《认知神经科学》课程教学资源（参考文献）[Milner, B., Squire, L. R., & Kandel, E. R.（1998）]Cognitive neuroscience and the study of memory

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Neuron, Vol. 20, 445–468, March, 1998, Copyright 1998 by Cell Press Cognitive Neuroscience Review and the Study of Memory that eventually led to the independent discipline of experimental psychology. In its early years, experimental psychology was concerned primarily with the study of Brenda Milner,* Larry R. Squire,† and Eric R. Kandel‡§ *Montreal Neurologic Institute Montreal, Quebec H3A 2B4 sensation, but by the turn of the century the interests Canada of psychologists turned to behavior itself—learning, †Veterans Affairs Medical Center memory, attention, perception, and voluntary action. San Diego, California 92161 The development of simple experimental methods for and University of California studying learning and memory—first in humans by HerSan Diego, California 92093 mann Ebbinghaus in1885 and a few years later inexperi- ‡Center for Neurobiology and Behavior mental animals by Ivan Pavlov and Edgar Thorndike— College of Physicians and Surgeons led to a rigorous empirical school of psychology called Columbia University behaviorism. Behaviorists, notably James B. Watson Howard Hughes Medical Institute and Burrhus F. Skinner, argued that behavior could be New York, New York 10032 studied with the precision achieved in the physical sciences, but only if students of behavior abandoned speculation about what goes on in the mind (the brain) and The neurosciences have grown rapidly over the last half focused instead on observable aspects of behavior. For behaviorists, unobservable mental processes, espe- century. This growth has been stimulated by two impor- cially abstractions like perception, selective attention, tant developments. First, molecular biology has trans- and memory, were deemed inaccessible to scientific formed cellular neurobiology and has led to a new con- study. Instead, behaviorists concentrated on examin- ceptual framework for signaling, a molecular framework ing—objectively and precisely—the relationship be- that encompasses not only signaling in nerve cells but tween specific physical stimuli and observable re- in all the cells of the body. Second, work on brain and sponses in intact animals. Their early successes in cognition, which was traditionally associated with a number of different disciplines, has merged into a single rigorously studying simple forms of behavior, including discipline: cognitive neuroscience. This has provided a learning, encouraged them to treat all processes that intervene between the stimulus (input) and behavior new framework for the study of memory, perception, (output) as irrelevant to a scientific study of behavior. action,language, and perhaps even conscious awareness. Thus, behaviorism largely ignored mental processes. As In this review, we will consider the second development by focusing on one aspect of cognitive neuro- a result, the science of behavior was defined in terms of the limited techniques used to study it. This emphasis science: recent progress in memory research. In so do- reduced the domain of experimental psychology to a ing, we also want to consider the broader question: to what degree can these two independent and disparate restricted set of problems, and it excluded from study some of the most fascinating features of mental life. strands—molecular neurobiology and cognitive neuroscience—be united? Can molecular biology enlighten By the 1960s, it was not difficult for the founders of cognitive psychology—George Miller, Ulric Neisser, the study of cognitive processes, such as learning and memory, as it has other areas of biology, such as devel- Herbert Simon, and others—to convince the scientific opment? In turn, can cognitive neuroscience define community of the narrowness of behaviorism. These novel phenomena that will lead to a completely new set early cognitive psychologists, building on the earlier eviof molecular mechanisms and insights? dence from Gestalt psychology, European neurology, and work by the British psychologist Frederic Bartlett, The Emergence of Cognitive Neuroscience sought to demonstrate that our knowledge of the world Cognitive neuroscience originated in two disciplines: in is based on our biological apparatus for perceiving the psychology, in the development of rigorous methods world, and that perception is a constructive process for analyzing behavior and cognition, and in systems dependent not only on the information inherent in a neurobiology, in the effort to understand the structure stimulus but also on the mental processing of the perand function of neuronal circuits of the sensory and ceiver. Thus, cognitive psychology was concerned not motor systems of the brain. The fusion of these two simply with specifying the input and output for a particudisciplines was facilitated as well by the emergence of lar behaviorbut also with analyzing the processby which a coherent neuroscience—an interdisciplinary approach sensory information is transformed into perception and to the nervous system that encouraged the idea that the action—that is, with evaluating how a stimulus leads to techniques and concepts of neurobiology and systems a particular behavioral response. In redirecting scientific neuroscience might be usefully applied to the analysis attention to mental operations, cognitive psychologists of cognition. focused on information processing, on the flow of senUntil the beginning of the nineteenth century, the study sory information from sensory receptors to its eventual of normal mental activity was a part of philosophy, and use in memory and action. It was implicit in the cognitive the chief method for understanding the mind was intro- approach to behavior that each perceptual or motor act spection. By the middle of the nineteenth century, intro- has an internal representation in the brain: a representaspection began to give way to experimental approaches tion of information in patterns of neural activity. Once cognitive psychologists acknowledged that internal representations are an essential component of §To whom correspondence should be addressed

