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A degraded, black-and-white image of an object, which appears meaningless on first presentation, is easily identified after a single exposure to the original, intact image. This striking example of perceptual learning reflects a rapid (one-trial) change in performance, but the kind of learning that is involved is not known. We asked whether this learning depends on conscious (hippocampus-dependent) memory for the images that have been presented or on an unconscious (hippocampus-independent) change in the perception of images, independently of the ability to remember them. We tested five memory-impaired patients with hippocampal lesions or larger medial temporal lobe (MTL) lesions. In comparison to volunteers, the patients were fully intact at perceptual learning, and their improvement persisted without decrement from 1 d to more than 5 mo. Yet, the patients were impaired at remembering the test format and, even after 1 d, were impaired at remembering the images themselves. To compare perceptual learning and remembering directly, at 7 d after seeing degraded images and their solutions, patients and volunteers took either a naming test or a recognition memory test with these images. The patients improved as much as the volunteers at identifying the degraded images but were severely impaired at remembering them. Notably, the patient with the most severe memory impairment and the largest MTL lesions performed worse than the other patients on the memory tests but was the best at perceptual learning. The findings show that one-trial, long-lasting perceptual learning relies on hippocampus-independent (nondeclarative) memory, independent of any requirement to consciously remember., Competing Interests: The authors declare no competing interest.

Encoding activity in the medial temporal lobe, presumably evoked by the presentation of stimuli (postonset activity), is known to predict subsequent memory. However, several independent lines of research suggest that preonset activity also affects subsequent memory. We investigated the role of preonset and postonset single-unit and multiunit activity recorded from epilepsy patients as they completed a continuous recognition task. In this task, words were presented in a continuous series and eventually began to repeat. For each word, the patient's task was to decide whether it was novel or repeated. We found that preonset spiking activity in the hippocampus (when the word was novel) predicted subsequent memory (when the word was later repeated). Postonset activity during encoding also predicted subsequent memory, but was simply a continuation of preonset activity. The predictive effect of preonset spiking activity was much stronger in the hippocampus than in three other brain regions (amygdala, anterior cingulate, and prefrontal cortex). In addition, preonset and postonset activity around the encoding of novel words did not predict memory performance for novel words (i.e., correctly classifying the word as novel), and preonset and postonset activity around the time of retrieval did not predict memory performance for repeated words (i.e., correctly classifying the word as repeated). Thus, the only predictive effect was between preonset activity (along with its postonset continuation) at the time of encoding and subsequent memory. Taken together, these findings indicate that preonset hippocampal activity does not reflect general arousal/attention but instead reflects what we term "attention to encoding.", Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

We explored the relationship between memory performance and conscious knowledge (or awareness) of what has been learned in memory-impaired patients with hippocampal lesions or larger medial temporal lesions. Participants viewed familiar scenes or familiar scenes where a change had been introduced. Patients identified many fewer of the changes than controls. Across all of the scenes, controls preferentially directed their gaze toward the regions that had been changed whenever they had what we term robust knowledge about the change: They could identify that a change occurred, report what had changed, and indicate where the change occurred. Preferential looking did not occur when they were unaware of the change or had only partial knowledge about it. The patients, overall, did not direct their gaze toward the regions that had been changed, but on the few occasions when they had robust knowledge about the change they (like controls) did exhibit this effect. Patients did not exhibit this effect when they were unaware of the change or had partial knowledge. The findings support the idea that awareness of what has been learned is a key feature of hippocampus-dependent memory., Competing Interests: The authors declare no conflict of interest.

When individuals select the recently studied (and familiar) item in a multiple-choice memory test, they direct a greater proportion of viewing time toward the to-be-selected item when their choice is correct than when their choice is incorrect. Thus, for both correct and incorrect choices, individuals indicate that the chosen item is old, but viewing time nevertheless distinguishes between old and new items. What kind of memory supports this preferential viewing effect? We recorded eye movements while participants made three-alternative, forced-choice recognition memory judgments for scenes. In experiment 1 ( n = 30), the magnitude of the preferential viewing effect was strongly correlated with measures of conscious, declarative memory: recognition accuracy as well as the difference in confidence ratings and in response times for correct and incorrect choices. In four analyses that minimized the contribution of declarative memory in order to detect a possible contribution from other processes, the preferential viewing effect was absent. In experiment 2, five memory-impaired patients with medial temporal lobe lesions exhibited a diminished preferential viewing effect. These patients also exhibited poor recognition accuracy and reduced differences in confidence ratings and response times for correct and incorrect choices. We propose that the preferential viewing effect is a phenomenon of conscious, declarative memory and is dependent on the medial temporal lobe. The findings support the link between medial temporal lobe function and declarative memory. When the effects of experience depend on the medial temporal lobe, the effects reflect conscious memory., Competing Interests: The authors declare no conflict of interest.

