foster Learning fluenced learning, and then, based on University of Oregon. He led this shift in Izquierdo could not help but become what was known about the mechanisms of the field after he showed that a variety of interested in science. His father was a action of the drugs, made inferences drugs could enhance a newly acquired pharmacologist, and his mother had a about what was going on in the brain. memory. This finding established mem- background in pharmacy. Born in 1937, These experiments provided the founda- ory consolidation as a biochemical phe- Izquierdo spent his youth in tion for his lifelong interest in the mo- nomenon and opened new pathways attending school, learning to play the gui- ’ lecular mechanisms of memory building. for memory research. Over the years, tar, and spending time on his grandfather s McGaugh and Izquierdo developed a farm. In his teens, conversations about During the same time, Izquierdo tight friendship. In fact, Izquierdo credits science with his uncle, a practicing doctor, worked in the laboratory of distinguished McGaughwithteachinghimhowto pushed him to consider a career in science. neuroscientist Eduardo De Robertis, who think about memory. Izquierdo entered medical school at the is known for discovering neurotubules “He used to say that the most salient University of Buenos Aires, Buenos Aires, and synaptic vesicles. De Robertis proved an influential mentor, teaching Izquierdo aspect of memory is ,” says Argentina, in 1955 and in 1959, decided to “ pursue his doctorate in pharmacology. about neuroscience as well as “life in Izquierdo. And I started thinking about While at school, he worked with histolo- general,” says Izquierdo. why. No one remembers what happened gist Roberto Mancini to study the effects Izquierdo’s transition from medicine to last afternoon, no one remembers the of hyperglycemia on the testes. They dis- neuroscience was well timed. The late covered that hypoglycemia caused lesions 1950s marked the birth of psychopharma- This is a Profile of a recently elected member of the Na- in the testes that were not unlike those cology and as a consequence, neuro- tional Academy of Sciences to accompany the member’s it produced in the brain. chemistry. Memory research was becoming Inaugural Article on page 10279 in issue 30 of volume 105.

www.pnas.org/cgi/doi/10.1073/pnas.1010117107 PNAS | August 24, 2010 | vol. 107 | no. 34 | 14947–14949 Downloaded by guest on October 2, 2021 third word of my previous sentence. So, then, police repression after that every of conscious animals and found them all forgetting is a major thing. And memory night, and so, it was really a messy place to be essentially correct. We ended up consolidation is a multi-faceted process.” to live,” he recalls. “We had two children, being some of the strongest advocates of After he completed his doctorate in they were small, and so we decided a role of long-term potentiation in mem- pharmacology in 1962, he moved to the to leave.” ory consolidation,” says Izquierdo. University of California, Los Angeles, CA They settled in his wife’s hometown of From these experiments, Izquierdo (UCLA) for postdoctoral training with , Brazil, where Izquierdo set developed a thorough understanding of neuroscientist Jose Segundo. There, Iz- up shop in the Pharmacology Department the biochemical events needed to make quierdo added electrophysiology to his at the Federal University of Rio Grande a memory. Using the single-trial platform- palette of techniques and explored do Sul. There, he continued using phar- learning test, he discovered that in the first whether it was possible to learn during macological means to probe the bio- several hours after training, the memory is sleeping, “something that is still impossible chemical mechanisms behind learning. stored in the hippocampus and several to prove,” he says. He soon shifted his focus from modu- other areas of the brain (2). Recently, During his second year at UCLA, he lating memory to understanding the these findings were found to apply to worked with John Green, a neuroscientist mechanisms behind it. For that, he mea- other nonaversive and different forms of who taught him intracellular physiology. sured RNA synthesis and neurotransmit- learning (3). Izquierdo implanted glass microelectrodes ter levels in brain regions, such as the “That gave us a good picture of what into neurons in the hippocampus or spinal hippocampus, suspected to be involved memory-making is all about,” he says. cord and stimulated afferent pathways to with making memories. the cell from which he was recording. He Clinical Implications and Green were measuring “postsynaptic In the early 1980s, Izquierdo began to test potentiation,” a phenomenon in which One can effectively block a theory known as “state dependency,” repetitive stimulation of axons enhances postulated by Steven Zornetzer, a close the response of the neurons innervated by short-term memory friend of Izquierdo’s who worked at the those axons for a few minutes. They hy- US