Neuron 446 behavior, they had to come to grips with the fact that of information about the organization and anatomy of most mental processes were still largely inaccessible higher functions, including memory. Lesionstudies have to experimental analysis. Without direct access to the shown that cognition is not unitary but that there are neural substrates of internal representations it was diffi- several cognitive systems, each with independent inforcult, if not impossible, to understand the path from per- mation-processing modules. For example, the visual ception to action. At about this time, the work of Vernon system of primates, a prototypicalcognitive system, has Mountcastle on somatic sensation, David Hubel and specialized anatomical pathways for processing inforTorsten Wiesel on vision, and Edward Evarts on the mation about color, form, and movement. control of movement inaugurated the neuronal analysis Finally, computational science has made a distinctive of perception and voluntary action. Moreover, during contribution to cognitive neuroscience. Computers made the 1970s, Evarts and Mountcastle developed tech- it possible to model the activity of large populations of niques for studying the activity of single cells in the neurons and to begin to test ideas about how specific brains of awake, behaving monkeys. In their hands, and components of the brain contribute to particular cogniin work that followed by Robert Wurtz, Apostolos Geor- tive processes. To understand the neural organization gopoulos, William Newsome, and others, single-unit of a complex behavior like speech, we must understand studies in monkeys led to the first correlations between not only the properties of individual cells and pathways cognitive processes (such as perception, attention, and but also the network properties of functional circuits decision making) and patterns of firing of individual cells in the brain. While network properties arise from the in specific brain regions. This work changed the way properties of individual neurons in the network, they behavior was studied both in experimental animals and need not be explainable in terms of the behavior of in humans; the focus now was on the information pro- individual cells. Computational approaches are helpful cessing in the brain that leads to behavior. for characterizing the system as whole, for obtaining The need for greater anatomical knowledge led to a formal descriptions of what the system is capable of renaissance of neuroanatomy, evident in the develop- doing, and for determining how the interacting constit- ment of new techniques for tracing connections be- uent elements account for system properties. tween neurons by Sanford Palay at the NIH, Walle Nauta This review focuses on the topic of memory, but one at MIT, Matthew and Jennifer LaVail at Harvard, and aspect of cognitive neuroscience. We have not at- Max Cowan at Washington University. The search for tempted to document fully the remarkable progress that new neuroanatomical methods and the need to bridge has been achieved in our understanding of how the anatomy and function led to the application of neuro- nervous system learns and remembers. Rather, we fo- imaging techniques (positron emission tomography [PET] cus on two key components in the study of memory, as scanning and functional magnetic resonance imaging viewed through thework that the three of us have carried [MRI]) to cognitive problems. This major advance, pio- out with our colleagues during the past severaldecades. neered by Marcus Raichle and Michael Posner and by The first component is concerned with analyzing what Seiji Ogawa, Ken Kwong, and others, made it possible memory is, where it is stored, and what brain systems to relate changes in activity in large populations of neu- are involved. This is the systems problem of memory. rons to specific cognitive acts in living humans. By com- The second component of memory is concerned with paring the results of cellular recordings in nonhuman analyzing how memory is stored. This is the molecular primates and the results of neuroimaging in humans, it problem of memory. has become possible to study directly the neural correlates of sensory processing, motor actions, and cognitive processes. Where Are Memories Stored? In the 1960s and 1970s, there was also renewed inter- The question of where memory is stored emerged at est in the traditional discipline of neuropsychology. Early the beginning of the 19th century as part of the larger students of brain and behavior like Karl Lashley and question—to what degree can any mental process be Donald Hebb used the term neuropsychology broadly localized within the brain? The first person to address to encompass studies of experimental animals as well this question was Franz Joseph Gall, who made two as studies of humans. In this sense, cognitive neurosci- major conceptual contributions. First, Gall attempted to ence is the modern forum for the same topics and issues abolish mind–brain dualism. He argued, based on his that engaged Lashley and Hebb earlier in this century. Studies of patients with brain injury or disease that af- anatomical studies, that the brain is the organ of the mind. Second, he appreciated that the cerebral cortex fects mental function have always been a vital part of neuropsychology, and such studies formed one of the is not homogenous but contains distinctive centers that control specific mental functions. Gall therefore pro- foundations of cognitive neuroscience. As first clearly shown for language by Pierre Paul posed the idea of cortical localization. Gall asserted that Broca in 1863, patients with lesions of specific regions the brain does not act as a unitary organ but is divided of the brain exhibit quite specific cognitive deficits. Fol- into at least 27 faculties (others were added later), each lowing Broca and Wernicke, the neuropsychological at- corresponding to a specific mental faculty. He thought tempt at regional localization remained strong in Europe that even the most abstract and complex of human and in Canada but was in good part neglected in the traits, such as generosity and secretiveness, are localUnited States, with the exception of the work of Arthur ized to discrete areas of the brain. Benton, Hans-Lukas Teuber, and Norman Geschwind. Gall was not an experimentalist. He rejected the study As we shall see, continuing study of the behavioral con- of neurological lesions and the surgical manipulation of sequences of brain lesions proved to be a rich source experimental animals and instead attempted to locate