Eye movements can reflect memory. For example, participants make fewer fixations and sample fewer regions when viewing old versus new scenes (the repetition effect). It is unclear whether the repetition effect requires that participants have knowledge (awareness) of the old-new status of the scenes or if it can occur independent of knowledge about old-new status. It is also unclear whether the repetition effect is hippocampus-dependent or hippocampus-independent. A complication is that testing conscious memory for the scenes might interfere with the expression of unconscious (unaware), experience-dependent eye movements. In experiment 1, 75 volunteers freely viewed old and new scenes without knowledge that memory for the scenes would later be tested. Participants then made memory judgments and confidence judgments for each scene during a surprise recognition memory test. Participants exhibited the repetition effect regardless of the accuracy or confidence associated with their memory judgments (i.e., the repetition effect was independent of their awareness of the old-new status of each scene). In experiment 2, five memory-impaired patients with medial temporal lobe damage and six controls also viewed old and new scenes without expectation of memory testing. Both groups exhibited the repetition effect, even though the patients were impaired at recognizing which scenes were old and which were new. Thus, when participants viewed scenes without expectation of memory testing, eye movements associated with old and new scenes reflected unconscious, hippocampus-independent memory. These findings are consistent with the formulation that, when memory is expressed independent of awareness, memory is hippocampus-independent., (Published by Cold Spring Harbor Laboratory Press.)

In earlier work, patients with hippocampal damage successfully path integrated, apparently by maintaining spatial information in working memory. In contrast, rats with hippocampal damage were unable to path integrate, even when the paths were simple and working memory might have been expected to support performance. We considered possible ways to understand these findings. We tested rats with either hippocampal lesions or lesions of medial prefrontal cortex (mPFC) on three tasks of spatial or nonspatial memory: path integration, spatial alternation, and a nonspatial alternation task. Rats with mPFC lesions were impaired on both spatial and nonspatial alternation but performed normally on path integration. By contrast, rats with hippocampal lesions were impaired on path integration and spatial alternation but performed normally on nonspatial alternation. We propose that rodent neocortex is limited in its ability to construct a coherent spatial working memory of complex environments. Accordingly, in tasks such as path integration and spatial alternation, working memory cannot depend on neocortex alone. Rats may accomplish many spatial memory tasks by relying on long-term memory. Alternatively, they may accomplish these tasks within working memory through sustained coordination between hippocampus and other cortical brain regions such as mPFC, in the case of spatial alternation, or parietal cortex in the case of path integration. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Conscious memory for a new experience is initially dependent on information stored in both the hippocampus and neocortex. Systems consolidation is the process by which the hippocampus guides the reorganization of the information stored in the neocortex such that it eventually becomes independent of the hippocampus. Early evidence for systems consolidation was provided by studies of retrograde amnesia, which found that damage to the hippocampus-impaired memories formed in the recent past, but typically spared memories formed in the more remote past. Systems consolidation has been found to occur for both episodic and semantic memories and for both spatial and nonspatial memories, although empirical inconsistencies and theoretical disagreements remain about these issues. Recent work has begun to characterize the neural mechanisms that underlie the dialogue between the hippocampus and neocortex (e.g., "neural replay," which occurs during sharp wave ripple activity). New work has also identified variables, such as the amount of preexisting knowledge, that affect the rate of consolidation. The increasing use of molecular genetic tools (e.g., optogenetics) can be expected to further improve understanding of the neural mechanisms underlying consolidation., (Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.)

We evaluated two different perspectives about the function of the human hippocampus--one that emphasizes the importance of memory and another that emphasizes the importance of spatial processing and scene construction. We gave tests of boundary extension, scene construction, and memory to patients with lesions limited to the hippocampus or large lesions of the medial temporal lobe. The patients were intact on all of the spatial tasks and impaired on all of the memory tasks. We discuss earlier studies that associated performance on these spatial tasks to hippocampal function. Our results demonstrate the importance of medial temporal lobe structures for memory and raise doubts about the idea that these structures have a prominent role in spatial cognition.

Hippocampal damage has been thought to result in broad memory impairment. Recent studies in humans, however, have raised the possibility that recognition memory for faces might be spared. In five experiments we investigated face recognition in patients with hippocampal lesions (H) or large medial temporal lobe (MTL) lesions, including patients where neurohistological information was available. Recognition of novel faces was unequivocally intact in H patients but only at a short retention interval. Recognition memory for words, buildings, inverted faces, and famous faces was impaired. For MTL patients, recognition memory was impaired for all materials and across all retention intervals. These results indicate that structures other than the hippocampus, perhaps the perirhinal cortex, can support face recognition memory in H patients under some conditions. The fact that the faces were novel when recognition memory was intact does not fully account for our findings. We propose that the role of the hippocampus in recognition memory is related to how recognition decisions are accomplished. In typical recognition tasks, participants proceed by forming an association between a study item and the study list, and the recognition decision is later made based on whether participants believe the item was on the study list. We suggest that face recognition is an exception to this principle and that, at short retention intervals, participants can make their recognition decisions without making explicit reference to the study list. Important features of faces that might make face recognition exceptional are that they are processed holistically and are difficult to verbally label.

Declarative memory for rapidly learned, novel associations is thought to depend on structures in the medial temporal lobe (MTL), whereas associations learned more gradually can sometimes be supported by nondeclarative memory and by structures outside the MTL. A recent study suggested that even rapidly learned associations can be supported by structures outside the MTL when an incidental encoding procedure termed "fast mapping" (FM) is used. We tested six memory-impaired patients with bilateral damage to hippocampus and one patient with large bilateral lesions of the MTL. Participants saw photographs and names of animals, plants, and foods that were previously unfamiliar (e.g., mangosteen). Instead of asking participants to study name-object pairings for a later memory test (as with traditional memory instructions), participants answered questions that allowed them to infer which object corresponded to a particular name. In a second condition, participants learned name-object associations of unfamiliar items by using standard, explicit encoding instructions (e.g., remember the mangosteen). In FM and explicit encoding conditions, patients were impaired (and performed no better than a group that was given the same tests but had not previously studied the material). The same results were obtained in a second experiment that used the same procedures with modifications to allow for more robust learning and more reliable measures of performance. Thus, our results with the FM procedure and memory-impaired patients yielded the same deficits in learning and memory that have been obtained by using other more traditional paradigms.

