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Searching for the Memory New Research Sheds Light—Literally—On Recall Mechanisms by Christof Koch

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Searching for the Memory New Research Sheds Light—Literally—On Recall Mechanisms by Christof Koch (consciousness redux) Searching for the Memory New research sheds light—literally—on recall mechanisms BY CHRISTOF KOCH The difference between false gion as far as learning is concerned. page 76], and you will not be able to memories and true ones is the The most singular feature of science form new explicit memories, whereas same as for jewels: it is always the that distinguishes it from other human losses of large swaths of visual cortex false ones that look the most real, activities, such as art or religion, and leave the subjects blind but without the most brilliant. gives it a dynamics of its own, is prog- memory impairments. Yet percepts and memo- THIS QUOTE by surrealist ries are not born of brain re- painter Salvador Dalí comes gions but arise within intri- to mind when pondering the cate networks of neurons, latest wizardry coming out of connected by synapses. Neu- two neurobiology laborato- rons, rather than chunks of ries. Before we come to that, brain, are the atoms of however, let us remember thoughts, consciousness and that ever since Plato and Aris- remembering. totle first likened memories to impressions made onto wax Implanting a False tablets, philosophers and nat- Memory in Mice ural scientists have searched If you have ever been the for the physical substrate of victim of a mugging in a des- memories. In the first half of olate parking garage, you the 20th-century psycholo- may carry that occurrence gists carried out carefully with you to the end of your controlled experiments to days. Worse, whenever you look for the so-called memo- walk into a parking struc- ry engram in the brain. ture, you become anxious, One of the most influen- your heart rate goes up and tial was Karl Lashley of Har- you begin to sweat. You have vard University. He trained been fear-conditioned by the rats to run through mazes, event. Fear conditioning has turning left here and right proved to be a fruitful ave- ) over there, to find bits of nue into the molecular and food. Lashley would then make lesions ress. It results from the steady and cu- neuronal basis of learning and remem- in various parts of their cerebral cortex, mulative accumulation of knowledge, bering. Mice, the experimental animals man with maze with man the highly convolved sheet of neurons the emendation and cleansing of inaccu- of choice, can easily be fear-conditioned ( crowning the brain and situated just un- racy and inconsistency, and the under- by placing them in one particular envi- derneath the skull. He crystallized the standing that comes from constantly ronmental context—say, a chamber with insights he obtained in his lifelong ef- querying nature through empirical in- black walls, white floor, dim lighting and Getty Images forts in two maxims. His principle of vestigation coupled with theory. In the the smell of vinegar—and applying brief mass action stipulated that the cerebral case of the physical substrate of memo- electrical shocks to the floor under their IEMISCH cortex is holistically involved in memo- ries, today’s neuroscience research has paws. If the mouse is returned to this H ALF ry storage. That is, the more cortex that turned Lashley’s two principles on their cage the next day, it “freezes” in place, R is destroyed, the worse the memory of head. We now know that certain brain becoming totally immobile for a fraction ); the animal, with no regard to what spe- structures, such as the hippocampus, are of a minute or longer, in anticipation of Koch cific part of the cortex is removed. In- involved in specific types of memory. another shock. Freezing is an instinctual deed, according to Lashley’s second Lose that region on both sides of the reaction to threats, as most predators are principle, of equipotentiality, any area brain, such as the unfortunate patient wired to look for movements to pinpoint HRISTOF KOCH ( KOCH HRISTOF of cortex can substitute for any other re- HM did [see “Mind in Pictures,” on their next meal. Put the mouse into an C 22 SCIENTIFIC AMERICAN MIND July/August 2012 Neurons, rather than chunks of brain, are the ( atoms of thoughts, consciousness and remembering.) environment that looks and smells dif- thing bad about to happen. That is, neu- ferent from the one it was conditioned in, ral circuits in the dentate gyrus of the and much less freezing occurs. hippocampus wired up to express an Two American teams of researchers, aversive event that happened at B are suf- one at the Massachusetts Institute of ficient to evoke the associated aversive