Review: Milner, Squire, and Kandel 447 Figure 1. Hebb and Penfield D. O. Hebb (right) and Wilder Penfield (left) in 1958 on the occasion of Hebb delivering the 24th Annual Hughlings Jackson lecture at the Montreal Neurological Institute. mental faculties by examining the surface of the skulls with the size of the cortical area removed, not with its of individuals well endowed with particular functions. specific location (Lashley, 1929). Many years later, with Perhaps not surprisingly, with this approach he misiden- additional experimental work, it was possible to arrive tified the function of most parts of the cortex. This ana- at a different understanding of Lashley’s famous contomically oriented approach to personality Gall called clusion. organology. Later, Gall’s associate, Gaspard Spurz- Perhaps the first effective answer to Lashley came heim, adopted the better-known term phrenology to de- from Donald Hebb (Figure 1, right). In his book The Orgascribe this approach. nization of Behavior, Hebb (1949) convinced many that Gall’s ideas were subjected to experimental analysis it was possible to think seriously about the brain proby Pierre Flourens in France in the late 1820s. Flourens cesses underlying memory. He developed concrete proattempted to isolate the contributions of different parts posals based on biological facts, taking into considerof the nervous system to behavior by removing from the ation the neuronal circuitry that might contribute to brains of experimental animals the functional centers memory storage. To explain Lashley’s result that learnidentified by Gall. From these experiments, Flourens ing could not be localized to a single brain region, Hebb concluded that individual sites in the brain are not suggested that assemblies of cells work together to sufficient for specific behaviors such as sexual behavior represent information and that these assemblies are and romantic love and that all regions of the brain— distributed over large areas of cortex. Sufficient numespecially the cerebral hemispheres of the forebrain— bers of interconnected cells will survive most lesions to participate in every mental function. He proposed that ensure that information can still be represented. The any part of the cerebral hemisphere is able to perform idea of a distributed memory store was far sighted. With all the functions of the hemisphere. Injury to a specific the accumulation of additional evidence, it has become area of the cerebral hemisphere should therefore affect apparent that no single memory center exists, and many all higher functions equally. parts of the nervous system participate in the represenDespite the findings of Broca and Wernicke on the tation of any single event. localization of language, the ensuing debate between Hebb influenced many students and colleagues—in cortical localization and equipotentiality in cognitive particular, Brenda Milner, who in 1957 described the function dominated thinking about mental processes, remarkable patient H. M. (Scoville and Milner, 1957). including memory, well into the first half of the twentieth H. M. had sustained a bilateral resection of the medial century. For example, in the period from 1920 to 1950, structures of the temporal lobe in 1953 to relieve severe this dispute could be followed in the work of Karl epilepsy. It was immediately evident following the surLashley, perhaps the dominant figure in American neu- gery that H. M. had a very profound impairment of recent ropsychology in the first half of this century. Lashley memory in the apparent absence of other intellectual explored the surface of the cerebral cortex in the rat, loss (Scoville, 1954). He could not remember what he systematically removing different cortical areas. In so had for breakfast, and he could not find his way around doing, he failed repeatedly to identify any particular the hospital or recognize members of the hospital staff brain region that was special to or necessary for the (except Scoville, whom he had known for many years). storage of memory. Based on these experiments, It seemed as though his life from the surgery onwards Lashley formulated the law of mass action, according was not contributing to his store of knowledge. He was to which the extent of the memory defect was correlated able to hold immediate impressions in his mind, but as

Neuron 448 soon as his attention was diverted they were lost. In to that of Penfield’s two patients, except that it was contrast, old memories from his childhood seemed to more severe. Again, there had been no intellectual loss; be intact. in fact, H. M.’s IQ had risen postoperatively, from 104 In fact, the encounter with H. M. was not the first to 117, presumably because he was having far fewer encounter with this kind of memory impairment. During seizures. His capacity for sustained attention was also the early 1950s, Wilder Penfield (Figure 1, left) began to remarkable. Thus, Milner showed that he could retain carry out unilateral removals of parts of the frontal or the number 584 for at least 15 minutes by continuous temporal lobe as a treatment for patients with localized rehearsal, combining and recombining the digits acinjury causing seizures. The temporal-lobe removals cording to an elaborate mnemonic scheme, but the motypically included the anterior temporal neocortex to- ment his attention was diverted by a new topic, the gether with the uncus, amygdala, and anterior parahip- whole event was forgotten. pocampal gyrus and hippocampus on the medial aspect H. M.’s success in remembering a three-digit number of the hemisphere. Milner and Penfield found that these for 15 minutes in the absence of distraction was at first removals produced at most mild material-specific mem- sight consistent with Drachman’s view that amnesics ory deficits that varied in kind with the side of the lesion. can hold a simple memorandum indefinitely provided But, unexpectedly, Milner and Penfield encounteredtwo that no interfering activity claims their attention (Drachpatients with a severe, persistent, and generalized im- man and Arbit, 1966). Yet it was already clear that for pairment of recent memory, following a removal limited H. M. verbal rehearsal played a key role in this holding to the left temporal lobe. Because both patients had process. In contrast, certain simple nonverbal stimuli undergone extensive preoperative testing, it was easy were forgotten by him within less than a minute. The to establish that this was a selective impairment of mem- evidence for this comes from delayed paired compariory, with no accompanying intellectual loss (Penfield son and delayed matching studies. and Milner, 1958). The impairment was manifested clini- In 1959, Konorski described a method for testing cally as a profound anterograde amnesia, such that the memory of single events, which was later adapted for experiences of daily life were forgotten as soon as the work with human subjects by Stepien and Sierpinski focus of attention shifted to a new topic. In addition, one (1960). This technique, called by Milner “delayed paired patient showed a retrograde amnesia covering salient comparison,” consists of presenting two stimuli in sucevents of the preceding few months and the other cession, separated by a short time interval. The subject showed a retrograde amnesia covering the 4 preceding must then indicate whether the second stimulus is the years. same as or different from the first. This means that subTo account for this unexpected memory loss, Milner jects must retain an impression of the first stimulus in and Penfield (1955) hypothesized that in each case there order to compare the second one with it. Task difficulty must have been a pre-existing, but undetected, atrophic may be increased by lengthening the intratrial interval lesion in the hippocampal region of the opposite hemi- or by introducing an intratrial