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SCIENCE'S COMPASS 28. F. Desdouits, J. C. Siciliano, P. Greengard , J. A. Girault, 40. A. A. Fienberg eta/., Science 281, 838 (1998). have worked in our laboratory. I would particularly Proc. Nat/. Acad. Sci. U.S.A. 92, 2682 {1995). 41. P. B. Allen, C. C. Ouimet, P. Greengard, Proc. Nat/. like to mention A. C. Naim, who has been a dose 29. A. Nishi, G. L Snyder, P. Greengard, }. Neurosci. 17, Acad. Sci. U.S.A. 94, 9956 (1997). colleague and friend for more than 20 years. Th1s 8147 (1997). 42. Z. Van et al.. Nature Neurosd. 2, 13 {1999). work has also benef1ted enormously from collabora­ 30. G. L Snyder, A. A. Fienberg. R. L Huganir, P. Green­ 43. J.-A. Girault, H. C. Hemmings Jr., K. R. Williams, A. C. tions w1th eKcellent scientists at several other uni­ gard,j. Neuroscl. 18, 10297 (1998) Nairn, P. Greengard, }. Bioi. Chem. 264, 21748 versities. Our work on regulation of 10n pumps was 31 . P. Svenningsson eta/., Neurosd. 84. 223 {1998). (1989). carried out in collaboration with A. Aperia at the 32. A. Nishi, G. L Snyder, A. C. Naim, P. Greengard, 44. F. Desdouits, D. Cohen, A. C. Nalm, P. Greengard, J.·A. Karolinska Institute. We continue to collaborate with }. Neurochem. 72, 2015 {1999). Girault, }. Bioi. Chem. 270, 8772 (1995). R. L Huganir, who was at The Rockefeller University, 33, P. Svenningsson et al .. j. Neurochem. 75, 248 {2000). 45. J, A. Bibb eta/., Nature 402(6762), 669 (1999). and Is now at The johns Hopkins University School of 34. G. l. Snyder et at .. j. Neurosci. 20, 4480 (2000). 46. E. F. da Cruz e Silva et a/.,}. Neurosci. 1 5(5), 3375 Medicine and with E. J. Nestler, who was at the Yale 35. A. A. Flenberg. P. Greengard, Brain Res. Rev. 31, 313 (1995). University School of MediCine and is now at the (2000). 47. P. Greengard, J, jen, A. C. Naim. C. F. Stevens, Science University of Texas Southwestern Medical Center. 36. P. Svenningsson et a/., Proc. Nat/. Acad. Sci. U.S.A. 253, 1135 (1991). Much of our electrophysiological work has been done 97, 1856 (2000). 48. l.-Y Wang. M. W. Salter, J. F. MacDonald, Science in collaboration with D. J. Surmeier at Northwestern 37. A. Nishi eta/., Proc. Nat/. Acad. Sci. U.S.A. 97, 12840 253. 1132 (1991). University. The work of our research group has been (2000). 49. l. Hsieh-Wilson et al .. unpublished data. very generously supported for over 30 years by the 38. J. A. Bibb eta/., Nature 410, 376 {2001). SO. C. Rosenmund eta/., Nature 368, 853 (1994). National Institutes of Health, including the National 39. H. C. Hemmings Jr .. P. Greengard, H. Y. L Tung. P. 51. The work summarized here reflects outstanding con· Institute of Mental Health, the National Institute on Cohen, Nature 310, 503 (1984). tributions from many highly gifted associates who Drug Abuse, and the National Institute on Aging. REVIEW: NEUROSCIENCE The Molecular Biology of Memory Storage: A Dialogue Between Genes and Synapses Eric R. Kandel* form. This was the approach that AJden Spen­ One of the most remarkable aspects of an animal's behavior is the ability to modify cer and l took when we joined forces at Nil I in that behavior by learning. an ability that reaches its highest form in human beings. For 1958 to study the cellular properties of the me, learning and memory have proven to be endlessly fascinating mental processes hippocampus, the part of the mammalian brain because they address one of the fundamental features of human activity: our ability thought to be most directly involved in aspects to acquire new ideas from experience and to retain these ideas over time in memory. of complex memory (/). We initially asked. Moreover, unlike other mental processes such as thought, language, and conscious­ rather na'ivcly: Are the electrophysiological ness, learning seemed from the outset to be readily accessible to cellular and properties of the pyramidal cells of the hip­ molecular analysis. I, therefore, have been curious to know: What changes in the brain pocampus. which were thought to be the key when we learn? And, once something is learned, how is that information retained in hippocampal cells involved in memory storage, the brain? I have tried to address these questions through a reductionist approach that fundamentally different from other neurons in would allow me to investigate elementary forms of learning and memory at a cellular molecular level-as specific molecular activities within identified nerve cells. the brain? With study, it became clear to us that all nerve cells, including the pyramidal cells of the hippocampus. have similar signaling prop­ erties. Therefore. the inoinsic signaling proper­ first became interested in the study of mem­ the National Institutes of Health (NlH) in Be­ ties of neurons