You MUST REMEMBER THIS Finding the master switch for long-term memory BY JOHN B. CONNOLLY AND TIM TULLY Alfredo Castaneda, Retablo of the Forgotten, 1994 N BOOK NINE OF HOMER'S EPIC THE ODYSSEY with a contrived, complex mathematical formula. After a hurricane carries the hero, Odysseus, and his several minutes' study Shereshevsky reproduced the for­ fleet of ships far off course, to the land of the mula with complete fidelity. Astoundingly, fifteen years lat­ I lotus-eaters. When the storm finally subsides, er, when Shereshevsky was asked to generate the formula, Odysseus sends two ofhis best men and a runner ashore to he did so without error. Such a "gift"-commonly called reconnoiter. The men fail to return, and so Odysseus sets photographic memory-was a double-edged sword for the offfrom his ships to rescue them. But the rescue party is ill Russian mnemonist. He had difficulty combining memo­ prepared for what it finds on shore. The missing men are ries ofthe same individual and thus struggled with person­ neither dead nor hostages; instead they survive in a dream­ al interaction. Indeed, Shereshevsky's memory so inter­ like state, devoid ofall recollections, feasting with the na­ fered with his ability to work that he ended his days as a tives on the fruits and blossoms of the lotus flower. They "memory man" in a music hall. have lost all memory ofwho and what they are: they have Most people, fortunately, inhabit the more hospitable lost their psyches. middle ground between lotus-eater and mnemonist. That Homer clearly understood that memory is an integral felicitous state turns out to be-like many other dynamic part ofwho a person is. Previous experiences inextricably biological processes-the net result of countervailing ac­ link a person to the perception ofselfand others, and they tivities that either activate or repress. In our work at the serve to color almost all behavior. Fortunately, the plight Cold Spring Harbor Laboratory in Cold Spring Harbor, of Odysseus's men is temporary; dragged back to their New York, we have devised ways of studying memory in ships at last, they regain their memories, their senses and Drosophila melanogaster, the common fruit fly. In principle, their identities. our experiments combine the classic experimental design For people suffering from genuine memory disorders, of the turn-of-the-century Russian physiologist Ivan however, the fates are not so kind. In 1968 the Russian Petrovich Pavlov with late-twentieth-century genetic en­ neuropsychologist Alexander R. Luria published The Mind gineering. First we try to create associations between pre­ ofa Mnemonist, a book devoted to the remarkable case of viously unrelated stimuli in the insects, measure the one Shereshevsky. Apparently Shereshevsky could remem­ strength of the associations and determine how long the ber everything he had ever encountered in his life. Luria memory ofthe associations persists. Then we seek the ge­ described one occasion when he presented Shereshevsky netic underpinnings of the associative process. MaY/]lIl1e /996· THE SCIENCES 37 Rene Magritte, Souvenir de Voyage III, 1951 E HAVE CONFIRMED IN FLIES WHAT But our findings may go far beyond the humble fruit fly. psychologists and neurobiologists have All animals, it seems, from invertebrates to vertebrates, W long suspected in larger animals: memo- form long-lasting memories in basically the same way. Fur­ ries are formed in distinct phases, each new phase over­ thermore, the genes identified in fruit flies also occur in the lapping the preceding one. Short-term memory (STM) other staples of the biological laboratory-in mollusks, gives rise to middle-term memory (MTM), which under chicks, mice and rabbits-and in humans. To the extent certain conditions becomes consolidated into a long­ that their functions have not changed over the long evolu­ lasting memory. But more, by analyzing flies that carry tionary span since insects and mammals diverged, those single-gene mutations, we have discovered that each genes may hold the key to the understanding ofmemory memory phase is closely associated with the function of in humans. Such a prospect offers both promise and threat. certain discrete sets of genes. In particular, we have been There is a hope that people with disorders of memory­ able to identify a gene that can enhance and suppress long­ Alzheimer's disease, for instance-could one day be helped lasting-memory formation in flies: We can make a fly into with drugs developed through our genetic insights. But a mnemonist or a lotus-eater. Our work is the first exam­ there is concern as well-concern that, as with all drugs ple of a genetic manipulation that enhances long-lasting ushered in from the new era of medical genetics, the use memory in any organism. Thus it begins to show what or abuse ofa pill ofmemory or a shot offorgetfulness will really makes memory tick. be solely at the discretion ofthe drug administrator. 