distraction. Prisko (1963; sphere, so that when the surgeon removed the anterior cited by Milner, 1972) used the Konorski method to demhippocampus and parahippocampal gyrus in the left onstrate H. M.’s rapid forgetting of simple perceptual hemisphere, he effectively deprived the patients of me- material. She sampled five different sets of stimuli (three dial temporal-lobe function bilaterally. The reason that visual and two auditory), each set constituting a sepaMilner and Penfield focused on the hippocampal region rate task. The stimuli used were clicks, tones, shades was that one patient, P. B., had had his temporal lobec- of red, light flashes, and nonsense patterns. At least five tomy in two stages, and it was only after removal of the values were assigned to each variable, to prevent as far medial structures of the temporal lobe that the memory as possible the use of verbal mediation to bridge the loss was seen. Their hypothesis was confirmed 9 years retention interval. All paired stimuli were easily discrimilater, when P. B. died of a pulmonary embolism and the nable at zero intratrial delay. These proved to be exautopsy findings revealed thepresence of long-standing tremely easy tasks for normal subjects, who rarely made extensive right hippocampal atrophy, whereas the rest errors even with a 60-second delay and an interpolated of the right temporal lobe, including the amygdala and distraction. In contrast, H. M. performed all tasks well the parahippocampal gyrus, showed no significant ab- at zero delay, but with increasing intratrial intervals his normality. In contrast, on the operated (left) side, the 22 performance deteriorated sharply, so that at the 60- mm of the hippocampus that remained appeared to be second delay scores were approaching the chance level normal (Penfield and Mathieson, 1974). and were not further impaired by distraction. Milner and Penfield reported these two cases at the Subsequently, Sidman, Stoddard, and Mohr (1968) 1955 meeting of the American Neurological Association confirmed Prisko’s findings, using a delayed matchingin Chicago, and Scoville read their abstract. He called to-sample technique that allowed the plotting of discrimPenfield and said that he thought he had seen a similar ination gradients to show how far the subject’s choice memory disturbance in a patient of his (H. M.) in whom of a matching stimulus deviates from the sample stimuhe had carried out a bilateral medial temporal-lobe re- lus as the intratrial interval lengthens. In the nonverbal section, also in an attempt to control epileptic seizures. form of their task, H. M. was required to indicate which Penfield asked Milner if she would like to go down to one of eight ellipses matched the sample stimulus. With Hartford, Connecticut to study the patient, and that is zero delay he chose correctly most of the time, showing how the memory deficit in H. M. became more widely a normal discrimination of axis-ratios, but with increasknown. ing delays his performance deteriorated until, at 32 secClinically, H. M.’s memory disorder appeared identical onds, the sample no longer exerted any control over his

Review: Milner, Squire, and Kandel 449 Figure 2. H. M. Showed Improvement in a Task Involving Learning Skilled Movements In this test, he was taught to trace a line between the two outlines of a star, starting from the point S (Figure 2A), while viewing his hand and the star in a mirror. He showed steady improvement over the 3 days of testing, although he had no idea that he had ever done the task before. (The graph in Figure 2B plots the number of times, in each trial, that he strayed outside the boundaries as he drew the star.) Adapted from Milner (1962). choice. In contrast, H. M. had no difficulty with a verbal reaches the points of the star, one tends to move the version of the task, which required the matching of con- hand in the wrong direction. Eventually, with practice, sonant trigrams. However, as with other short-term ver- we can all learn to draw the outline of a star in a mirror. bal memory tasks, he succeeded only by constant re- It is a new sensorimotor skill, a visual-motor skill, and hearsal; his lips could be seen moving throughout the it is acquired across many trials. Milner was able to delay period. show that H. M. could learn that kind of task quite well. These and other related studies (Milner and Taylor, She took H. M. through 30 trials of mirror drawing spread 1972) concur in showing that H. M. can register percep- over 3 days, and he exhibited a typical learning curve (Figure 2B). Yet at the end he had no idea he had ever tual information normally, but that the information ceases to be available to him within about 30–40 sec- done the mirror drawing task before: this was learning onds. Milner (1972) suggested that such results support without any sense of familiarity. Nowadays, we are well aware that such dissociations are possible following a the distinction between a primary memory process with discrete brain lesion, but for Milner, looking at it for the a rapid decay and an overlapping secondary process first time, it was quite astonishing. Her finding contrib- (impaired in H. M.) by which the long-term storage of uted some of the early evidence that there is more than information is achieved. one memory system in the brain. Interestingly, even before the study of patient H. M. There Are Multiple Memory Systems in the Brain inaugurated empirical work on the different memory sys- H. M.’s failure on delayed matching and delayed com- tems of the brain, similar ideas had been proposed by parison tasks, which assess memory after a single pre- philosophers and psychologists on the basis of intuition sentation, did not rule out the possibility that he might and introspection. For example, in 1949, Gilbert Ryle, a be capable of some learning with intensive practice, or philosopher of mind at Oxford, proposed the existence indeed that certain kinds of learning might take place of two types of knowledge: knowing how, as in knowl- at a normal rate. Accordingly, Milner and her students edge of motor skills, and knowing that, as in the knowl- embarked on a variety of learning studies with H. M., edge of facts and events. Some years later Jerome including stylus maze tasks, both visual (Milner, 1965) Bruner, one of the founders of cognitive psychology, and tactual (Corkin, 1965). With one notable exception, called “knowing how” a memory without record. Memthese studies merely served to demonstrate H. M.’s ex- ory without record, Bruner argued, occurs in the case treme difficulties with new learning, as evident also in of experiences that “change the nature of the organism, his daily life. The exception was in the domain of motor change his skills, or change the rules by which he operskills, where, in 1962, Milner showed that H. M. could ates, but are virtually inaccessible in memory as specific learn a mirror-drawing task efficiently with stable reten- encounters.” Here, the neural machinery that supports tion from day to day (Figure 2A). a behavior is presumably modified directly. He called If one is shown a picture of a double-margin star “knowing that” a memory with record, a repository of (Figure 2) and asked to draw a line between the two information about the facts and events of everyday life. margins, one can do that very easily. However, if one has The demonstration of intact motor skill learning in to do it while seeing one’s hand and the star reflected in patient H. M. marked the beginning of a period of experia mirror, then it becomes quite difficult. When one mental work that eventually established the biological

