Similarity in Form and Function of the Hippocampus in Rodents, Monkeys, and Humans

Similarity in form and function of the hippocampus in rodents, monkeys, and humans

Robert E. Clarka,b,1 and Larry R. Squirea,b,c,d

aVeterans Affairs Medical Center, San Diego, CA 92161; and Departments of bPsychiatry, cNeurosciences, and dPsychology, University of California at San Diego, La Jolla, CA 92093

Edited by Francisco J. Ayala, University of California, Irvine, CA, and approved March 26, 2013 (received for review February 13, 2013) We begin by describing an historical scientific debate in which the the following summary: “Man is the sole species of his genus, the fundamental idea that species are related by evolutionary descent sole representative of his order and subclass. Thus I trust has been was challenged. The challenge was based on supposed neuroan- furnished the confutation of the notion of a transformation of the atomical differences between humans and other primates with ape into man, which appears from a favourite old author to have respect to a structure known then as the hippocampus minor. The been entertained by some in his day” (2). debate took place in the early 1860s, just after the publication of It has been argued (3) that this reclassification must have been Darwin’s famous book. We then recount the difficult road that due, at least in part, to Owen’s knowledge of the forthcoming was traveled to develop an animal model of human memory im- publication of Charles Darwin’s On the Origin of Species (1). It pairment, a matter that also turned on questions about similarities was well known even before publication that Darwin’s book would and differences between humans and other primates. We then emphasize a clear physiological and anatomical relationship describe how the insight that there are multiple memory systems among species and argue that all species descended from common helped to secure the animal model and how the animal model was stock (in addition to proposing the theory of “natural selection” as ultimately used to identify the neuroanatomy of long-term declar- the mechanism for driving evolution). ative memory (sometimes termed explicit memory). Finally, we Owen based his new classification on three ostensible neuro- describe a challenge to the animal model and to cross-species anatomical differences in brain structure between humans and comparisons by considering the case of the concurrent discrim- other animals, including nonhuman primates. He suggested that ination task, drawing on findings from humans and monkeys. these three anatomical features were fundamental because these We suggest that analysis of such cases, based on the under- structures were not just different in humans and other primates standing that there are multiple memory systems with different but were found uniquely in the human brain (2). According to properties, has served to emphasize the similarities in memory Owen, the first fundamental difference between humans and ani- function across mammalian species. mals was that only in humans was there a posterior lobe. Specifically, only the human cerebrum extended over and beyond the extent of ere, we describe the successful development during the past the cerebellum. The second difference was that only humans have Hfew decades of a model of human memory and human memory a posterior horn or cornu of their lateral ventricles (a portion of the impairment in monkeys and rodents. This work, which focused on lateral ventricle that extends posteriorly and laterally). The third the hippocampus and anatomically related brain regions, provides and most important difference was that only humans have a hip- a robust illustration of similar neuroanatomy and function across pocampus minor. fl species. The expectation that the study of experimental animals Within the oor of the lateral ventricles are two prominent should yield insights into the organization of human memory is structures: a large structure referred to at that time as the hip- certainly reasonable when considered in the light of evolution and pocampus major (now known simply as the hippocampus) and evolutionary theory. Indeed, the central idea behind the study of a smaller structure known then as the hippocampus minor. The fl nonhuman mammals is the notion that what can be learned about hippocampus minor is a ridge in the oor of the posterior horn of mammalian behavior and mammalian brains can improve un- the lateral ventricle. The original term for the hippocampus derstanding of the human brain and the human condition. However, minor, and the term in current use, is the calcar avis. The calcar “ ’ ” this perspective was not so easily attained. We begin by describing avis is a Latin term meaning cock s spur due to its resemblance an historical scientific debate in which this fundamental idea (con- to the spurs found on rooster legs. Owen’s reclassification was met with a vigorous opposition, led tinuity between nonhumans and humans) was challenged on the – basis of supposed neuroanatomical differences between humans principally by Thomas Henry Huxley (1825 1895). Huxley was and other primates. The debate took place in the early 1860s, just a British biologist, paleontologist, and anatomist. In his lifetime, after the 1859 publication of Darwin’s On the Origin of Species (1). he served as President of the Royal Society, President of the We then describe the difficult road that was traveled to develop an Geological Society, and President of the British Association for the Advancement of Science, and he was one of Darwin’smost animal model of human memory impairment. vocal scientific supporters. The debate between Owen and Huxley Hippocampus Minor and Brain Anatomy was anticlimactic in one sense because Huxley was easily able to ’ In 1859, Sir Richard Owen (1804–1892), the renowned British demonstrate that Owen s three criteria, including the hippocampus minor, were not only identifiable in all primate species comparative anatomist and paleontologist, and superintendent of the Natural History Department of the British Museum, member of the Royal Society, and author of more than 600 scientific pub- This paper results from the Arthur M. Sackler Colloquium of the National Academy of lications, published a provocative and controversial paper (2). He Sciences, “In the Light of Evolution VII: The Human Mental Machinery,” held January argued that humans should be reclassified as distinct and separate 10–12, 2013, at the Arnold and Mabel Beckman Center of the National Academies of from other primates. Up to this point, Linnaeus classification had Sciences and Engineering in Irvine, CA. The complete program and audio files of most placed humans, apes, and monkeys into the single order Primates. presentations are available on the NAS Web site at www.nasonline.org/evolution_vii. Owen’s new classification created not only a new order for humans Author contributions: R.E.C. and L.R.S. wrote the paper. (Bimana “two-handed ones”) but a new subclass for humans The authors declare no conflict of interest. (Archencephala “ruling brain”), which placed humans well apart This article is a PNAS Direct Submission. from other primates. On the final page of his essay, Owen provided 1To whom correspondence should be addressed. E-mail: [email protected].