would themselves not give us ory in 1950 as a result of my readings in thesda from 1957 to 1960, I focused on learning key insights into memory storage (2). The Ip sychoanalysis while still an undergraduate more about the biology ofthe brain and became unique functions of the hippocampus had to at Harvard College. Later, dunng medical train­ interested in knowing how learning produces arise not so much from the intrinsic properties ing. I began to find the psychoanalytic approach changes in the neural networks of the brain. of pyramidal neurons but from the pauem of limiting because it tended to treat the brain, the My purpose in translating questions about functional interconnections of these cells. and organ that genertltes behavior, as a black box. In the psychology of learning into the empirical how those interconnections are affected by the mid- 1950s, while sti ll in medical school. I language of biology was not to replace the logic learning. To tackle that problem we needed to began to appreciate that during my lifetime the of psychology or psychoanalysis with the logic know how sensory information about a learning black box of the brain would be opened and that of cellular molecular biology, but to try to join task reaches the hippocampus and how infor­ the problems of memory storage. once the ex­ these two disciplines and to contribute to a new mation processed by the hippocampus influenc­ clusive domain of psychologists and psychoan­ synthesis that would combine the mentalistic es behavioral output. This was a fom1idable alysts, could be investigated with the methods psychology of memory storage with the biology challenge, since the hippocampus bas a large of modem biology. As a result. my interest in of neuronal signaling. I hoped further that the number of neurons and an immense nurnber of memory shifted from a psychoanalytic to a biological analysis of memory might carry with interconnections. lt seemed unlikely that we biological approach. As a postdoctoral fe llow at it an extra bonus, that the study of memory would be able to work out in any reasonable storage might reveal new aspects of neuronal period of time how the neural networks. in signaling. Indeed, this has proven true. which the hippocampus was embedded. partic­ Howard Hughes Medical Institute, Center for Neuro­ ipate in behavior and how those networks are biology and Behavior, College of Physicians and Sur· A Radical Reductionist Strategy to geons of Columbia University, New York State Psy­ affected by learning. chiatric Institute, 1051 Riverside Drive, New York, NY learning and Memory To bring the power of modem biology to 10032, USA. E-mail: [email protected] At first thought, someone interested in learning bear on the sn1dy of learning, it seemed nec­ *This essay is adapted from the author's address to and memory might be tempted to tackle the essary to take a very different approach- a the Nobel Foundation. December 2000. problem in its most complex and interesting radically reductionist approach. We needed 1030 2 NOVEMBER 2001 VOL 294 SCIENCE www.sciencemag.org SCIENCE'S COMPASS to study not the most complex but the sim­ tern i!; made up of a small number of nerve ing (5-7). As we examined these three plest mstances of memory storage, and to cells: many of these are gtgantic: and (as forms of learning, we were struck by the study them in animals that were most tracta­ became evident to me later) many are unique­ resemblance each had to corresponding ble experimentally. Such a reductionist ap­ ly identifiable (3, 4). Whereas the mammali­ forms of learning in h1gher vertebrates and proach was hardly new in 20th-century biol­ an brain has a trillion central nerve cells. humans. As with vertebrate learning. mem­ ogy. One need only think of the use of Dro­ Aplysia has only 20,000. and the simplest ory storage for each type of learning in sophila in genetics, of bacteria and bacterio­ behaviors that can be modified by learning Aplysia has two phases: a transient memory phages in molecular biology. and of the squid may directly involve less than 100 central that lasts minutes and an enduring memory giant axon in the study of the conduction of nerve cells. ln addition to being few in num­ that lasts days. Conversion of short-term to nerve impulses. Nevertheless, when tt ean1e bers, these cells are the largest nerve cells in long-tenn memory storage requires spaced to the study of behavior, many mvestigators the animal kingdom. reaching up to 1000 tJ.m repetition-practice makes perfect. even in were reluctant to use a reductionist strategy. in diameter, large enough to be seen with the snails (Fig. I B) (6-8). In the 1950s and 1960s many biologists and naked eye.

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