Neuron 450 reality of multiple memory systems. This later work made storing representations about facts and episodes. Nonit clear that the spared memory capacities of H. M. and declarative memory is neither true nor false. It underlies other amnesic patients with bilateral medial temporal- changes in skilled behavior and the ability to respond lobe lesions are not limited to motor skills. Motor skills appropriately to stimuli through practice, as the result of are a subset of a large collection of learning and memory conditioningor habit learning. It also includes changes in abilities, all of which are spared in amnesia and indepen- the ability to detect or identify objects as the result of dent of the medial temporal lobe. In 1968, Warrington recent encounters, a phenomenon known as priming. and Weiskrantz demonstrated what turned out to be In the case of nondeclarative memory, performance another kind of preserved learning ability in a group of changes as the result of experience, which justifies the six amnesic patients, one after a right temporal lobec- term memory, but performance changes without providtomy and five with alcoholic Korsakoff’s psychosis. Us- ing conscious access to any prior episodes (Squire et ing a version of the Gollin Figures task (Gollin, 1960), al., 1993; Schacter and Tulving, 1994). Many forms of Warrington and Weiskrantz asked their patients to try nondeclarative memory, such as habituation, sensitizato identify line drawings of common objects and animals tion, and classical conditioning, are phylogenetically an- (such as a chair or an elephant) from which most of the cient and well developed in invertebrate animals that contour lines had been removed. This is initially quite do not have a medial temporal lobe or hippocampus. difficult with the most fragmented drawings, but over A number of nondeclarative forms of memory have successive presentations the contour is gradually filled been subjected to intensive study. In humans, perhaps in until the subject can name the item depicted. On a the best studied example of nondeclarative memory is second presentation of the task, 1 hour later, normal priming, first explored by Warrington and Weiskrantz subjects show considerable savings, requiring fewer (1968) and by Milner et al. (1968). Endel Tulving, Daniel contour cues to name the items. On this incomplete Schacter, Larry Squire, and others have explored several figures task and on an analogous fragmented words paradigms in which subjects see lists of words, pictures task, Warrington and Weiskrantz found marked savings of objects, or nonverbal material such as novel objects in their amnesic patients, with good retention 4 weeks or designs (Weiskrantz, 1990; Tulving and Schacter, later, although the patients did not remember doing the 1990). Subsequently, subjects are tested with both old tasks before. It is true that the amnesic group showed and new items and asked to name words or objects as less savings than the age-matched control group, but quickly as possible, to complete fragments to form this was only to be expected, given that the control whole items, or to make rapid decisions about items. subjects could recall most of the items and anticipated For example, when the first few letters (MOT__) of a seeing them again. recently studied word (MOTEL) are presented, priming Milner subsequently replicated the findings for the is evidenced in the tendency to complete the word fragGollin figures with H. M. Interestingly, H. M.’s initial per- ment to form the study word instead of other possible formance on the firstexposure to thematerial was above words. Severely amnesic patients exhibit fully intact the control mean, illustrating his superior perceptual priming, despite being unable to recognize as familiar abilities. On retesting, 1 hour later, he reduced his error the items that had been presented previously. score by 48%, although he did not remember seeing any Other forms of nondeclarative memory also have been of the drawings before. Moreover, he showed residual studied. These include habit memory, which refers to savings 4 months later (Milner et al., 1968). This long- gradually acquired dispositions or tendencies that are term effect of a prior visual experience, which Milner specific to a set of stimuli and that guide behavior. Habit called “perceptual learning,” is an instance of what is learning survives hippocampal damage in humans and now known as priming, a form of learning distinct from experimental animals but is impaired by damage to motor skill and which, in this case, is probably mediated the caudate nucleus (Packard et al., 1989; Knowlton et by higher visual cortical areas. al., 1996). Emotional learning, as in the development of phobias or in fear conditioning, is dependent on the amygdala. Anenormous amount has beenlearned about The Declarative and Nondeclarative the essential structures and connections involved in Memory Systems emotional learning, particularly from studies in which In 1980, Neal Cohen and Larry Squire showed that amne- rats learn to fear a neutral stimulus such as a tone (fear sic patients could learn the task of reading mirror- conditioning and fear-potentiated startle) (LeDoux, 1995; reversed print as wellas normal subjects.These findings Davis et al., 1997). The amygdala has also been shown to broadened further the scope of what amnesic patients beimportant for emotional learning in humans (Damasio, could do and suggested a fundamental distinction in 1995; Cahill et al., 1996). Moreover, the amygdala is the way all of us process and store information about essential not only for emotional learning itself; it also the world. The major distinction is between declarative exerts modulatory effects on other memory systems memory and a collection of nondeclarative, noncon- (McGaugh et al., 1996). For example, the amygdala is scious forms of memory. responsible for the enhancement of declarative, conDeclarative memory (Figure 3) is what is ordinarily scious memory, which normally occurs with emotional meant by the term memory. It depends on the integrity arousal (Adolphs et al., 1997). of the medial temporal lobe and affords the capacity for Perhaps the best studied example of nondeclarative conscious recollections about facts and events. Declar- memory in mammals is classical Pavlovian conditioning ative memory is propositional—it can be either true or of discrete behavioral responses. A body of work initifalse. It is involved in modelling the external world and ated in the early 1980s by Richard Thompson and his