www.pnas.org/cgi/doi/10.1073/pnas.1301225110 PNAS Early Edition | 1of6 Downloaded by guest on October 1, 2021 available for study but that the relative size of the hippocampus could maintain and use information for a short time in immediate minor was larger in some primate species than in humans (4–6). memory (and working memory) so long as the material could be During the course of his investigations, Huxley also discovered that effectively rehearsed. With distraction, the information was lost. the hippocampal fissure in primates actually consisted of two sep- Third, medial temporal lobe structures are not the ultimate re- arate fissures. The more anterior fissure retained the name hip- pository of long-term memory because H.M.’s memory for remote pocampal fissure, whereas the more posterior fissure was renamed events remained largely intact. by Huxley as the calcarine sulcus because the calcar avis, or hip- At the time that H.M. was first described, the anatomy of the pocampus minor, is, in fact, formed by the deep inward penetration medial temporal lobe was poorly understood and it was not known of the calcarine sulcus (5). The hippocampus minor debate can be what specific damage (within the large region included in his sur- said to have concluded when Sir Charles Lyell, Great Britain’s gery) was responsible for his memory impairment. Accordingly, leading geologist and one of its most eminent scientists, reviewed in efforts were begun to address this question in experimental ani- detail the hippocampus minor debate (7). Lyell authoritatively mals. In fact, these efforts began almost immediately when Scoville concluded, without reservation, that the hippocampus minor de- himself went to Montreal and performed the same surgery in bate was settled in Huxley’s favor. Lyell’s conclusion was all the monkeys that he had performed with H.M (14). However, these more compelling because Lyell had not fully embraced Darwin’s monkeys and others with medial temporal lobe lesions were able to theory of evolution. learn tasks that seemed similar to tasks that H.M. could not learn. Despite its brief lifetime, the debate over the hippocampus The difficulty was that it was not yet appreciated that humans minor was important. It has been suggested by some historians (8, and experimental animals can approach ostensibly similar tasks 9) that Huxley intended to show not only that Owen was incorrect using different strategies (Multiple Memory Systems). For example, but that he must have been intentionally obfuscating the facts. monkeys learn visual discrimination tasks gradually over many Huxley admitted as much in a letter he sent to Sir Charles Lyell on trials in a fashion that is now referred to as habit learning. In the August 17, 1862 (the letter is reproduced in ref. 10). In this letter, monkey, this kind of learning depends on the basal ganglia rather Huxley references a line from a well-known poem by the noted than the medial temporal lobe (15, 16). By contrast, humans learn paleontologist, Sir Philip Egerton. Huxley wrote: “I do not think the same task by directly memorizing the stimulus material. In the you will find room to complain of any want of distinctness in my decade that followed H.M.’s initial description, extensive work definition of Owen’s position touching the Hippocampus ques- in rats with hippocampal lesions also failed to reproduce H.M.’s tion. I mean to give the whole history of the business in a note, so impairment. For example, rats with hippocampal lesions, like that the paraphrase of Sir Ph. Egerton’sline‘To which Huxley monkeys, performed normally on simple visual discrimination replies that Owen he lies,’ shall be unmistakable.” Huxley’s effort problems (17). Lesioned rats were also unimpaired at learning to damaged the scientific reputation of perhaps the most prominent press a bar for food and at various shock avoidance tasks (reviewed antievolutionist of the time and helped pave the way for the broad in ref. 18). In short, it was clear from the work carried out during scientific acceptance of evolution by scientists during the following the 1960s that the behavioral impairments observed in rats with decades (excellent reviews of the hippocampus minor debate are hippocampus lesions