Office of Naval Research, Arlington, pothesized that postsynaptic potentiation without affecting the VA. Zornetzer suggested that memories would be a basis for events that are crucial are best retrieved when the brain’s to learning and memory-making. long-term form. chemical state at the time of retrieval “We thought that this was the thing,” matches the one present at the time says Izquierdo, “until 9 years later, a Briton of consolidation. called Tim Bliss, presently a good friend of For this work, Izquierdo used an “If you are frightened and your brain mine, discovered a similar process that aversive conditioning model. He and his releases a lot of noradrenaline and dopa- could last hours or days and called it long- colleagues would place an animal on a mine, then you are more likely to re- term potentiation. That ended up being platform, and if it stepped off, it got a member other fearful memories, rather the real thing.” shock. The procedure is the animal than happy or sexual ones, in which the Izquierdo credits Green with having the equivalent of learning to look left when brain’s chemical brew is probably differ- greatest influence on both his scientific crossing a street, says Izquierdo. The ent,” says Izquierdo. “We tested this hy- career and life in general. “He taught me shock instills a powerful memory in the pothesis, and we found that to be true” (4). how to live a paper, which is much more rat that can last more than 2 years, The finding went largely unnoticed until than just writing it.” depending on the strength of the shock. recently, says Izquierdo. Now, state de- This was a potent research tool, because pendency has come into vogue because of Setting Up Shop “you could do a lot of things to that links to mental disease, such as depression By 1964, Izquierdo returned to Argentina memory right at the time when it was and drug addiction. where, in 1966, he became a full professor being consolidated, seconds after train- “When a person is depressed, their at the University of Cordoba. For a few ing had been completed,” says Izquierdo. brain goes into a specific neurochemical years, he continued the electrophysiology Izquierdo’s team generally gave the rats state and begins to remember bad mem- work that he had done in Green’s lab, but a very mild shock, because they did not ories and sad things,” he says. “That’s why his efforts were swiftly thwarted. In Ar- want to create a lifelong memory, just one depression is so dangerous.” gentina, he says, money was tight, and it that could be modified with drugs, hor- That is not the only finding that has had was “practically impossible” to do the mones, or other treatments. By the late medical implications. Some of Izquierdo’s type of intracellular recordings that other 1970s and early 1980s, they began study- memory biochemistry studies led to the scientists were doing in the United States, ing the effects of drugs delivered directly observation that simple exposure to Britain, Australia, Japan, and Sweden. into restricted regions of the brain. novelty—new surroundings, a new task, “It was kind of frustrating, because In fact, they successfully used this tech- a change of task—triggers a series of technically, we were falling behind,” says nique to test the findings of other research- molecular events in the hippocampus that Izquierdo. “We couldn’t keep up.” ers, including of Columbia enhances information retrieval. Clinicians Assessing his resources, he shifted back University, New York, NY, who was ex- have used this finding to help patients to , conducting behavioral ploring the effects of drug treatments on with Alzheimer’s disease, mild cognitive studies while studying and fiddling with neurons and the long-term potentiation impairment, and even the despondency the chemistry within the brain. that had been discovered by Tim Bliss. that arises from chronic disease in a hos- “We went on to discover a lot of “The pioneers in the field were not pital ward (5, 6). mechanisms that modulate memories actually using even rats,” explains In addition, Izquierdo’s research influ- while they are being made and eventually, Izquierdo. Instead, they used slices of enced a technique routinely used by when they are retrieved,” he says. tissue to investigate not learning but long- mental health providers to treat learned He focused on this work for 7 years until term potentiation. fear syndromes, including phobias and he had to leave Cordoba in 1973 when “We tested all the things that Kandel posttraumatic stress disorder. Called political turmoil erupted in Argentina. and others were trying in hippocampal “extinction” by researchers and “exposure “There were bombings every day and slices so successfully in the hippocampus therapy” by clinicians, this technique