Review: Milner, Squire, and Kandel 451 Figure 3. A Taxonomy of Mammalian Memory Systems This taxonomy lists the brain structures and connections thought to be especially important for each kind of declarative and nondeclarative memory. colleagues has focused on basic delay conditioning of David Amaral has recently reviewed the results of a the rabbit eyeblink response (conditioned stimulus 5 magnetic resonance imaging study of H. M. (Corkin et tone; unconditioned stimulus 5 airpuff; conditioned re- al., 1997). He finds that Scoville’s removal was in fact sponse 5 eyeblink). Based on anatomical findings, elec- exactly as he had described it, except that the resection trical stimulation, and reversible lesion techniques, the only extends about 5 cm posteriorly in both hemiresults provide strong evidence that the essential mem- spheres, instead of the radical 8 cm originally reported. ory trace circuit includes the cerebellum and related Thus, in both hemispheres the removal included the brain stem circuitry and that the memory traces them- amygdala, the perirhinal and entorhinal cortex, and the selves are formed and stored in the cerebellum (Thomp- anterior hippocampus. The parahippocampal cortex son and Krupa, 1994). To date, eyeblink conditioning was largely spared. Most importantly, the temporal neoprovides the clearest information about the localization cortex and the temporal stem were spared. If the roles of a memory within the mammalian brain. of these various structures were to be understood, an animal model clearly was needed. In humans, several kinds of nondeclarative memory have been studied, which are likely based on perceptual learning. These include adaptation-level effects, the Nonhuman Primate Models of Declarative Memory ability to resolve random-dot stereograms, the ability to As soon as H. M. was described in 1957, efforts began to establish an animal model of his condition in the rat learn the regularities of “artificial grammars” by studying and monkey. If the concept of conscious recollection lawfully ordered letter strings, and the ability to acquire is central to declarative memory, how can declarative knowledge about categories. In category learning, one memory be studied in experimental animals? Several extracts and stores information about the prototype (or characteristics have been useful in extending the notion representative instance) of a series of items by studying many different items that, when averaged together, de- of declarative memory to mice, rats, and monkeys (Eichenbaum, 1997). These include its flexibility and the scribe the prototype. All these forms of memory are ability to use it inferentially in novel situations. It took intact in amnesic patients (Squire et al., 1993; Squire considerable time to achieve such a model, and the first and Zola-Morgan, 1996). These kinds of memory likely results of lesion studies in the monkey were puzzling. involve changes within the same cortical areas responsi- Animals with bilateral medial temporal-lobe resections ble for perceiving and analyzing the materials that are similar to what was described in H. M. showed normal studied. performance on visual discrimination learning tasks, even when concurrent trials on a different task were What Parts of the Medial Temporal Lobe interpolated as potential “distractors” for the discrimina- Are Important for Memory? tion learning. This led many investigators to question The behavioral studies reviewed above provide compel- either thehuman findings or the validity of cross-species ling evidence that the human declarative memory sys- comparisons. It was not until the early 1980s, with the tem is critically dependent upon the medial temporal concept of multiple memory systems and the idea that region. Yet we still have much to learn about the relative amnesia impaired only one kind of memory, that it beimportance of specific structures within the region for came clearer which memory tasks were appropriate to memory processes and the mode of interaction of these give to experimental animals. The beginning of the solustructures with other brain areas. Although Scoville and tion came in 1978 when Mort Mishkin described severe Milner (1957) drew attention to the hippocampus in the deficits in monkeys with bilateral medial temporal-lobe title to their paper, this was only because in their experi- lesions, when the monkeys were given a one-trial task ence bilateral removals limited to the amygdala and un- of object recognition memory (delayed nonmatching to cus did not result in amnesia; they never claimed that the sample). This finding was consistent with the severe hippocampal lesions alone were responsible for H. M.’s impairment shown by H. M. on single-trial delayed severe memory loss. matching tasks

Neuron 452 Figure 4. The Medial Temporal-Lobe Memory System in the Monkey (A) Ventral view of a monkey brain illustrating the cortical areas underlying the hippocampus that are part of the medial temporal-lobe system. Blue, perirhinal cortex; pink, entorhinal cortex; green, parahippocampal cortex. The periamygdaloid cortex (yellow) is not thought to be a part of the system. (B) Schematic view of the memory system. The entorhinal cortex is a major source of projections to the hippocampal region, which includes the dentate gyrus (DG), the cell fields of the hippocampus, and the subicular complex (S). Nearly two-thirds of the cortical input to entorhinal cortex originates in the adjacent perirhinal and parahippocampal cortices, which in turn receive projections from unimodal and polymodal areas in the frontal, temporal, and parietal lobes. The entorhinal cortex also receives other direct inputs from orbital frontal cortex, insular cortex, and superior temporal gyrus. All these projects are reciprocal. The 1978 paper did not settle matters all at once but H. M., as well as the two patients described by Penfield by the early 1980s, after additional work by Mishkin, and Milner (1958), appeared to have intact memory for Zola-Morgan, and others, an animal model of human remote events that occurred years before their surgery. amnesia in the monkey was established. With this Subsequently, formal tests that asked about past public model, the question of precisely which structures within events also showed amnesic patients to have impaired memory for events leading up to the amnesia but intact the medial temporal lobe were important could be sysmemory for more remote events (Squire et