did not provide an adequate description of provided in refs. 3, 9). the memory impairment seen in humans with hippocampal dam- In the end, the hippocampus minor debate provided another age. Accordingly, investigators studying rats tended not to relate example of the similarities in neuroanatomical organization among their work to studies of memory-impaired patients and were more all primate species, including humans. The same would later prove likely to interpret their findings within the framework of response to be true for hippocampal function and for the organization of inhibition as first outlined by Pavlov (19). In fact, in a review of the long-term memory across species ranging from rodents to primates. literature on the hippocampus and behavior published a decade However, as described in the sections that follow, the continuity of after the description of H.M., Robert Douglas (18) wrote: memory function across species was in serious doubt for nearly Hippocampal lesions obviously do not impair learning in general, even two decades. when the learning involves retention for long periods of time. Thus, the animal and human data would appear to be in contradiction. This Hippocampus and the Modern Era of Memory Research contradiction could be ‘resolved’ by postulating that the hippocampus The modern era of memory research, and the first insights about the has a different basic function in man and beast. Such a solution to hippocampus and the organization of memory, began with the de- this problem is generally unacceptable to physiological psychologists, scription of patient H.M. by William Beecher Scoville and Brenda however. Another possible resolution of this paradox is that the recent Milner (11). Patient H.M. had a history of minor and major seizures memory loss in man is a secondary effect of a different type of primary that were unresponsive to antiepileptic medication. Eventually, with disorder. The author has chosen the latter course, and suggests that the consent of the family, the surgeon Scoville attempted to relieve the recent memory loss in man is a genuine phenomenon, but that it is a byproduct of interference during storage and not due to a lack of the seizures with an experimental surgical intervention that involved ability to store, per se. resecting the medial aspect of the temporal lobe bilaterally. Sub- sequently, MRI scans showed that the lesion was bilaterally sym- These comments made it clear that a large animal literature was metrical and included the medial temporal polar cortex, virtually all substantially out of register with the human work and that exper- the entorhinal cortex and amygdaloid complex, and the anterior half imentalists were beginning to doubt the basic idea that medial of the intraventricular aspect of the hippocampal formation [i.e., temporal lobe damage produced an impairment in memory. Fur- dentate gyrus (DG), hippocampus, subicular complex]. The peri- thermore, if one did suppose that medial temporal lobe damage in rhinal cortex was substantially damaged as well, with some sparing humans impaired memory, then to understand the data from of its ventrocaudal aspect (12). The surgery succeeded in that it animals, one must consider the possibility, however unsatisfactory, reduced the frequency and severity of the seizures, but it left H.M. that memory is organized differently in humans and other animals. with profound amnesia. The subsequent systematic evaluation of H.M. and other Multiple Memory Systems patients with similar damage established three fundamental During the 1960s and 1970s, it was not yet understood that dif- principles (13). First, memory is a distinct cerebral ability that ferent tasks of learning and memory could be supported by dif- is separate from other cognitive functions, such as perception, ferent brain systems. Many of the tasks given to animals with intelligence, personality, and motivation. Second, short-term hippocampal lesions were, in fact, skill-based tasks that amnesic memory and long-term memory are distinct functions, because patients would have been able to acquire (20), or they were tasks H.M. had severely impaired long-term memory. However, he that animals could learn as a skill even if humans tended to learn