In four experiments, we explored the capacity for spatial mental imagery in patients with hippocampal lesions, using tasks that minimized the role of learning and memory. On all four tasks, patients with hippocampal lesions performed as well as controls. Nonetheless, in separate tests, the patients were impaired at remembering the materials that had been used to assess mental imagery. The findings suggest that the hippocampus is not needed for constructing many forms of spatial imagery but is needed for the formation of long-term memory. In future studies of the neural organization of spatial mental imagery, it will be important to separate the contribution of spatial processing from the contribution of learning and memory.

We tested proposals that medial temporal lobe (MTL) structures support not just memory but certain kinds of visual perception as well. Patients with hippocampal lesions or larger MTL lesions attempted to identify the unique object among twin pairs of objects that had a high degree of feature overlap. Patients were markedly impaired under the more difficult task conditions. However, the deficit was fully rescued when patients used a pencil to draw lines between the twin pairs, thereby eliminating the need to hold material in memory as they worked at each display. The perceptual demands of the task were presumably the same with or without this memory aid. Accordingly, the results suggest that the deficit on this and similar tasks, which involve comparisons across stimuli, are better understood in terms of impaired memory rather than impaired perception.

The hippocampus and other medial temporal lobe structures have been linked to both memory and spatial cognition, but it has been unclear how these ideas are connected. We carried out parallel studies of path integration in patients with medial temporal lobe lesions and rats with hippocampal lesions. Subjects entered a circular arena without vision, searched for a target, and then attempted to return to the start location. Patients performed accurately, and as well as controls, so long as the outward path was relatively direct and the target was found within 20 s. In sharp contrast, rats with hippocampal lesions were impaired, even when the outward path was shorter than 1 m, involved no turns, and the target was found within 3 s. We suggest that patients succeeded because performance could be supported by working memory and that patients and rats differ after hippocampal lesions in their ability to construct a coherent working memory of spatial environments.

We evaluated recent proposals that structures in the medial temporal lobe (MTL)--in particular, perirhinal cortex--support not just memory but certain kinds of perceptual abilities as well. Specifically, it has been suggested that the perirhinal cortex supports the perceptual abilities needed to accomplish visual discrimination performance when the stimuli have complex features and overlapping elements. However, the tasks that have been studied are quite challenging. Stimulus features must be held in working memory while attention shifts among the several parts of the display. When working memory capacity is exceeded, performance must depend on retrieval from long-term memory. Five patients with limited hippocampal lesions and one patient with large MTL lesions were asked to identify the unique object among twin pairs of objects that had a high degree of feature overlap and perceptual similarity. The patient groups performed similarly to controls when there were few objects and features in the displays, but exhibited abrupt declines in performance when the displays contained more objects and more features. Notably, the impairment was observed in memory-impaired patients with hippocampal lesions, not only in association with large MTL lesions that included perirhinal cortex. The pattern of performance suggested that patients encountered difficulty because working memory capacity was exceeded in the more difficult conditions such that performance needed to depend at least in part on long-term memory. Furthermore, when the burden on working memory was removed entirely, the patient with large MTL lesions performed as well as controls. Accordingly, we suggest that deficits on difficult discrimination tasks reported for patients with MTL lesions are due to impaired memory rather than impaired perception.

Neuroimaging and lesion studies have seemed to converge on the idea that the hippocampus selectively supports recollection. However, these studies usually involve a comparison between strong recollection-based memories and weak familiarity-based memories. Studies that avoid confounding memory strength with recollection and familiarity almost always find that the hippocampus supports both recollection and familiarity. We argue that the functional organization of the medial temporal lobe (MTL) is unlikely to be illuminated by the psychological distinction between recollection and familiarity and will be better informed by findings from neuroanatomy and neurophysiology. These findings indicate that the different structures of the MTL process different attributes of experience. By representing the widest array of attributes, the hippocampus supports recollection-based and familiarity-based memory of multiattribute stimuli., (Published by Elsevier Ltd.)

Work with patient H.M., beginning in the 1950s, established key principles about the organization of memory that inspired decades of experimental work. Since H.M., the study of human memory and its disorders has continued to yield new insights and to improve understanding of the structure and organization of memory. Here we review this work with emphasis on the neuroanatomy of medial temporal lobe and diencephalic structures important for memory, multiple memory systems, visual perception, immediate memory, memory consolidation, the locus of long-term memory storage, the concepts of recollection and familiarity, and the question of how different medial temporal lobe structures may contribute differently to memory functions.

Memories are initially stored in a labile state and are subject to modification by a variety of treatments, including disruption of hippocampal function. We infused a sodium channel blocker (or CNQX) to inactivate the rat dorsal hippocampus reversibly for 1 week following training on a task of spatial memory (the water maze). Previous work with conventional lesions has established that the dorsal hippocampus is essential for both the acquisition and expression of memory in this task. The question in the present study was whether chronic disruption of neuronal activity in the dorsal hippocampus after training would abolish memory or whether memory would survive extended disruption of hippocampal activity. As expected from earlier work, we found that performance was impaired during the infusion period. The critical test occurred 1 week after the lesion was reversed. We found that retention of the water maze recovered to control levels. Accordingly, sustained hippocampal activity following training is not obligatory for either the maintenance of long-term spatial memory or its subsequent retrieval., (Copyright © 2009 Wiley-Liss, Inc.)

