Profile of Ivan Izquierdo

As a boy, Ivan Antonio Izquierdo,who was elected a foreign mem-ber of the National Academy ofSciences in May 2007, became

fascinated by the concept of memory afterreading the short story “Funes el Memo-rioso” or “Funes: The Memorious.” Thestory, written by Jorge Luis Borges, de-scribes a young man who had a perfectmemory: he could reconstruct an entireday of his life in full detail, but it took hima full day to do so. “It was a demonstrationthat a perfect memory is simply not pos-sible,” remarks Izquierdo, who went on tobecome a neuroscientist and lay the foun-dation for understanding the molecularbasis of short- and long-term memory.“But that made the field [of memory] in-teresting to many people.”Izquierdo’s experiments have revealed

howspecific regions of the brain influence theconsolidation of memories and how moodcan affect memory retrieval. Some of hisfindings have influenced clinical therapies forposttraumatic stress disorder and improvingmemory retrieval in Alzheimer’s patients.Born in Argentina and now a Brazilian

citizen, Izquierdo has received more than 50national and international honors andawards for his research, including election tothe Brazilian Academy of Sciences in 1977,receipt of the two highest civilian badges ofhonor in Brazil in 1996 and 2007, and re-ceipt of Brazil’s most prestigious scienceprize, the Conrado Wessel Award, in 2008.In his PNAS Inaugural Article (1),

Izquierdo seeks to identify molecularmarkers that may predict why some mem-ories are better consolidated than others.His findings show that the hippocampusand amygdala work in parallel duringmemory consolidation, not in series aswas thought.

Friendships Foster LearningIzquierdo could not help but becomeinterested in science. His father was apharmacologist, and his mother had abackground in pharmacy. Born in 1937,Izquierdo spent his youth in Buenos Airesattending school, learning to play the gui-tar, and spending time on his grandfather’sfarm. In his teens, conversations aboutscience 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 topursue his doctorate in pharmacology.While at school, he worked with histolo-gist Roberto Mancini to study the effectsof hyperglycemia on the testes. They dis-covered that hypoglycemia caused lesionsin the testes that were not unlike thoseit produced in the brain.

By 1959, Izquierdo was transitioningfrom medicine to neuroscience. Workingin his father’s lab, he began to study thepharmacology of learning in rats. Hetrained the rats, injected them with vari-ous drugs, measured how the drugs in-fluenced learning, and then, based onwhat was known about the mechanisms ofaction of the drugs, made inferencesabout what was going on in the brain.These experiments provided the founda-tion for his lifelong interest in the mo-lecular mechanisms of memory building.During the same time, Izquierdo

worked in the laboratory of distinguishedneuroscientist Eduardo De Robertis, whois known for discovering neurotubulesand synaptic vesicles. De Robertis provedan influential mentor, teaching Izquierdoabout neuroscience as well as “life ingeneral,” says Izquierdo.Izquierdo’s transition from medicine to

neuroscience was well timed. The late1950s marked the birth of psychopharma-cology and as a consequence, neuro-chemistry. Memory research was becoming

more “scientific and less theoretical,” ex-plains Izquierdo. The brain was no longerbeing regarded as a “black box. Peoplewere making measurements,” he says.One of those people was James

McGaugh, a neuroscientist then at theUniversity of Oregon. He led this shift inthe field after he showed that a variety ofdrugs could enhance a newly acquiredmemory. This finding established mem-ory consolidation as a biochemical phe-nomenon and opened new pathwaysfor memory research. Over the years,McGaugh and Izquierdo developed atight friendship. In fact, Izquierdo creditsMcGaugh with teaching him how tothink about memory.“He used to say that the most salient

aspect of memory is forgetting,” saysIzquierdo. “And I started thinking aboutwhy. No one remembers what happenedlast afternoon, no one remembers the

Ivan Izquierdo.

This is a Profile of a recently elected member of the Na-tional Academy of Sciences to accompany the member’sInaugural Article on page 10279 in issue 30 of volume 105.

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PROFIL

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third word of my previous sentence. So,forgetting is a major thing. And memoryconsolidation is a multi-faceted process.”After he completed his doctorate inpharmacology in 1962, he moved to theUniversity of California, Los Angeles, CA(UCLA) for postdoctoral training withneuroscientist Jose Segundo. There, Iz-quierdo added electrophysiology to hispalette of techniques and exploredwhether it was possible to learn duringsleeping, “something that is still impossibleto prove,” he says.During his second year at UCLA, he

worked with John Green, a neuroscientistwho taught him intracellular physiology.Izquierdo implanted glass microelectrodesinto neurons in the hippocampus or spinalcord and stimulated afferent pathways tothe cell from which he was recording. Heand Green were measuring “postsynapticpotentiation,” a phenomenon in whichrepetitive stimulation of axons enhancesthe response of the neurons innervated bythose axons for a few minutes. They hy-pothesized that postsynaptic potentiationwould be a basis for events that are crucialto learning and memory-making.“We thought that this was the thing,”

says Izquierdo, “until 9 years later, a Britoncalled Tim Bliss, presently a good friend ofmine, discovered a similar process thatcould last hours or days and called it long-term potentiation. That ended up beingthe real thing.”Izquierdo credits Green with having the

greatest influence on both his scientificcareer and life in general. “He taught mehow to live a paper, which is much morethan just writing it.”