2of6 | www.pnas.org/cgi/doi/10.1073/pnas.1301225110 Clark and Squire Downloaded by guest on October 1, 2021 the task by memorizing the material. Establishing an animal hyperactivity, increased distractibility, motor impairments, and model of human memory impairment would require developing other nonspecific effects). This study, and subsequent studies, that tasks for animals that assessed the same kind of memory that is relied especially on the DNMS task (27), documented the suc- impaired in humans after medial temporal lobe damage. cessful establishment of an animal model of human medial The kind of memory that is impaired is now typically referred temporal lobe amnesia. to as declarative memory (21). Declarative memory is flexibly The DNMS task with trial-unique stimuli was subsequently expressed and provides conscious access to facts and events. It is adapted for use with rats (28). This new task used trial-unique impaired when structures of the medial temporal lobe are dam- objects that could be displaced to obtain food rewards just as in the aged. In contrast, the term nondeclarative memory refers to version developed for monkeys (28). Additionally, the test appa- various acquired skills and abilities that are not accessible to ratus was designed so that the delay between the sample and choice conscious knowledge but are expressed through performance and phases could be as short as 4 s. Work with this task demonstrated depend on different brain systems (22). Nondeclarative memory that lesions of the hippocampus, or lesions of the cortical regions is independent of the medial temporal lobe. adjacent to the hippocampus, produced a delay-dependent mem- A key advance in establishing a model of human medial ory impairment similar to what had been reported in the monkey temporal lobe amnesia was the development of one-trial memory (29). Thus, this new task successfully extended the animal model of tests for the monkey. In 1974, Gaffan (23) suggested that many medial temporal lobe memory impairment to the rat. Further work tests of memory in animals with hippocampal damage might not with this task demonstrated that the impairment in rats with hip- be similar to the tests that reveal memory impairment in patients. pocampal lesions was unambiguously a delay-dependent memory Accordingly, if one intends to relate work in animals to work in impairment (30) and that delay dependence was not a simple humans, it is not adequate to use any convenient task in which an consequence of the large amount of training given at the short animal must utilize memory. Rather, one must use “specifically delay during learning of the nonmatching rule (31). designed animal analogs of those tests that do reveal impairment Since the successful establishment of the DNMS task, another in human amnesiacs” (23). One of the tests that Gaffan used was memory task has become widely used. This task allows one-trial a one-trial test of visual recognition memory, which had been learning to be studied in humans and experimental animals in refined for use in monkeys by Benjamin Weinstein (24). In this a straightforward and simple way (32). The visual paired-compari- test (initially referred to as the “matching-from-sample delayed son (VPC) task was initially developed to study the development of reaction procedure”), monkeys were presented with a single vision in human infants (33). In this task, two identical stimuli are object that they displaced for a food reward (the sample phase). presented side-by-side for a period (e.g., 1–2 min). Immediately Memory for the sample object was then tested after a delay by afterward, the infant is presented with the recently viewed stimulus presenting the sample object together with a new object (choice along with a novel stimulus. The finding is that infants preferentially phase). The monkey was trained to select (i.e., match) the object look at the novel stimulus, presumably because they remember the that had been presented previously during the sample phase. already presented and now less interesting stimulus. This work Unique objects were used on each trial so that judgment of fa- established the VPC task as a reliable test of visual recognition miliarity was sufficient to identify the correct object. The demand memory. The task takes advantage of a spontaneous preference for on memory could be increased by increasing the delay between novelty (which is preserved across mammalian species), and it has the sample and choice phases. This task became known as the the advantage of not requiring any verbal instruction or rule “delayed matching to sample” (DMS) task. Monkeys with lesions learning. This feature makes the task an excellent tool for studying of the fornix, thought to mimic the effects of hippocampal preverbal human infants and experimental animals. damage, impaired performance in a delay-dependent fashion. The VPC test was subsequently adapted for the monkey (34), the Performance was intact at a delay of 10 s but impaired at delays of rat (35), and the mouse (36). When used with primates, this task is 70 s and 130 s (23). generally referred to as the VPC task, because it is a test of visual An alternative version of the DMS task was also developed and recognition memory. In the rat and mouse, the animal physically referred to as the delayed nonmatching to sample (DNMS) task explores the objects so that visual, olfactory, and tactile information (25). In this case, monkeys were trained to select the new object can be used to guide performance during the test phase. Accord- during the choice phase (i.e., nonmatch the sample object). In ingly, in the rodent, this task is typically referred to with other a critical experiment (26), monkeys were given lesions designed to descriptors, such as “novel object recognition” (NOR), “novel ob- mimic the damage sustained by H.M. The key group received hip- ject preference,”“spontaneous object preference,” or “spontaneous pocampus plus amygdala lesions, together with the cortex un- object recognition.” Here, we refer to it as the NOR task. derlying these two structures. Other monkeys received smaller Recent findings with the VPC and NOR tasks are consistent with lesions of the hippocampus (and underlying cortex) or lesions of the findings using the DNMS task. For example, memory-impaired amygdala (and underlying cortex). Note that the underlying cortical patients with damage that included the hippocampus exhibited areas damaged by surgery were not specifically targeted but were memory impairment on the VPC test (37). Furthermore, monkeys damaged during the surgical approach to the hippocampus and (38), rats (39), and mice (40) with selective hippocampal damage, amygdala. Postoperatively, the animals reacquired the nonmatching or transient disruption of hippocampal function, exhibited delay- rule, and the delay between the sample and choice phases was then dependent memory impairments when tested with the VPC/NOR increased progressively from 10 s to 30 s, 60 s, and 120 s. The result task (a summary of the work in animals with hippocampal lesions is was that hippocampal or amygdala lesions (combined with the un- provided in refs. 41, 42). The NOR task has now largely replaced derlying cortical areas that were damaged in this study) yielded only the DNMS task for the assessment of recognition memory in the a mild impairment but that the combined lesion (hippocampus experimental animal (42, 43). plus amygdala and underlying cortex) produced a marked, delay- dependent deficit that was especially severe at the longer delays. Organization of Long-Term Declarative Memory The demonstration of delay-dependent impairments in perfor- Work in the experimental animal during the past three decades mance was critical for identifying this impairment as a memory used these tasks to identify a system of anatomically connected impairment. When performance is spared at short delays and se- structures in the medial temporal lobe that, when damaged, pro- lectively impaired at longer delays (when the demand on memory is duce memory impairment like the impairment first revealed by greatest), one can rule out a variety of alternative explanations for the study of H.M. (reviewed in ref. 32). The system of structures the impairment (e.g., the ability to identify objects; motivational important for memory includes the hippocampus and the adjacent changes; as well as secondary effects of the lesion, such as entorhinal, perirhinal, and parahippocampal cortices (44). The