al., 1989; tematically explored. The identification of the anatomical components of the medial temporal-lobe memory Rempel-Clower et al., 1996). This loss of premorbid memory (retrograde amnesia) can cover months or even system required about 10 years of experimental work years, depending on the extent of medial temporal-lobe (Squire and Zola-Morgan, 1991). The important struc- damage (Rempel-Clower et al., 1996). tures are the hippocampus proper, the dentate gyrus, Studies of remote memory and retrograde amnesia the subicular complex, and the entorhinal cortex (which in amnesic patients necessarily rely on retrospective together comprise the hippocampal formation) and the methods and imperfect tests. As a result, it is difficult adjacent, anatomically related cortex: the perirhinal and to compare performance across past time periods. For parahippocampal cortices (Figure 4). The amygdala these reasons, the phenomenon of retrograde amnesia proved not to be a component of the declarative memory has begun to beexamined prospectively inexperimental system, although it can exert a modulatory action on animals. To date, eight different studies have been car- declarative memory. ried out in which equivalent amounts of training were A lesion restricted to any of the major components given at two or more times before bilateral damage to of this system has a significant effect on declarative the hippocampal formation, and retention was assessed memory. Indeed, two amnesic patients have been de- shortly after surgery (Figure 5). The work has involved scribed (R. B. and G. D.) who, following an ischemic mice, rats, rabbits, and monkeys and a variety of mem- event, had bilateral lesions limited to the CA1 region of ory tasks including object discrimination learning, con- the hippocampus (Zola-Morgan et al., 1986; Rempel- text-specific fear conditioning, maze learning, and trace Clower et al., 1996). Their deficit was qualitatively similar conditioning of the eyeblink reflex. In seven of the eight to H. M.’s impairment, though quantitatively it was much studies, clear evidence was obtained for temporally milder. It is now clear that the severity of H. M.’s memory graded retrograde amnesia, which covered a period impairment depends not only on his hippocampal dam- ranging from a few days to about a month before surage but on the fact that his surgery included the hippo- gery. In the eighth study (Bolhius et al., 1994), memory campal region togetherwith theperirhinal and entorhinal was affected similarly at the time points tested, although cortices (Corkin et al., 1997). performance was always at chance levels so that no A key feature of medial temporal-lobe function is that difference between the two time points could have been the medial temporal lobe is involved in memory for a detected. limited period of time after learning. The initial evidence Recent accounts of temporally graded retrograde amfor this idea came from the observation that patient nesia propose that medial temporal-lobe structures

Review: Milner, Squire, and Kandel 453 Figure 5. Summary of Findings from Eight Studies that Have Examined Retrograde Amnesia Prospectively In these studies, an equivalent amount of training was given at each of two or more times before hippocampal formation damage, and retention was assessed shortly after surgery. In each case, the data show the performance of control (CON) and operated animals (H 5 hippocampus, EC 5 entorhinal cortex, FX 5 fornix) as a function of the interval between training and surgery. Control animals typically exhibited forgetting as the interval between training and surgery increased. In seven of the eight studies, operated animals exhibited temporally graded retrograde amnesia. They were impaired at retaining material they had learned recently, but they retained remotely learned material as well as control animals. In addition, the operated animals typically retained remotely learned material better than recently learned material. In the lower left panel, the dotted line denotes chance performance. From left to right, beginning on the top row, the studies are by Winocur (1990); ZolaMorgan and Squire (1990); Kim and Fanselow (1992); Cho, Beracochea, and Jaffard (1993); Bolhuis, Stewart, and Jaffard (1993); Kim, Clark, and Thompson (1995); Cho and Kesner (1996); and Wiig, Cooper, and Bear (1996). direct a gradual process of reorganization and stabiliza- places and objects, and this type of memory has many tion by changing the organization of cortical repre- of the characteristics of human declarative memory, afsentations, for example, by gradually binding together fording, for instance, the flexible use of relational inforthe multiple, geographically separate cortical regions mation about multiple distal cues. As we shall see in that together store memory for a whole event (Alvarez the sections that follow, the possibility of studying deand Squire, 1994; McClelland et al., 1995). After suffi- clarative memory in mice has opened this form of memcient time has passed, the hippocampal formation is ory to a molecular genetic approach. not needed to support storage or retrieval of declarative memory, and long-term memory is fully dependent on The Molecular Biological Approach the neocortex (reviewed by Squire and Alvarez, 1995). to Memory Storage The different components of the medial temporal lobe How are we to think about the cellular and molecular need not have equivalent roles in declarative memory; mechanisms of memory storage? Bythe end of the ninedifferent structures within the medial temporal lobe are teenth century, biologists had come to appreciate that likely to carry out different subfunctions. As damage mature nerve cells have lost their capacity to divide. increases, fewer strategies may be available for storing This fact prompted Santiago Ramo´ n y Cajal to propose memory, with the result that memory impairment be- that learning does not result in the proliferation of new comes more severe. To study the functions of the indi- nerve cells but instead causes existing nerve cells to vidual regions in humans would require many patients grow more branches and to strengthen their connecwith very specific brain lesions. Fortunately, recent tions with other nerve cells so as to be able to communianatomical and behavioral studies indicate that, even cate with them more effectively (Ramon y Cajal, 1894). though there are differences in detail, the anatomical This prescient idea raised three sets of questions. and functional organization of the medial temporal-lobe First, does memory involve persistent changes in synsystem is similar in humans, nonhuman primates, and aptic strength? If so, what are the molecular underpinsimpler mammals such as rats and mice (Squire, 1992; nings of these synaptic changes? Mayford etal., 1996). Moreover, even the mouse requires Second, how do short-term synaptic changes differ this memory system for the storage of memory about from the changes that support long-term storage? Do

