Larry R. Squire

Memory and the hippocampus: a synthesis from findings with rats, monkeys, and humans.

This article considers the role of the hippocampus in memory function. A central thesis is that work with rats, monkeys, and humans--which has sometimes seemed to proceed independently in 3 separate literatures--is now largely in agreement about the function of the hippocampus and related structures. A biological perspective is presented, which proposes multiple memory systems with different functions and distinct anatomical organizations. The hippocampus (together with anatomically related structures) is essential for a specific kind of memory, here termed declarative memory (similar terms include explicit and relational). Declarative memory is contrasted with a heterogeneous collection of nondeclarative (implicit) memory abilities that do not require the hippocampus (skills and habits, simple conditioning, and the phenomenon of priming). The hippocampus is needed temporarily to bind together distributed sites in neocortex that together represent a whole memory.

The medial temporal lobe memory system

Studies of human amnesia and studies of an animal model of human amnesia in the monkey have identified the anatomical components of the brain system for memory in the medial temporal lobe and have illuminated its function. This neural system consists of the hippocampus and adjacent, anatomically related cortex, including entorhinal, perirhinal, and parahippocampal cortices. These structures, presumably by virtue of their widespread and reciprocal connections with neocortex, are essential for establishing long-term memory for facts and events (declarative memory). The medial temporal lobe memory system is needed to bind together the distributed storage sites in neocortex that represent a whole memory. However, the role of this system is only temporary. As time passes after learning, memory stored in neocortex gradually becomes independent of medial temporal lobe structures.

A Neostriatal Habit Learning System in Humans

Amnesic patients and nondemented patients with Parkinsons disease were given a probabilistic classification task in which they learned which of two outcomes would occur on each trial, given the particular combination of cues that appeared. Amnesic patients exhibited normal learning of the task but had severely impaired declarative memory for the training episode. In contrast, patients with Parkinsons disease failed to learn the probabilistic classification task, despite having intact memory for the training episode. This double dissociation shows that the limbic-diencephalic regions damaged in amnesia and the neostriatum damaged in Parkinsons disease support separate and parallel learning systems. In humans, the neostriatum (caudate nucleus and putamen) is essential for the gradual, incremental learning of associations that is characteristic of habit learning. The neostriatum is important not just for motor behavior and motor learning but also for acquiring nonmotor dispositions and tendencies that depend on new associations.

Memory systems of the brain: A brief history and current perspective

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.

Cognitive Neuroscience and the Study of Memory

As Neuron prepares to enter the twenty-first century, the neurosciences, whose six decades of achievement we celebrate in this issue of the journal, have matured. With this maturation, the neurosciences now have moved from the peripheral position they occupied in the 1940s to a central position within the biological sciences. There has been remarkable progress in understanding neuronal and synaptic signaling. These advances now invite a structural approach to visualize the static and dynamic structures of ion channels, receptors, and the molecular machinery for vesicle transport, fusion, and exocytosis.Similarly, an understanding in outline of the development of the nervous system has been achieved by a molecular approach. Specific molecules have been identified as inducers and morphogens, constructs that previously were shrouded in mystery. Progress in this area has in turn made possible a molecular-based neurology, a neurology that will, one hopes, finally be able to address the degenerative diseases of the brain that have for so long eluded our best scientific efforts.The remarkable advances in the cellular understanding of the organization of the somatosensory and visual system by Vernon Mountcastle and Hubel and Wiesel have helped turn our interest to perception and in the broader sense to cognitive psychology. In turn, contact between cognitive psychology and neuroscience has given us a new approach to the classic problems of the mind such as memory—on which we have here focused.But, of all the fields in neuroscience, in fact, of all the fields in all of science, the problems of cognitive neuroscience—the problems of perception, action, memory, attention, and consciousness on an intellectually satisfying biological level—offer the most difficult and the greatest challenge for the next millennium. In the fullness of time, advance in these areas may grant us insight into and perhaps solutions for some of the most debilitating diseases confronting medical science—schizophrenia, depression, and Alzheimers disease.We have here focused on only one component of cognitive neuroscience, that of memory. As we indicated in the introduction, the problem of memory has two components—the molecular problem of memory and the systems problem of memory. In the last four decades substantial progress has occurred in both areas.On the molecular level, a core signaling pathway has been identified that is used in a variety of nondeclarative and declarative forms of memory to convert short-term to long-term memory. Thus, these two major forms of memory use common elementary mechanisms for storage. Most likely the cAMP–PKA–MAPK–CREB pathway represents only one of what is likely to be several core mechanisms for achieving this transformation. The tasks ahead for a deeper understanding of molecular mechanisms are fairly clear. Although we now know something about the switch from short-term to long-term memory, we know only a small percentage of the downstream genes and proteins, for example, the proteins required for the growth of new synaptic connections. Drosophila, Aplysia, and perhaps C. elegans should contribute importantly to further gene discovery. Because we now know that the molecular mechanisms are at least in part shared across species and forms of memory, it also will be important to direct this molecular analysis to the simpler instances of nondeclarative memory in mice, using fear conditioning and the amygdala and eyeblink conditioning and the vestibulo-ocular reflex, whose modifications occur in the cerebellum and its deep nuclei.The greatest challenges, however, lie in the systems biology of memory and in particular in the biology of declarative, conscious memory. We do not, as yet, understand the functions of the various subdivisions of the medial temporal-lobe system. Analyses of perception indicate that the visual image is deconstructed and processed in the cortex in a series of parallel processing streams. However, despite clear evidence for parallel anatomical pathways in the hippocampus, it has not been possible to delineate their functional significance. By analogy to the visual system, it would seem likely that different regions of the medial temporal-lobe system (the parahippocampal and perirhinal cortices, the entorhinal cortex, the dentate gyrus, the CA1 and CA3 regions of the hippocampus, and the subiculum) have specialized functional roles in memory storage: they might each mediate the store of different aspects of learned information (Figure 9Figure 9). Alternatively, memory itself requires several operations such as encoding, storage, consolidation, and retrieval. Perhaps different regions carry out these different types of operations. To intervene in each of the critical regions and explore each of these component processes, we will need further improvements in genetic methods.It also will be important to understand how acquired representations in the hippocampus act to support memory. For example, how does the spatial map, evident in the hippocampus, relate to spatial memory? How is this spatial map read out? How is the map of space in the hippocampus reflected in our conscious recollection of a space? That of course leads to a still larger question: how does declarative information become available to conscious introspection? How are nonspatial memories that are declarative represented in the hippocampus? How is it transformed from a hippocampal-dependent process to a hippocampal-independent and presumably neocortical-dependent process that is capable of being scanned by conscious attention in ways that we are still very far from understanding? Clearly one Decade of the Brain (and of Neuron) has not been enough. Will a millennium suffice?§To whom correspondence should be addressed.