Setting Up ShopBy 1964, Izquierdo returned to Argentinawhere, in 1966, he became a full professorat the University of Cordoba. For a fewyears, he continued the electrophysiologywork that he had done in Green’s lab, buthis efforts were swiftly thwarted. In Ar-gentina, he says, money was tight, and itwas “practically impossible” to do thetype of intracellular recordings that otherscientists were doing in the United States,Britain, Australia, Japan, and Sweden.“It was kind of frustrating, because

technically, we were falling behind,” saysIzquierdo. “We couldn’t keep up.”Assessing his resources, he shifted back

to neurochemistry, conducting behavioralstudies while studying and fiddling withthe chemistry within the brain.“We went on to discover a lot of

mechanisms that modulate memorieswhile 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 whenpolitical turmoil erupted in Argentina.“There were bombings every day and

then, police repression after that everynight, and so, it was really a messy placeto live,” he recalls. “We had two children,they were small, and so we decidedto leave.”They settled in his wife’s hometown of

Porto Alegre, Brazil, where Izquierdo setup shop in the Pharmacology Departmentat the Federal University of Rio Grandedo Sul. There, he continued using phar-macological means to probe the bio-chemical mechanisms behind learning.He soon shifted his focus from modu-

lating memory to understanding themechanisms behind it. For that, he mea-sured RNA synthesis and neurotransmit-ter levels in brain regions, such as thehippocampus, suspected to be involvedwith making memories.

One can effectively block

short-term memory

without affecting the

long-term form.

For this work, Izquierdo used anaversive conditioning model. He and hiscolleagues would place an animal on aplatform, and if it stepped off, it got ashock. The procedure is the animalequivalent of learning to look left whencrossing a street, says Izquierdo. Theshock instills a powerful memory in therat 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 thatmemory right at the time when it wasbeing consolidated, seconds after train-ing had been completed,” says Izquierdo.Izquierdo’s team generally gave the rats

a very mild shock, because they did notwant to create a lifelong memory, just onethat could be modified with drugs, hor-mones, or other treatments. By the late1970s and early 1980s, they began study-ing the effects of drugs delivered directlyinto restricted regions of the brain.In fact, they successfully used this tech-

nique to test the findings of other research-ers, including Eric Kandel of ColumbiaUniversity, New York, NY, who was ex-ploring the effects of drug treatments onneurons and the long-term potentiationthat had been discovered by Tim Bliss.“The pioneers in the field were not

actually using even rats,” explainsIzquierdo. Instead, they used slices oftissue to investigate not learning but long-term potentiation.“We tested all the things that Kandel

and others were trying in hippocampalslices so successfully in the hippocampus

of conscious animals and found them allto be essentially correct. We ended upbeing some of the strongest advocates ofa role of long-term potentiation in mem-ory consolidation,” says Izquierdo.From these experiments, Izquierdo

developed a thorough understanding ofthe biochemical events needed to makea memory. Using the single-trial platform-learning test, he discovered that in the firstseveral hours after training, the memory isstored in the hippocampus and severalother areas of the brain (2). Recently,these findings were found to apply toother nonaversive and different forms oflearning (3).“That gave us a good picture of what

memory-making is all about,” he says.

Clinical ImplicationsIn the early 1980s, Izquierdo began to testa theory known as “state dependency,”postulated by Steven Zornetzer, a closefriend of Izquierdo’s who worked at theUS Office of Naval Research, Arlington,VA. Zornetzer suggested that memoriesare best retrieved when the brain’schemical state at the time of retrievalmatches the one present at the timeof consolidation.“If you are frightened and your brain

releases a lot of noradrenaline and dopa-mine, then you are more likely to re-member other fearful memories, ratherthan happy or sexual ones, in which thebrain’s chemical brew is probably differ-ent,” says Izquierdo. “We tested this hy-pothesis, and we found that to be true” (4).The finding went largely unnoticed until

recently, says Izquierdo. Now, state de-pendency has come into vogue because oflinks to mental disease, such as depressionand drug addiction.“When a person is depressed, their

brain goes into a specific neurochemicalstate and begins to remember bad mem-ories and sad things,” he says. “That’s whydepression is so dangerous.”That is not the only finding that has had

medical implications. Some of Izquierdo’smemory biochemistry studies led to theobservation that simple exposure tonovelty—new surroundings, a new task,a change of task—triggers a series ofmolecular events in the hippocampus thatenhances information retrieval. Clinicianshave used this finding to help patientswith Alzheimer’s disease, mild cognitiveimpairment, and even the despondencythat arises from chronic disease in a hos-pital ward (5, 6).In addition, Izquierdo’s research influ-

enced a technique routinely used bymental health providers to treat learnedfear syndromes, including phobias andposttraumatic stress disorder. Called“extinction” by researchers and “exposuretherapy” by clinicians, this technique

14948 | www.pnas.org/cgi/doi/10.1073/pnas.1010117107 Trivedi

relies on repetition of a conditionedstimulus without traumatic consequences.Izquierdo showed that prolonged expo-sure to the platform without the footshock accelerated and deepened fear ex-tinction (7).