It has been proposed that a core network of brain regions, including the hippocampus, supports both past remembering and future imagining. We investigated the importance of the hippocampus for these functions. Five patients with bilateral hippocampal damage and one patient with large medial temporal lobe lesions were tested for their ability to recount autobiographical episodes from the remote past, the recent past, and to imagine plausible episodes in the near future. The patients with hippocampal damage had intact remote autobiographical memory, modestly impaired recent memory, and an intact ability to imagine the future. The patient with large medial temporal lobe lesions had intact remote memory, markedly impaired recent memory, and also had an intact ability to imagine the future. The findings suggest that the capacity for imagining the future, like the capacity for remembering the remote past, is independent of the hippocampus.

fMRI studies of recognition memory have often been interpreted to mean that the hippocampus selectively subserves recollection and that adjacent regions selectively subserve familiarity. Yet, many of these studies have confounded recollection and familiarity with strong and weak memories. In a source memory experiment, we compared correct source judgments (which reflect recollection) and incorrect source judgments (often thought to reflect familiarity) while equating for old-new memory strength by including only high-confidence hits in the analysis. Hippocampal activity associated with both correct source judgments and incorrect source judgments exceeded the activity associated with forgotten items and did so to a similar extent. Further, hippocampal activity was greater for high-confidence old decisions relative to forgotten items even when source decisions were at chance. These results identify a recollection signal in the hippocampus and may identify a familiarity signal as well. Similar results were obtained in the parahippocampal gyrus. Unlike in the medial temporal lobe, activation in prefrontal cortex increased differentially in association with source recollection.

In rodents, the novel object recognition task (NOR) has become a benchmark task for assessing recognition memory. Yet, despite its widespread use, a consensus has not developed about which brain structures are important for task performance. We assessed both the anterograde and retrograde effects of hippocampal lesions on performance in the NOR task. Rats received 12 5-min exposures to two identical objects and then received either bilateral lesions of the hippocampus or sham surgery 1 d, 4 wk, or 8 wk after the final exposure. On a retention test 2 wk after surgery, the 1-d and 4-wk hippocampal lesion groups exhibited impaired object recognition memory. In contrast, the 8-wk hippocampal lesion group performed similarly to controls, and both groups exhibited a preference for the novel object. These same rats were then given four postoperative tests using unique object pairs and a 3-h delay between the exposure phase and the test phase. Hippocampal lesions produced moderate and reliable memory impairment. The results suggest that the hippocampus is important for object recognition memory.

New granule cells are born throughout life in the dentate gyrus of the hippocampal formation. Given the fundamental role of the hippocampus in processes underlying certain forms of learning and memory, it has been speculated that newborn granule cells contribute to cognition. However, previous strategies aiming to causally link newborn neurons with hippocampal function used ablation strategies that were not exclusive to the hippocampus or that were associated with substantial side effects, such as inflammation. We here used a lentiviral approach to specifically block neurogenesis in the dentate gyrus of adult male rats by inhibiting WNT signaling, which is critically involved in the generation of newborn neurons, using a dominant-negative WNT (dnWNT). We found a level-dependent effect of adult neurogenesis on the long-term retention of spatial memory in the water maze task, as rats with substantially reduced levels of newborn neurons showed less preference for the target zone in probe trials >2 wk after acquisition compared with control rats. Furthermore, animals with strongly reduced levels of neurogenesis were impaired in a hippocampus-dependent object recognition task. Social transmission of food preference, a behavioral test that also depends on hippocampal function, was not affected by knockdown of neurogenesis. Here we identified a role for newborn neurons in distinct aspects of hippocampal function that will set the ground to further elucidate, using experimental and computational strategies, the mechanism by which newborn neurons contribute to behavior.

H.M. is probably the best known single patient in the history of neuroscience. His severe memory impairment, which resulted from experimental neurosurgery to control seizures, was the subject of study for five decades until his death in December 2008. Work with H.M. established fundamental principles about how memory functions are organized in the brain.

We investigated the relationship between experience-dependent eye movements, hippocampus-dependent memory, and aware memory. We measured eye movements in young adults, older adults, and memory-impaired patients with damage to the medial temporal lobe as they viewed 120 novel scenes and 120 previously viewed scenes. Participants indicated if each scene was old or new and also gave a confidence rating for the memory judgment. Young adults and older adults explored old scenes less than they explored new scenes, but the patients did not. For the young and older adults, this effect was observed only when participants were aware of the scene's familiar or novel status. In a second experiment, young adults viewed scenes that were either new, had been viewed previously, or had been viewed previously but had been changed (i.e., an object within the scene was either added or removed). The only instructions were to pay attention to the scenes and view each scene as it appeared, and there was no expectation that memory would be tested. Directly after the first altered scene was presented, participants were asked to classify the scene as new, old, or old but changed. Participants who were aware of the manipulation preferentially viewed the changed region, but participants who were unaware did not. These findings suggest that experience-dependent eye movements reflect hippocampus-dependent (and aware) memory, even when participants have no expectation that memory is being tested; and they are consistent with the view that awareness of what is learned is a fundamental characteristic of hippocampus-dependent memory.