38 THE SCIENCES· May/Julle 1996 O ST PEOPLE ARE AWARE OF THEIR ABILITY The second feature oflong-lasting memory, derived from to remember both recent and long-past experiments on animals, is that its formation depends on M events-the weather yesterday, as well as protein synthesis. The emerging view among neurobiolo­ the toys and stuffed animals they had as children. But how, gists is that memory is ultimately stored as a permanent exactly, do they remember such events? Do memories ex­ change in the way certain neurons communicate with each ist as isolated facts or discrete processes, quanta of infor­ other in the brain. Neurons connect to each other by way mation stored in some well-demarcated region of the of synapses, which they have in abundance. When long­ brain? Or are memories in some way holographic, diffused lasting memory appears, existing synaptic connections seem over the entire nervous system? to strengthen or grow. Proteins, synthesized within the neu­ In the 1950s, after years ofeffort to find the seat ofmem­ rons, are necessary raw materials for that process, in the same ory in the brain, the American psychologist Karl S. Lash­ way bricks are necessary for extensions to a brick house. ley rejected the idea that memories are localized, and he The classic experiments demonstrating the need for conjectured that memories protein synthesis in long­ are "statistical features of THE GENE WE IDENTIFIED CAN ENHANCE lasting-memory formation temporal patterns." Since were done in 1963. Wesley then, however, numerous or suppress long-term memory. C. Dingman, a psychiatrist studies of people whose We can make a fruit fly at Chestnut Hill Hospital in brains are partly incapaci­ Rockville, Maryland, and tated have led to what is into a mnemonist or a lotus-eater. Michael B. Sporn, a phar- now the prevailing view macologist at the Dart­ among neurobiologists: that mouth School of Medicine specific memories are indeed stored in specific sites. In in Hanover, New Hampshire, injected rats with a drug that 1904 the German biologist Richard Semon coined the inhibits protein synthesis. When the rats were injected just term engram for the site ofmemory storage-where mem­ before being trained to negotiate a water maze, they quick­ ory would physically manifest itself as a "change of the ly forgot what they had learned about the maze. But when organic substance." the rats were injected only after the training period, they re­ The classiccase study ofan epileptic man known as H.M. membered more about the maze; and the later the injec­ demonstrated one ofthe most striking features ofmemory tions, the more they remembered. After a certain interval, storage: whatever underlies long-lasting memory appears to what they learned about the maze was "committed to be physically distinct from learning and from short-term memory," and the subsequent injection of the inhibitor memory. In 1953, to quell his severe bouts ofepilepsy, sur­ drug had no effect. Thus a long-term memory (LTM) de­ geons removed significant portions of the hippocampus, pendent on protein synthesis became progressively resistant amygdala and temporal lobe ofH.M.'s brain. Although the to inhibitors after training. effects of the epilepsy were attenuated, the surgery left H.M. unable to transfer new information into permanent OTH FEATURES OF LONG-LASTING-MEMORY memory, though he could remember new information for formation-its resistance to disruption by a short time. As a result, H.M. lives in a perpetual present B anesthesia and its dependence on protein syn- where "every day is alone by itself, whatever enjoyment I've thesis-exist in the subject ofour investigations, the fruit fly. had, and whatever sorrow I've had... ." His memories from We first train our flies, as Pavlov trained his dogs, to associ­ before the surgery, however, remain intact. ate a neutral stimulus with a stimulus that usually elicits a Long-lasting memory forms in many animal species, strong behavioral response. To do so, we trap about a hun­ and psychologists and neurobiologists have often pointed dred flies at a time in a cylindrical chamber much like a test to two general features ofthe process. One feature is retro­ tube, whose inner surface is covered with an electrifiable grade amnesia: newly acquired information can be lost if grid. At one end ofthe chamber we attach an "odor cup" one is subjected to head trauma, shock treatment, hypo­ that gives off one of two odors: octanol, which smells like thermia, anesthetics or insults that lead to unconscious­ licorice, or methylcyclohexanol, which smells a lot like ten­ ness. Typically, the amnesia reaches backward in time from nis shoes inJuly. By passing air through the chamber, we ex­ the moment ofthe unconsciousness to an earlier moment pose the flies to one of the odors, and we simultaneously before which memory is unaffected by the trauma.