Mining Memory’s SecretsSince 1988, much of Izquierdo’s researchhas been a collaboration with Jorge H.Medina at the University of BuenosAires. Theirs is “the longest lasting andmost productive association between sci-entific labs in the history of Latin Amer-ica,” says Izquierdo. “Our joint work isthe most cited in the continent.”That work includes what Izquierdo

considers his most important paper. In1997, his team began studying the sepa-ration of short-term memory, which lastsa few hours, and long-termmemory, whichcan last for 1 day or a lifetime. Contrary towhat researchers at the time believed, heshowed that there was not one short-termmemory pathway that then led to long-term memory. Instead, the two processeshappened in parallel. One can effectivelyblock short-term memory without affect-ing the long-term form (8). “It is not mymost cited paper but probably is my mostimportant paper,” he says.In 2004, Izquierdo established what

would rapidly become the most cited re-

search lab in Brazil: theMemory Center atthe Pontifical Catholic University of PortoAlegre, Porto Alegre, Brazil. There, incollaboration with Medina in BuenosAires, the researchers combine precisebiochemical assays with drug-infusionprocedures. Using these techniques,Izquierdo, Medina, and coworkers dis-covered another phase of memory,something they call “memory persis-tence.” This is a mechanism that begins∼12 h after the brain creates a memoryand determines whether it will stay in thebrain or not (9).Izquierdo and his colleagues are now

looking for molecular markers that maypredict why some memories are betterconsolidated than others. This work isthe subject of his Inaugural Article (1),which shows that the hippocampus andamygdala work in parallel during memoryconsolidation, not in series as researcherspreviously thought. Immediately afteran event, during the first few hours ofmemory formation, the hippocampusand amygdala both contribute to mem-ory consolidation, each using its ownspecific set of enzymes. Then, daysafter that, memories are no longer con-trolled by these two areas but rather bycortical regions.Indeed, Izquierdo believes that there

are probably copies of a single memory

scattered around the brain. This diver-sification protects against lesions that weexperience every day as little arteries inthe brain clog.“When I remember the face of my

mother,” he says, “I tend to rememberthe faces of other people in her family orthings she did. There are lots of overlaps.We probably keep many copies of manymemories, some more exact than others,some with certain sorts of overlaps, somewith others.”Izquierdo keeps his memory sharp

outside of the lab by writing short stories.He has published 50–60 stories, pennedusually during late-night bursts of crea-tivity. The stories generally take placearound the time of World War II or in thebackdrop of cities he has lived in, andthey feature important events from hischildhood and adolescence.At 72, Izquierdo has no immediate

plans to retire. He simply wants to con-tinue his research on memory consolida-tion and would like to understand howmemories persist. From his vivid de-scriptions of events 50 years ago, it is clearthat his memories do persist. Now, hewants to figure out why.

Bijal P. Trivedi, Freelance Science Writer

1. Cammarota M, et al. (2008) Parallel memory processingby the CA1 region of the dorsal hippocampus andthe basolateral amygdala. Proc Natl Acad Sci USA 105:10279–10284.

2. Izquierdo I, et al. (2006) Different molecular cascades indifferent sites of the brain control memory consolida-tion. Trends Neurosci 29:496–505.

3. Clarke JR, Cammarota M, Gruart A, Izquierdo I, Delga-do-García JM (2010) Plastic modifications induced byobject recognition memory processing. Proc Natl AcadSci USA 107:2652–2657.

4. Izquierdo I (1984) Endogenous state dependency. Neurobi-ology of Learning and Memory, eds Lynch G, McGaugh JL,Weinberger NM (Guilford, New York), pp 333–350.

5. Izquierdo LA, et al. (2001) Novelty enhances retrieval:Molecular mechanisms involved in rat hippocampus.Eur J Neurosci 13:1464–1467.

6. Winograd M, Viola H (2004) Detection of novelty, butnot memory of spatial habituation, is associated withan increase in phosphorylated cAMP response element-binding protein levels in the hippocampus. Hippocam-pus 14:117–123.

7. Cammarota M, Bevilaqua LR, Kerr D, Medina JH,Izquierdo I (2003) Inhibition of mRNA and protein syn-thesis in the CA1 region of the dorsal hippocampusblocks reinstallment of an extinguished conditionedfear response. J Neurosci 23:737–741.

8. Izquierdo I, et al. (1998) Mechanisms for memory typesdiffer. Nature 393:635–636.

9. Bekinschtein P, et al. (2007) Persistence of long-termmemory storage requires a late protein synthesis- andBDNF-dependent phase in the hippocampus. Neuron53:261–277.

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