Functional magnetic resonance imaging studies of recognition memory have often been interpreted to mean that the hippocampus supports recollection and that the adjacent perirhinal cortex supports familiarity. Other work points out that these studies have confounded recollection and familiarity with strong and weak memories. In a source memory study, we used two novel approaches to data analysis that allowed item memory strength and source memory strength to be assessed independently. First, we identified regions in both hippocampus and perirhinal cortex in which activity varied as a function of subsequent item memory strength while source memory strength was held constant at chance levels. Second, we identified regions in prefrontal cortex in which activity varied as a function of subsequent source memory strength while item memory strength was held constant. These findings suggest that activity in the medial temporal lobe is predictive of subsequent memory strength, whereas activity in prefrontal cortex is predictive of subsequent recollection.

Previous findings of intact remote autobiographical memory in patients with medial temporal lobe damage have been questioned on the grounds that the narrative recollections were impoverished and fact-like and that the methods were not sufficiently sensitive to detect an impairment. We adopted a newer method, the Autobiographical Interview [Levine B, Svoboda E, Hay JF, Winocur G, Moscovitch M (2002) Psychol Aging 17:677-689], which uses extensive probing to elicit an average of 50 or more details per memory (in contrast to the approximately 20 details per memory elicited with previous methods). We found that autobiographical recollection was impaired in patients with medial temporal lobe damage when memories were drawn from the recent past but fully intact when memories were drawn from the remote past. Impaired remote autobiographical memory, which has sometimes been reported with this and other tests, is likely caused by significant damage outside the medial temporal lobe.

We acquired large data sets of calendar performance from two autistic calendar savants, DG and RN. An analysis of their errors and reaction times revealed that (1) both individuals had knowledge of calendar information from a limited range of years; (2) there was no evidence for the use of memorized anchor dates that could, by virtue of counting away from the anchors, allow correct responses to questions about other dates; and (3) the two individuals differed in their calendar knowledge, as well as in their ability to perform secondary tasks in which calendar knowledge was assessed indirectly. In view of the fact that there are only 14 possible annual calendars, we suggest that both savants worked by memorizing these 14 possible calendar arrangements.

For many tasks and species, remote memory (but not recent memory) is spared after damage to the hippocampus. An exception to this pattern of findings has been that both recent and remote memory are impaired after hippocampal lesions when rats are trained in the conventional water maze task. We explored the effect of introducing a navigational beacon for rats to use during testing. Four identical beacons were hung directly over each of the water maze quadrants, equidistant from each other (multiple-beacon maze). One of the beacons was always directly over the hidden platform. By using distal spatial cues, rats could select the correct beacon and use that beacon as a guide to the hidden platform. Probe tests indicated that rats did use the beacons to guide performance throughout training. Two months after the completion of training, rats were given hippocampal or sham lesions. Controls performed well, but the lesion group performed at chance on the retention probe trials. Furthermore, the rats with lesions not only searched indiscriminately in all four quadrants, they also did not use the beacons. These results indicate that impaired performance in the water maze after hippocampal damage reflects more than a loss of spatial information.

Recently, there has been renewed interest in the organization and neurobiology of remote memory, and the pace of work in this area has accelerated. Yet the recent literature does not suggest that a consensus is developing, and there is disagreement about both facts and their interpretation. This article undertakes a comprehensive review of the three kinds of evidence that have been most prominent in recent discussion: studies of retrograde amnesia in memory-impaired patients who have well-characterized lesions, neuroimaging of healthy volunteers, and work with experimental animals including lesion studies, imaging and mouse genetics. The available evidence tells a coherent story and leads to some straightforward conclusions about the neuroscience of remote memory.

We explored the circumstances in which rats engage either declarative memory (and the hippocampus) or habit memory (and the dorsal striatum). Rats with damage to the hippocampus or dorsal striatum were given three different two-choice discrimination tasks (odor, object, and pattern). These tasks differed in the number of trials required for learning (approximately 10, 60, and 220 trials). Dorsal striatum lesions impaired discrimination performance to a greater extent than hippocampal lesions. Strikingly, performance on the task learned most rapidly (the odor discrimination) was severely impaired by dorsal striatum lesions and entirely spared by hippocampal lesions. These findings suggest that discrimination learning in the rat is primarily supported by the dorsal striatum (and habit memory) and that rats engage a habit-based memory system even for a task that takes only a few trials to acquire. Considered together with related studies of humans and nonhuman primates, the findings suggest that different species will approach the same task in different ways.

The hippocampus and adjacent medial temporal lobe structures are known to support declarative memory, but there is not consensus about what memory functions the hippocampus might support that are distinct from the functions of the adjacent cortex. One idea is that the hippocampus is specifically important for allocentric spatial memory, e.g., the hippocampus is especially needed to remember object locations when there is a shift in viewpoint between study and test. We tested this proposal in two experiments. Patients with damage limited to the hippocampus were given memory tests for object locations in a virtual environment. In the first experiment, participants studied locations of a variable number of images (one to five) and tried to remember the image locations from either the same viewpoint as during study (shift of 0 degrees) or a different viewpoint (shift of 55 degrees, 85 degrees, or 140 degrees). In each viewpoint condition (shifts of 0 degrees, 55 degrees, 85 degrees, and 140 degrees), patients performed normally when remembering one or two image locations. Further, performance declined to a similar degree in each viewpoint condition as patients tried to remember increasing numbers of image locations. In the second experiment, participants tried to remember four images after viewpoint shifts of 0 degrees, 55 degrees, 85 degrees, or 140 degrees. Patients were mildly impaired at all conditions (shifts of 0 degrees, 55 degrees, 85 degrees, and 140 degrees), and the impairment was no greater when viewpoint shifted. We conclude that damage to the hippocampus does not selectively impair viewpoint-independent spatial memory. Rather, hippocampal damage impairs memory as the memory load increases.