Clark and Squire PNAS Early Edition | 3of6 Downloaded by guest on October 1, 2021 amygdala is not part of this system. Note also that in the rat, the parahippocampal cortex is referred to as the postrhinal cortex; however, anatomical organization is preserved across the three species (Fig. 1). The hippocampus, deﬁned here as the DG, cornu ammonis (CA)3, and CA1, is anatomically situated to receive highly processed information from widespread neocortical regions through three cortical areas, the entorhinal, perirhinal, and parahippocampal cortices, as well as through other direct projections to the entorhinal cortex from outside the temporal lobe (Fig. 2). The main pathway for the transmission of sensory information to the hippocampus is the entorhinal cortex. Layer II of the

Fig. 2. Schematic view of the connections within the medial temporal lobe memory system. The hippocampus, defined here as the DG, CA3, CA1, and subiculum (S), is anatomically situated to receive highly processed information from widespread neocortical regions through three temporal cortical areas, the entorhinal, perirhinal, and parahippocampal cortices (in the rat, the term postrhinal cortex replaces the term parahippocampal cortex), as well as through other direct projections to the entorhinal cortex from areas outside the temporal lobe. The figure shows a simplified view of the way in which information enters the hippocampus from the superficial layers (II and III) of the entorhinal cortex and then flows in a largely unidirectional feed-forward direction to return (predominantly) ultimately to the deep layers of entorhinal cortex (IV and V). The output and input layers refer to the entire entorhinal cortex and not to its medial or lateral subdivisions.