Neuron 454 they occur at different loci, or can the same neuron store or even many thousands of nerve cells for perfectly good information for both short- and long-term memory? long-term storage of a variety of different memories. Third, if memory storage results from changes in spe- These early behavioral studies in invertebrates led to cific synaptic connections, do declarative memory and the delineation of a family of psychological concepts the various nondeclarative forms of memory use differ- that paralleled those first described in vertebrates by ent molecular mechanisms for storage, or are the stor- both the classical behaviorists—Pavlov and Thorndike— age mechanisms used by these two memory systems and their modern counterparts—Kamin, Rescorla, and fundamentally similar? Wagner. These concepts included the distinction beTo explore these ideas, neurobiologists developed a tween various forms of associative and nonassociative number of model systems for the specific purpose of learning, the role of contingency as opposed to mere optimizing the ability to study synaptic change in the contiguity, short-term memory consolidation, storage, context of behavioral memory storage, with the ultimate retrieval of long-term memory, and forgetting. Subsegoal of identifying the cellular and molecular basis of quent cellular studies of these simple forms of learning the synaptic changes responsible for the storage (see, illustrated that these concepts, initially inferred from for example, Kandel and Tauc, 1964; Thompson and purely behavioral studies, could now be approached Spencer, 1966; Kandel and Spencer, 1968). The reduc- directly in terms of their underlying cellular and molecular mechanisms (reviewed by Kandel, 1976; Hawkins tionist approach to nondeclarative memory storage began with the cell biological studies of the marine snail and Kandel, 1984; Carew and Sahley, 1986). Thus, the ability to analyze learning-related synaptic mechanisms Aplysia by Kandel (Kandel and Tauc, 1964) and with the brought to light not only a new set of mechanistic in- genetic studies of Drosophila by Benzer (Benzer, 1967). sights into the plastic properties of individual synaptic connections, but in so doing these studies brought con- Cell Biological and Molecular Insights into creteness and clarity to the psychological concepts Nondeclarative Memory Storage themselves. For example, by identifying significant com- The cell biological studies in Aplysia (Kandel and Tauc, ponents of the neural circuits underlying simple behav- 1964; Kupfermann and Kandel, 1969; Castellucci et al., iors such as the gill-withdrawal reflex in Aplysia, the tail 1970) were soon joined by studies of other invertebrates flick in the crayfish, feeding in Limax or Aplysia, and including other opisthobranch snails, specifically Her- phototaxis in Hermissenda, studies in invertebrates de- missenda (Alkon, 1974) and Pleurobranchaea(Davis and lineated how elements in the behavioral circuits them- Gillette, 1978), the land snail Limax (Gelperin, 1975), selves changed when behavior was modified by various crayfish (Krasne, 1969), and honey bees (Menzel and forms of learning (reviewed by Carew and Sahley, 1986). Erber, 1978). The idea underlying these cell biological These findings illustrate that nondeclarative memory studies was that the simple brains of certain experimen- storage does not depend on specialized memory neu- tally tractable invertebrates combined the advantages rons or systems of neurons whose only function is to of having a relatively small number of nerve cells in the store rather than process information. Rather, simple brain with cells that (with the exception of the honey nondeclarative memory storage results from changes bee) are unusually large and readily identifiable. These in neurons that are themselves components of the reflex features made their behavior and their ability to modify pathway. The storage of nondeclarative memory is em- behavior by learning accessible tocellular and molecular bedded in the neural circuit that produces the behavior. analysis. Analogous reductionist approaches were also These studies therefore provided the first clear insight applied to the mammalian brain, in particular to the iso- that the organization and implementation of nondeclara- lated spinal cord (Spencer et al., 1966), to brain slices tive memory is different from declarative memory where of the hippocampus (Schwartzkroin and Webster, 1975), a whole neural system, the medial temporal-lobe mem- and to learned behavior dependent on the cerebellum ory system, is needed to ensure the remembrance of (McCormick and Thompson, 1984) and the amygdala things past. (Davis, 1995; LeDoux, 1995). Moreover, these cell biological studies illustrated sev- The first insight to emerge from this simple systems eral general principles about memory-related synaptic approach to nondeclarative memory was purely behav- plasticity. To begin with, the studies provided the first ioral. Studiesof invertebrates revealed that even animals direct evidence for two of Cajal’s prescient suggestions: with limited numbers of nerve cells—approximately that the synaptic connections between neurons mediat- 20,000 to 100,000 central neurons in the nervous sys- ing behavior are not fixed but can become modified by tems of Aplysia, Hermissenda, Pleurobranchaea, and learning, and that these modifications persist and can Limax and approximately 300,000 in Drosophila—had serve as elementary components of memory storage rather remarkable behavioral and learning capabilities (Figure 6; Castellucci et al., 1970, 1978; Zucker, 1971; (reviewed by Carew and Sahley, 1986). In fact, even the Castellucci and Kandel, 1974). In addition, these studies gill withdrawal reflex, perhaps the simplest behavioral showed that the same set of synaptic connections was reflex of Aplysia, could be modified by several different found to be able to participate in several different learnforms of learning—habituation, dishabituation, sensiti- ing processes and to be modified by them in opposite zation, classical conditioning, and operant conditioning directions. For example, the synaptic strength of a single (reviewed by Carew and Sahley, 1986). Moreover, each synaptic connection could be increased with sensitizaof these forms of learning could give rise to both short- tion and classical conditioning, and it could be deand long-term forms of nondeclarative memory as a creased with habituation (Castellucci et al., 1978; Carew function of the amount of repeated training. These stud- et al., 1979; Hawkins et al., 1983; Frost et al., 1985; ies suggested that an animal does not need a large brain Murphy and Glanzman, 1997; Bao et al., 1997, 1998)

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