Damage to the hippocampal region and related medial temporal lobe structures (perirhinal, entorhinal, and parahippocampal cortices) impairs new learning (anterograde amnesia) as well as memory for information that was acquired before the damage occurred (retrograde amnesia). We assessed retrograde amnesia with the Autobiographical Memory Interview (AMI) and with a news events test in six patients with damage limited primarily to the hippocampal region (H group) and two patients with large medial temporal lobe lesions (MTL group). On the news event test, the H group exhibited temporally limited retrograde amnesia covering approximately 5 years. On the same test, the MTL group exhibited an extensive retrograde amnesia covering decades. Nevertheless, performance was relatively spared for very remote time periods. On the AMI, all patients had intact remote autobiographical memory. Because our patients with hippocampal lesions, as well as our patients with large MTL lesions, performed normally on the AMI, patients who perform poorly on the same test presumably have damage beyond the hippocampus and related structures in the medial temporal lobe. The findings emphasize the difference in the extent of retrograde amnesia associated with hippocampal lesions and large MTL lesions.

We asked what kind of memory is operating when eye movements change as the result of experience. Participants viewed scenes that were either novel, repeated, or manipulated (i.e., a change was introduced in one region of the scene). Eye movements differed depending on the past viewing history of each scene. Participants made fewer fixations and sampled fewer regions when scenes were repeated than when scenes were novel. When scenes were altered, participants made more fixations in the altered region, spent more time looking at the altered region, and made more transitions into and out of the altered region than in unchanged (matched) regions in the repeated scenes. Importantly, these effects occurred only when individuals were aware that a change had occurred. Participants who were unaware that the scene had been altered looked at the changed scenes in the same way that they looked at repeated scenes. Thus, there was no indication that eye movements could reveal an unaware (unconscious) form of memory. Instead, eye movements reflected conscious memory of whether the scene was repeated or manipulated. The findings were the same when awareness was assessed after viewing all the scenes (experiment 1) and when awareness was assessed after each scene was presented (experiment 2). In experiment 3, memory-impaired patients with damage limited to the hippocampus were impaired at deciding whether scenes were novel, repeated, or manipulated. Thus, the ability to consciously recollect recent encounters with scenes reflects a form of hippocampus-dependent memory. The findings show that experience-dependent eye movements in response to altered scenes reflect conscious, declarative memory, and they support the link between aware memory, declarative memory, and hippocampus-dependent memory.

Studies of memory impairment in humans and experimental animals have been fundamental to learning about the organization of memory and its cellular and molecular substrates. When memory impairment occurs, especially after perturbations of the nervous system, the question inevitably arises whether the impairment reflects impaired information storage or impaired accessibility. This topic has been the subject of considerable commentary and experimental work over the years. In this reappraisal, I first consider four broad areas of behavioral study from the 1970s and 1980s that led to a dominant and compelling view of memory impairment as a deficit of information storage. Second, I identify some ambiguities that arise about how the terms "storage" and "retrieval" are applied, especially when the evidence is somewhat indirect and based on a behavioral-psychological level of analysis. I then review neurobiological findings that have been largely overlooked in these discussions. The relevant studies are ones where it has been possible to monitor neurons and synapses in direct relation to behavioral memory, for example, in animals with simple nervous systems and in single cell recordings from behaving monkeys. This work provides a straightforward and illuminating perspective on the question and confirms the view that first emerged from less direct evidence.

We tested recognition memory for items and associations in memory-impaired patients with bilateral lesions thought to be limited to the hippocampal region. In Experiment 1 (Combined memory test), participants studied words and then took a memory test in which studied words, new words, studied word pairs, and recombined word pairs were presented in a mixed order. In Experiment 2 (Separated memory test), participants studied single words and then took a memory test involving studied word and new words. In a separate test, they studied word pairs and then took a memory test involving studied word pairs and recombined word pairs. In both experiments, patients were impaired at memory for single items as well as memory for associations, suggesting that the hippocampus is important for both of these memory functions. In Experiment 1, patients appeared to be more impaired at associative memory than item memory. In Experiment 2, patients were similarly impaired at associative memory and item memory. These different findings are considered, including the fact that in Experiment 1 the results depended on the fact that controls produced unexpectedly low false-alarm rates to recombined pairs. We discuss single-item and associative memory from the perspective that the hippocampus and adjacent cortex work cooperatively to signal recognition and that simple dichotomies do not adequately describe the division of labor within the medial temporal lobe.

We studied item and source memory with fMRI in healthy volunteers and carried out a parallel study in memory-impaired patients. In experiment 1, volunteers studied a list of words in the scanner and later took an item memory test and a source memory test. Brain activity in the hippocampal region, perirhinal cortex, and parahippocampal cortex was associated with words that would later be remembered (item memory). The activity in these regions that predicted subsequent success at item memory predicted subsequent source memory to a similar degree. In experiment 2, memory-impaired patients with damage thought to be limited to the hippocampal region were given an item memory test and a source memory test, as in experiment 1. The patients were similarly impaired on the item memory test and the source memory test. Together, the findings suggest that medial temporal lobe structures broadly support recognition memory function and that item memory and source memory similarly depend on these structures.