14948 | www.pnas.org/cgi/doi/10.1073/pnas.1010117107 Trivedi Downloaded by guest on October 2, 2021 relies on repetition of a conditioned search lab in Brazil: the Memory Center at scattered around the brain. This diver- stimulus without traumatic consequences. the Pontifical Catholic University of Porto sification protects against lesions that we Izquierdo showed that prolonged expo- Alegre, Porto Alegre, Brazil. There, in experience every day as little arteries in sure to the platform without the foot collaboration with Medina in Buenos the brain clog. shock accelerated and deepened fear ex- Aires, the researchers combine precise “When I remember the face of my tinction (7). biochemical assays with drug-infusion mother,” he says, “I tend to remember procedures. Using these techniques, the faces of other people in her family or Mining Memory’s Secrets Izquierdo, Medina, and coworkers dis- things she did. There are lots of overlaps. Since 1988, much of Izquierdo’s research covered another phase of memory, “ We probably keep many copies of many has been a collaboration with Jorge H. something they call memory persis- memories, some more exact than others, Medina at the University of Buenos tence.” This is a mechanism that begins “ ∼ some with certain sorts of overlaps, some Aires. Theirs is the longest lasting and 12 h after the brain creates a memory ” most productive association between sci- and determines whether it will stay in the with others. entific labs in the history of Latin Amer- brain or not (9). Izquierdo keeps his memory sharp ica,” says Izquierdo. “Our joint work is Izquierdo and his colleagues are now outside of the lab by writing short stories. – the most cited in the continent.” looking for molecular markers that may He has published 50 60 stories, penned That work includes what Izquierdo predict why some memories are better usually during late-night bursts of crea- considers his most important paper. In consolidated than others. This work is tivity. The stories generally take place 1997, his team began studying the sepa- the subject of his Inaugural Article (1), around the time of World War II or in the ration of short-term memory, which lasts which shows that the hippocampus and backdrop of cities he has lived in, and a few hours, and long-term memory, which amygdala work in parallel during memory they feature important events from his can last for 1 day or a lifetime. Contrary to consolidation, not in series as researchers childhood and adolescence. what researchers at the time believed, he previously thought. Immediately after At 72, Izquierdo has no immediate showed that there was not one short-term an event, during the first few hours of plans to retire. He simply wants to con- memory pathway that then led to long- memory formation, the hippocampus term memory. Instead, the two processes andamygdalabothcontributetomem- tinue his research on memory consolida- happened in parallel. One can effectively ory consolidation, each using its own tion and would like to understand how block short-term memory without affect- specific set of enzymes. Then, days memories persist. From his vivid de- ing the long-term form (8). “It is not my after that, memories are no longer con- scriptions of events 50 years ago, it is clear most cited paper but probably is my most trolled by these two areas but rather by that his memories do persist. Now, he important paper,” he says. cortical regions. wants to figure out why. In 2004, Izquierdo established what Indeed, Izquierdo believes that there would rapidly become the most cited re- are probably copies of a single memory Bijal P. Trivedi, Freelance Science Writer

1. Cammarota M, et al. (2008) Parallel memory processing 4. Izquierdo I (1984) Endogenous state dependency. Neurobi- 7. Cammarota M, Bevilaqua LR, Kerr D, Medina JH, by the CA1 region of the dorsal hippocampus and ology of Learning and Memory, eds Lynch G, McGaugh JL, Izquierdo I (2003) Inhibition of mRNA and protein syn- the basolateral amygdala. Proc Natl Acad Sci USA 105: Weinberger NM (Guilford, New York), pp 333–350. thesis in the CA1 region of the dorsal hippocampus 10279–10284. 5. Izquierdo LA, et al. (2001) Novelty enhances retrieval: blocks reinstallment of an extinguished conditioned 2. Izquierdo I, et al. (2006) Different molecular cascades in Molecular mechanisms involved in rat hippocampus. fear response. J Neurosci 23:737–741. different sites of the brain control memory consolida- Eur J Neurosci 13:1464–1467. 8. Izquierdo I, et al. (1998) Mechanisms for memory types tion. Trends Neurosci 29:496–505. 6. Winograd M, Viola H (2004) Detection of novelty, but differ. Nature 393:635–636. 3. Clarke JR, Cammarota M, Gruart A, Izquierdo I, Delga- not memory of spatial habituation, is associated with 9. Bekinschtein P, et al. (2007) Persistence of long-term do-García JM (2010) Plastic modifications induced by an increase in phosphorylated cAMP response element- memory requires a late protein synthesis- and object recognition memory processing. Proc Natl Acad binding protein levels in the hippocampus. Hippocam- BDNF-dependent phase in the hippocampus. Neuron Sci USA 107:2652–2657. pus 14:117–123. 53:261–277.

Trivedi PNAS | August 24, 2010 | vol. 107 | no. 34 | 14949 Downloaded by guest on October 2, 2021