Retrograde amnesia and memory consolidation: a neurobiological perspective

The fact that information acquired before the onset of amnesia can be lost (retrograde amnesia) has fascinated psychologists, biologists, and clinicians for over 100 years. Studies of retrograde amnesia have led to the concept of memory consolidation, whereby medial temporal lobe structures direct the gradual establishment of memory representations in neocortex. Recent theoretical accounts have inspired a simple neural network model that produces behavior consistent with experimental data and makes these ideas about memory consolidation more concrete. Recent physiological and anatomical findings provide important information about how memory consolidation might actually occur.

Declarative and nondeclarative memory: Multiple brain systems supporting learning and memory

The topic of multiple forms of memory is considered from a biological point of view. Fact-and-event (declarative, explicit) memory is contrasted with a collection of non conscious (non-declarative, implicit) memory abilities including skills and habits, priming, and simple conditioning. Recent evidence is reviewed indicating that declarative and non declarative forms of memory have different operating characteristics and depend on separate brain systems. A brain-systems framework for understanding memory phenomena is developed in light of lesion studies involving rats, monkeys, and humans, as well as recent studies with normal humans using the divided visual field technique, event-related potentials, and positron emission tomography (PET).

The information that amnesic patients do not forget

The performance of three kinds of amnesic patients and control subjects was assessed using four methods for testing memory: free recall, recognition, cued recall, and word completion. Whereas amnesic patients were impaired on free recall, recognition, and cued recall, they were normal on word completion. Moreover, performance on the word-completion test declined at a normal rate reaching chance after about 120 min. The word-completion test resembled the cued-recall test in that the initial letters of previously presented words were given as cues. It differed from cued recall only in the instructions, which directed subjects away from the memory aspects of the test and asked them to complete each three-letter cue with the first word that came to mind. The present results offer an explanation of conflicting findings that have been obtained with amnesic patients on tests of the cued-recall type. The results are considered in terms of a process (activation or procedural learning), which is spared in amnesia and not dependent on the integrity of the damaged brain regions. Language: en

Recognition memory and the medial temporal lobe: a new perspective

Recognition memory is widely viewed as consisting of two components, recollection and familiarity, which have been proposed to be dependent on the hippocampus and the adjacent perirhinal cortex, respectively. Here, we propose an alternative perspective: we suggest that the methods traditionally used to separate recollection from familiarity instead separate strong memories from weak memories. A review of work with humans, monkeys and rodents finds evidence for familiarity signals (as well as recollection signals) in the hippocampus and recollection signals (as well as familiarity signals) in the perirhinal cortex. We also indicate ways in which the functions of the medial temporal lobe structures are different, and suggest that these structures work together in a cooperative and complementary way.

Three Cases of Enduring Memory Impairment after Bilateral Damage Limited to the Hippocampal Formation

Patient RB (Human amnesia and the medial temporal region: enduring memory impairment following a bilaterial lesion limited to field CA1 of the hippocampus, S. Zola-Morgan, L. R. Squire, and D. G. Amaral, 1986, J Neurosci 6:2950–2967) was the first reported case of human amnesia in which detailed neuropsychological analyses and detailed postmortem neuropathological analyses demonstrated that damage limited to the hippocampal formation was sufficient to produce anterograde memory impairment. Neuropsychological and postmortem neuropathological findings are described here for three additional amnesic patients with bilateral damage limited to the hippocampal formation. Findings from these patients, taken together with the findings from patient RB and other amnesic patients, make three important points about memory. (1) Bilateral damage limited primarily to the CA1 region of the hippocampal formation is sufficient to produce moderately severe anterograde memory impairment. (2) Bilateral damage beyond the CA1 region, but still limited to the hippocampal formation, can produce more severe anterograde memory impairment. (3) Extensive, temporally graded retrograde amnesia covering 15 years or more can occur after damage limited to the hippocampal formation. Findings from studies with experimental animals are consistent with the findings from amnesic patients. The present results substantiate the idea that severity of memory impairment is dependent on locus and extent of damage within the hippocampal formation and that damage to the hippocampal formation can cause temporally graded retrograde amnesia.