Technology led by Susumu Tonegawa memory, even though the subjects never and a second one under Mark Mayford had experienced anything bad in A. It is of the Scripps Research Institute in La an artificial memory—think Total Re- Jolla, Calif., exploited this standard test call—but to the mice it appeared real to manipulate the engram for this scary enough that they went into their defen- event. Part of the engram is found in the sive crouch. dentate gyrus (DG), a substructure of the Tagging neurons in the dentate gyrus, part This experiment proves that activat- hippocampus in the M.I.T. study, where- of the hippocampus deep inside the brain, ing on the order of 10,000 interlaced as the Scripps study did not specify the with specific proteins allows the astute ex- neurons in one very specific region of the perimentalist to track down and manipulate location of the engram. Shocking an ani- memories. Perhaps one day these technolo- brain is sufficient for a specific memory, mal in one context will activate a small gies can be adopted to delete old memories its engram. Whether these circuits are subset of DG neurons, around 2 to 4 per- and implant new ones at will? also necessary for this memory, that is, cent. A different context will be encoded whether deleting these neurons will re- by a separate sparse group of DG cells. while the rodents were getting used to move the memory—shades of Eternal The electrical activity in these cells trig- this context. A few days later the same Sunshine of the Spotless Mind—remains gers the expression of a small number of animals were placed into a new con- to be determined (soon). so-called immediate early genes. Both text—cages thlooked and smelled differ- Let me end with another evocative groups used mice that were genetically ent (environment B)—while they were quote from a film that routinely tops the manipulated so that the increased pro- electrically shocked. This robustly acti- list of the best science-fiction movies duction of one of these genes within a vated DG neurons that were furiously ever. I leave it to you, esteemed reader, to particular time window triggers a cas- encoding anything and everything about discover its source. It is a death soliloquy 22, 2012 22, RAM G cade of cellular events that ultimately this obviously dangerous place so that that speaks to the clarity and lucidity of EN leaves a permanent molecular tag on the the mice could avoid it in future. As in memories, real or false ones: MARCH AL P cell that can be made to glow. This label- all these transgenic mice, the activity ing allowed the experimentalists to later molecu lar ly labels these cells for subse- I’ve seen things you people ONLINE OCAM PP identify and reactivate the same set of quent reactivation. wouldn’t believe. Attack ships on HI A LISHED previously firing neurons using either In the crux of the experiment, the ro- fire off the shoulder of Orion. I’ve OF PUB beams of blue light introduced via fiber- dents were dropped into the neutral en- watched c-beams glitter in the dark optic cable (the M.I.T. group) or by deliv- vironment A that they had no cause to near the Tannhäuser Gate. All LATION U ery of a drug not naturally present in the fear. Indeed, without blue light these an- those moments will be lost in time, NATURE. IN STIM animal (the Scripps group). These ma- imals did not show any freezing. Yet in a like tears in rain. Time to die. M ., — AL nipulations deep-brain stimulation on beautiful confirmation of the power of ET ENETIC steroids—are made possible by the fan- optogenetics, when the blue light was CHRISTOF KOCH is chief scientific officer at U G LI TO tastic marriage of three technologies: turned on, the mice froze! Triggering the the Allen institute for Brain Science in Seat- P O “ pharmacology, optical stimulation and neurons that encoded environment B, in- tle and Lois and Victor Troendle Professor of IN ,” BY X.,” molecular biology [see “Playing the Body cluding its association with the painful Cognitive and Behavioral Biology at the Cali- Electric,” by Christof Koch; Scientific shock, induced the memory and made fornia Institute of Technology. He serves on RECALL Y the mice cower in expectation of some- Scientific American Mind’s board of advisers. MATERIAL American Mind, March/April 2010]. Y Y Now I will concentrate on the find- MEMOR ings from M.I.T. They had a group of (Further Reading) mice explore one particular environ- LEMENTAR FEAR ◆ Optogenetic Stimulation of a Hippocampal Engram Activates Fear Memory Recall. X. ment (let’s call it A). Later on, bombard- UPP S Liu et al. in Nature. Published online March 22, 2012. ATES V ing the DG with blue light triggered the ◆ Generation of a Synthetic Memory Trace. A. R. Garner et al. in Science, Vol.
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