Conventional lesion methods have shown that damage to the rodent hippocampus can impair previously acquired spatial memory in tasks such as the water maze. In contrast, work with reversible lesion methods using a different spatial task has found remote memory to be spared. To determine whether the finding of spared remote spatial memory depends on the lesion method, we reversibly inactivated the hippocampus with lidocaine either immediately (0-DAY) or 1 mo (30-DAY) after training in a water maze. For both the 0-DAY and 30-DAY retention tests, rats that received lidocaine infusions exhibited impaired performance. In addition, when the 0-DAY group was retested 2 d later, (when the drug was no longer active), the effect was reversed. That is, rats that had previously received lidocaine performed as well as control rats did. These findings indicate that the rodent hippocampus is important for both recent and remote spatial memory, as assessed in the water maze. What determines whether remote spatial memory is preserved or impaired following disruption of hippocampal function appears to be the type of task used to assess spatial memory, not the method used to disrupt the hippocampus.

A characteristic usually attributed to declarative memory is that what is learned is accessible to awareness. Recently, the relationship between awareness and declarative (hippocampus-dependent) memory has been questioned on the basis of findings from transitive inference tasks. In transitive inference, participants are first trained on overlapping pairs of items (e.g., A+B-, B+C-, C+D-, and D+E-, where + and - indicate correct and incorrect choices). Later, participants who choose B over D when presented with the novel pair BD are said to demonstrate transitive inference. The ability to exhibit transitive inference is thought to depend on the fact that participants have represented the stimulus elements hierarchically (i.e., A>B>C>D>E). We found that performance on five-item and six-item transitive inference tasks was closely related to awareness of the hierarchical relationship among the elements of the training pairs. Participants who were aware of the hierarchy performed near 100% correct on all tests of transitivity, but participants who were unaware of the hierarchy performed poorly (e.g., on transitive pair BD in the five-item problem; on transitive pairs BD, BE, and CE in the six-item problem). When the five-item task was administered to memory-impaired patients with damage thought to be limited to the hippocampal region, the patients were impaired at learning the training pairs. All patients were unaware of the hierarchy and, like unaware controls, performed poorly on the BD pair. The findings indicate that awareness is critical for robust performance on tests of transitive inference and support the view that awareness of what is learned is a fundamental characteristic of declarative memory.

Behavioral responses to a sensory stimulus are often guided by associative memories. These associations remain intact even when other factors determine behavior. The substrates of associative memory should therefore be identifiable by neuronal responses that are independent of behavioral choices. We tested this hypothesis using a paired-associates task in which monkeys learned arbitrary associations between pairs of visual stimuli. We examined the activity of neurons in inferior temporal cortex as the animals prepared to choose a remembered stimulus from a visual display. The activity of some neurons (22%) depended on the monkey's behavioral choice; but for a novel class of neurons (54%), activity reflected the stimulus that the monkey was instructed to choose, regardless of the behavioral response. These neurons appear to represent memorized stimulus associations that are stable across variations in behavioral performance. In addition, many neurons (74%) were modulated by the spatial arrangement of the stimuli in the display.

In humans and experimental animals, damage to the hippocampus or related medial temporal lobe structures severely impairs the formation of new memory but typically spares very remote memory. Questions remain about the importance of these structures for the storage and retrieval of remote autobiographical memory. We carried out a detailed volumetric analysis of structural brain images from eight memory-impaired patients. Five of the patients had damage limited mainly to the medial temporal lobe. These patients performed normally on tests of remote autobiographical memory. Three patients had medial temporal lobe damage plus significant additional damage to neocortex, and these patients were severely impaired. These findings account for previously reported differences in the recollective ability of memory-impaired patients and demonstrate that the ability to recollect remote autobiographical events depends not on the medial temporal lobe but on widely distributed neocortical areas, especially the frontal, lateral temporal, and occipital lobes.

There has been debate about whether differential delay eyeblink conditioning can be acquired without awareness of the stimulus contingencies. In 4 experiments, the authors reexamined this question. Older participants were tested with a tone and white noise (Experiment 1) or with 2 tones (Experiment 2). In addition, younger participants were tested with 2 tones (Experiment 3) or with 2 tones plus the parameters from an earlier study that had reported a relationship between conditioning and awareness (Experiment 4). Participants who were designated aware of the stimulus contingencies and participants who were designated unaware exhibited equivalent levels of differential eyeblink conditioning. Awareness of stimulus contingencies is not required for differential delay eyeblink conditioning when simple conditioned stimuli are used., (Copyright 2005 APA.)

Damage to the hippocampus typically produces temporally graded retrograde amnesia, whereby memories acquired recently are impaired more than memories acquired remotely. This phenomenon has been demonstrated repeatedly in a variety of species and tasks. It has also figured prominently in theoretical treatments of memory and hippocampal function. Yet temporally graded retrograde amnesia has not been demonstrated following hippocampal damage in spatial tasks like the water maze. We have assessed recent and remote spatial memory following hippocampal lesions in three different tests of spatial memory: (1) the standard water maze; (2) the Oasis maze, a dry-land version of the water maze; and (3) the annular water maze, where training and testing occur within a circular corridor. Training protocols were developed for each task such that retention of spatial memory could be expressed after very long retention intervals. In addition, retention in each task was assessed with single probe trials so that the assessment of remote memory did not depend on the ability to relearn across multiple trials. The findings were consistent across the three tasks. In the standard water maze (Experiment 1), spatial memory was impaired after training-surgery intervals of 1 day, 8 weeks, or 14 weeks. Similarly, in the Oasis maze (Experiment 2), spatial memory was impaired after training-surgery intervals of 1 day and 9 weeks. Finally, in the annular water maze (Experiment 3), spatial memory was impaired after training-surgery intervals of 9 weeks and 14 weeks. Dorsal hippocampal lesions impaired performance to the same extent as complete lesions. The impairment in remote spatial memory could reflect disruption of previously acquired spatial information. Alternatively, it is possible that in these tasks hippocampal lesions might produce an impairment in performance that prevents the expression of an otherwise intact spatial memory., ((c) 2004 Wiley-Liss, Inc.)