entorhinal cortex provides its major input. This unidirectional projection, forming part of the perforant pathway, provides a substantial input to the DG, which, in turn, provides the major input to CA3 via the mossy ﬁber projection. There is also a smaller unidirectional projection to CA3 from layer II of the entorhinal cortex. CA3 provides the major input to CA1 via the Schaffer collateral/ commissural pathway, but there is also a substantial recurrent as- sociational projection within the CA3 ﬁeld. CA1 also receives a direct projection from layer III of the entorhinal cortex, as does the subiculum (the temporoammonic pathway). Both the Schaffer collateral and temporoammonic projections to CA1 are unidirectional. CA1 primarily projects to the subiculum but also sends a projection to layer V of the entorhinal cortex. The subiculum sends projections primarily to layers IV and V of the entorhinal cortex (45). The hippocampus can be viewed as residing at the end of the Fig. 1. Ventral view of a human brain (Top), ventral view of a monkey brain processing hierarchy of the medial temporal lobe, receiving input (Middle), and lateral view of a rat brain (Bottom). The major cortical com- ponents of the medial temporal lobe are highlighted [perirhinal cortex (red), from both the perirhinal and parahippocampal cortices, as well as parahippocampal/postrhinal (blue), and entorhinal cortex (green)]. The or- the entorhinal cortex (Fig. 2). Guided by the anatomy, it seems ganization and connections of these structures are highly conserved across plausible that the hippocampus extends and combines functions these species. Brains are not drawn to scale. performed by the structures that project to it (41). Note also that

4of6 | www.pnas.org/cgi/doi/10.1073/pnas.1301225110 Clark and Squire Downloaded by guest on October 1, 2021 anatomical connections from different regions of neocortex enter selective damage to the caudate nucleus (50) were severely im- the medial temporal lobe at different points. Thus, the higher paired at learning the task. These findings suggested that monkeys visual areas TE and TEO project preferentially to the perirhinal learn the concurrent discrimination task via a trial-and-error, cortex. Conversely, spatial information that comes to the medial stimulus/response strategy that relies on nondeclarative memory. temporal lobe from parietal cortex arrives exclusively at the If so, the question naturally arises as to whether humans also have parahippocampal cortex. Consistent with these anatomical facts, a similar capacity for nondeclarative memory that could support damage to parahippocampal cortex was found to impair spatial learning of this same task. memory more than did damage to perirhinal cortex (46, 47), and To address this question, patients with large lesions of the me- damage to perirhinal cortex impaired performance on the visual dial temporal lobe, and essentially no residual declarative memory, DNMS task more than did damage to parahippocampal cortex were given extended training on the concurrent discrimination task (48). Finally, the relative segregation of visual and spatial in- over a period of several weeks (51). Fig. 3A shows the performance formation appears to be maintained within the entorhinal cor- of four control participants on the task. The controls learned the tex, such that the lateral entorhinal cortex processes more visual task easily within three sessions. One key feature of declarative information and the medial entorhinal cortex processes more memory is that it can be expressed flexibly. To demonstrate this spatial information. feature, the controls were given a sorting task 3–6 d after learning. The 16 objects used in this task were placed together on a table, Challenge to the Animal Model and to Cross-Species and participants were told that some of the objects had been Comparisons consistently designated as correct. They were then asked to sort the As discussed earlier, during the 1960s and early 1970s, the de- objects, placing the correct objects to one side of the table and the velopment of an animal model of human memory and human other objects to the other side. Fig. 3A shows that controls had no memory impairment was challenged by the fact that animals could difficulty with this modification of the task. use nondeclarative memory to solve some memory tasks that By contrast, patient E.P. gradually learned the object pairs humans typically approached using declarative memory. It there- across 36 test sessions (Fig. 3B) but then failed the sorting task fore became important to understand under what conditions this altogether 5 d later. Nonetheless, immediately afterward, E.P. occurs and to identify what kind of memory is used in each case. performed well in the standard task format (Fig. 3B). Seventeen This issue can be illustrated by considering concurrent discrimi- days later, E.P. again failed the sorting task but performed well nation learning, a standard task that has been used to study mam- in the original task format. The results for patient G.P. were malian memory for more than 50 y. In a common version of the task, essentially the same as for E.P. (Fig. 3C). eight pairs of objects are presented side-by-side five times each day, Some informal observations are informative. At the beginning one pair at a time in a mixed order, for a total of 40 trials. One object of each testing day, the patients were asked about the objects and in each pair is always correct, and a choice of the correct object about what had occurred on previous visits. However, they were yields a reward. The left/right position of the correct object varies never able to remember anything about earlier test sessions and randomly across trials. Humans readily learn this task, performing at could not describe how the objects had been used. Nonetheless, a level better than 80% correct after only 1 or 2 d of training (49). as training proceeded from day to day, both patients (without That performance ordinarily depends on declarative memory, and explicit instructions about what to do on each trial) readily on memorizing which object is correct in each pair, is demonstrated picked up one of the objects in each pair and turned it over to by the fact that task performance was correlated highly with the receive feedback (the word “correct” or “incorrect” was printed ability to describe the objects and by the fact that memory- under the base of each object). impaired patients performed poorly during the period that their Thus, both patients gradually acquired the standard eight-pair controls mastered the task. In contrast, this same task was ac- object discrimination task over many weeks; however, at the start quired at a normal rate by monkeys with hippocampal lesions of each session, they could not describe the task, the instructions, (16). Importantly, monkeys with hippocampal damage that also or the objects. The acquired knowledge was rigidly organized, included damage to the caudate nucleus (16) or monkeys with and performance collapsed when the task format was altered. The

Fig. 3. Performance on the concurrent discrimination task. (A) Controls (n = 4) learned the task easily within three sessions and performed well on the sorting task 3–6 d later (gray bar). The black bar shows performance immediately afterward, when participants were asked to verbalize their choices rather than reach for objects. Results are means ± SEM. (B) Patient E.P. gradually learned the object pairs across 18 wk. Five days later, he failed the sorting task (gray bar) but then, immediately afterward, performed well in the standard task format while verbalizing his responses (black bar). Seventeen days later, E.P. again failed the sorting task (gray bar) but performed perfectly when 40 trials were given exactly as in original training (white bar). (C) Patient G.P. learned the object pairs gradually during 14 wk. Like E.P., he failed the sorting task on two different occasions, 5 d after training and again 17 d later. In both instances, he performed well immediately afterward when the original task format was reinstated [verbalizing (black bar), standard task (white bar)]. The dashed line indicates chance performance (50% correct). Reproduced from ref. 51.

Clark and Squire PNAS Early Edition | 5of6 Downloaded by guest on October 1, 2021 findings indicate that humans possess a robust capacity for gradual anatomy and organization of mammalian memory. Still, challenges trial-and-error learning that can operate outside awareness for what can arise because these species have evolved under different selec- is learned and independent of the medial temporal lobe. What is tion pressures that can bias them to approach tasks with different fl acquired is in exible and altogether different from declarative strategies than the strategies used by humans. Analysis of such cases, fi memory. These ndings show that humans possess a nondeclarative based on our understanding that there are multiple memory systems learning system like other primates and suggest what the charac- with different properties, has, in the end, served to emphasize the teristics of this system are likely to be (e.g., inflexible, inaccessible similarities in memory function across mammalian species. to awareness). In summary, the development of a model of human memory ACKNOWLEDGMENTS. This work was supported by the Medical Research and human memory impairment in the monkey and rat is a suc- Service of the Department of Veterans Affairs, National Science Foundation cess story, and the work has provided important insight into the Grant 1120395, and National Institute of Mental Health Grant 24600.

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