The idea that memory is composed of distinct systems has a long history but became a topic of experimental inquiry only after the middle of the 20th century. Beginning about 1980, evidence from normal subjects, amnesic patients, and experimental animals converged on the view that a fundamental distinction could be drawn between a kind of memory that is accessible to conscious recollection and another kind that is not. Subsequent work shifted thinking beyond dichotomies to a view, grounded in biology, that memory is composed of multiple separate systems supported, for example, by the hippocampus and related structures, the amygdala, the neostriatum, and the cerebellum. This article traces the development of these ideas and provides a current perspective on how these brain systems operate to support behavior.

There is wide agreement that spatial memory is dependent on the integrity of the hippocampus, but the importance of the hippocampus for nonspatial tasks, including tasks of object recognition memory is not as clear. We examined the relationship between hippocampal lesion size and both spatial memory and object recognition memory in rats. Spatial memory was impaired after bilateral dorsal hippocampal lesions that encompassed 30-50% total volume, and as lesion size increased from 50% to approximately 100% of total hippocampal volume, performance was similarly impaired. In contrast, object recognition was intact after dorsal hippocampal lesions that damaged 50-75% of total hippocampal volume and was impaired only after larger lesions that encompassed 75-100% of hippocampal volume. Last, ventral hippocampal lesions that encompassed approximately 50% of total hippocampal volume impaired spatial memory but did not affect object recognition memory. These findings show that the hippocampus is important for both spatial memory and recognition memory. However, spatial memory performance requires more hippocampal tissue than does recognition memory.

The medial temporal lobe includes a system of anatomically related structures that are essential for declarative memory (conscious memory for facts and events). The system consists of the hippocampal region (CA fields, dentate gyrus, and subicular complex) and the adjacent perirhinal, entorhinal, and parahippocampal cortices. Here, we review findings from humans, monkeys, and rodents that illuminate the function of these structures. Our analysis draws on studies of human memory impairment and animal models of memory impairment, as well as neurophysiological and neuroimaging data, to show that this system (a) is principally concerned with memory, (b) operates with neocortex to establish and maintain long-term memory, and (c) ultimately, through a process of consolidation, becomes independent of long-term memory, though questions remain about the role of perirhinal and parahippocampal cortices in this process and about spatial memory in rodents. Data from neurophysiology, neuroimaging, and neuroanatomy point to a division of labor within the medial temporal lobe. However, the available data do not support simple dichotomies between the functions of the hippocampus and the adjacent medial temporal cortex, such as associative versus nonassociative memory, episodic versus semantic memory, and recollection versus familiarity.

In a recent study, rats with hippocampal lesions performed as well as did unoperated rats on an olfactory memory span task, performing approximately 80% correct even when the span length reached 24 odors. This finding seems potentially at odds with demonstrations that memory-impaired patients typically fail tasks in which large amounts of information must be retained. Accordingly, we have assessed recognition memory span performance for line drawings of objects, designs, and odors in amnesic patients with damage thought to be limited to the hippocampal region. The patients were impaired on all three tasks. We consider possible explanations for the difference between the findings for humans and rats, including the fact that olfactory function is particularly well-developed in rodents.

In a prior study of continuous recognition performance, data were reported in support of the hypothesis that the hippocampus is not needed to remember the individual components of a stimulus but is important for remembering associations between its components (Kroll et al. 1996. J Mem Lang 35:176-196). Patients with left hippocampal damage were able to endorse recently encountered words and to reject novel words, as well as disyllabic words in which one of the syllables had been previously encountered. However, they failed to reject words in which both syllables had been encountered independently in different words. We present data from five experiments designed to examine this finding in more detail. In each experiment, five patients with bilateral hippocampal damage and eight controls were tested using the same protocol as Kroll et al. (1996). On each trial, a two-component stimulus was presented. Stimuli could be entirely novel, novel with one previously encountered (repeated) component, novel but with both components repeated, or a true repetition. The first experiment was a direct replication using the same disyllabic words as Kroll et al. (1996). The second experiment used pseudo-words, constructed of two monosyllabic words (e.g., jambark). The third experiment used the same pairs of monosyllabic words, but presented separately on the screen to encourage participants to treat each component independently. The fourth experiment used pairs of objects, and the fifth experiment used face-house pairs. In all five experiments, patients with hippocampal damage exhibited impaired recognition memory. The impairment extended across all trial types with no evidence that hippocampal damage selectively (or disproportionately) impaired the associative or conjunctive component of memory. We discuss our findings in the light of the work by Kroll et al. (1996) and other recent neuropsychological, electrophysiological, and neuroimaging studies of hippocampal function and single-item and associative memory.