MEMORY CONSOLIDATION: PROLONGED PROCESS OF REORGANIZATION

The origin of the concept of memory consolidation is generally credited to Georg Elias Müller and his student Alfons Pilzecker. Their 300-page monograph, published in 1900, proposed that memory is not formed instantaneously at the time of learning but takes time to be fixed (or consolidated). The studies involved lists of nonsense syllables and focused especially on retroactive inhibition, the finding that when two lists are learned in succession, learning the second list interferes with subsequent recall of the first list. On the basis of this finding, they suggested that the processes needed to form memory continue for a period of time after learning, during which time they are vulnerable to interference. While this origin of the consolidation concept is widely known, it is not generally known that the interval across which the putative consolidation process operated in these early experiments was less than ten minutes.

The consolidation concept subsequently came into widespread usage and found application in a number of contexts. The term is often used to refer to the cascade of molecular events, including protein synthesis, that unfolds during the hours after learning and ultimately results in morphological growth and change at synapses. The term is also used in the context of observations that damage to the hippocampus or related structures can produce temporally graded retrograde amnesia: impairment of memories that were acquired weeks, months, and even years earlier, despite sparing of more remote memories. There need be no confusion among these usages if one notes that the former refers to molecular and cellular events within neurons and the latter to what retrograde amnesia has suggested about the brain systems involved in elaborating long-term memory. When one speaks about prolonged processes of reorganization (or prolonged consolidation), one is usually referring to this latter usage.

There are also other ways in which memory can undergo gradual change and reorganization across time that may be related to consolidation. For example, forgetting itself operates over a long period, with the result that details are lost and one is left with kernels of the past, the central meanings. One can forget the particulars while abstracting and retaining the main points. Thus, forgetting is not a passive process of progressive loss and dissolution but a dynamic process during which representations of the past within neocortex are continually reconstructed and reorganized. Events such as rehearsal and episodes of new learning also influence the structure of already established representations. These continuing influences on the structure of long-term memory are beyond the scope of this article.

A Brain System for Memory in the Temporal Lobe

In 1957 Scoville and Milner described the profound effects on memory following bilateral removal of the medial temporal lobe in a patient who became known as H.M. Comprehensive study of this patient established the fundamental principle that the ability to acquire new memories is a distinctly cerebral function, separable from other perceptual and intellectual functions. This discovery inspired efforts to develop an animal model of human memory impairment in the monkey and led eventually to the identification of the hippocampus and adjacent, anatomically related structures in the medial temporal lobe as components of a memory system important for the formation of long-term memory (Squire and Zola-Morgan, 1991). Disrupting the function of this system impairs the ability to form declarative memories (the ability to acquire new facts and events) while leaving intact a collection of nondeclarative memory abilities, including habits and skills, simple forms of conditioning, and other means by which experience can change how one interacts with the world. Disruption of medial temporal lobe function also causes retrograde amnesia—that is, the loss of memories that were acquired before the onset of amnesia. The finding that retrograde amnesia is typically temporally graded (most severe for recent events and less severe for remote events) suggested that medial temporal lobe structures are essential at the time of learning as well as after learning during a prolonged and gradual period of reorganization and consolidation. During consolidation, long-term memory is gradually stabilized within the neocortex.

Temporally Graded Retrograde Amnesia

The earliest evidence for temporally graded retrograde amnesia came from clinical observations of human patients recorded more than 100 years ago. Quantitative studies of retrograde amnesia began in the 1970s. For example, on a test of former one-season television programs, designed to permit the equivalent sampling of past time periods, psychiatric patients prescribed bilateral electroconvulsive therapy (ECT) for depressive illness exhibited temporallygraded retrograde amnesia covering about three years. Evidence relating temporally graded retrograde amnesia to the medial temporal lobe has come from patients for whom detailed neuropsychological information is available together with postmortem information about which structures were damaged. Such case material has shown that retrograde amnesia is brief when damage is limited to the CA1 field of the hippocampus (Zola-Morgan, Squire, and Amaral, 1986) and more extensive, covering fifteen years or more, when the damage is more extensive in this region (the CA fields, dentate gyrus, subiculum, and some cell loss in the entorhinal cortex) (Rempel-Clower, Zola, Squire, and Amaral, 1996). Despite reports of temporally graded retrograde amnesia in well-described patients, it is nevertheless the case that such studies depend on retrospective methods that make it difficult to document precisely the time course of the phenomenon. Accordingly, when prospective studies of retrograde amnesia in experimental animals began in the 1990s, the nature of retrograde amnesia, as well as the concept of consolidation, were placed on firmer ground.

Of more than ten studies that have been carried out in mice, rats, rabbits, and monkeys, most have found temporally graded retrograde amnesia following damage to the hippocampal region (Rempel-Clower, Zola, Squire, and Amaral, 1996; Squire, Clark, and Knowlton, 2001). The retrograde amnesia typically covers about one month. In addition, related work suggests that retrograde amnesia can become more extensive as damage extends beyond the hippocampus into adjacent medial temporal lobe structures. This pattern of findings implies that the hippocampus itself is important for memory for a relatively short period of time after learning and that the adjacent perirhinal and parahippocampal cortices remain important for a longer time. Ultimately, memory depends on widespread areas of the neocortex and is independent of the medial temporal lobe.

Uncertainties about Temporally Graded Retrograde Amnesia

Some uncertainties remain about temporally graded retrograde amnesia and its interpretation. First, there is not yet agreement as to whether spatial memories undergo the same kind of transition as nonspatial memories do—from a form that depends on the hippocampus and related structures to a form that is independent of these structures. On the one hand, the available data from humans suggest that spatial and nonspatial memory have the same status. For example, a profoundly amnesic patient with large medial temporal lobe lesions was able to recall the spatial layout of the neighborhood where he had lived as a child, and his memory in this respect was as good as the memory of healthy individuals who had lived as children in the same neighborhood (Teng and Squire, 1999). On the other hand, the findings from experimental animals are less clear. Some studies of rodents have found retrograde amnesia for spatial memory to be temporally graded after hippocampal lesions (Ramos, 1998; Squire, Clark, and Knowlton, 2001), but other studies have found memory to be affected similarly across past time periods (Sutherland et al., 2001).

A second uncertainty about temporally graded retrograde amnesia is whether episodic memory (that is, the recollection of autobiographical events) becomes independent of the medial temporal lobe in the same way that memory for general facts becomes independent. Some patients with medial temporal lobe lesions appear able to recollect specific events from their remote past as well as healthy individuals (Reed and Squire, 1997), whereas at least one patient with damage thought to be limited to the medial temporal lobe is described as quite incapable of remote episodic recollections (Cipolotti et al., 2001). A third source of uncertainty is that it is in principle possible to construct alternatives to a consolidation account of retrograde amnesia (Nadel and Moscovitch, 1997), although these ideas have difficulty accounting for the available facts (Knowlton and Fanselow, 1998).

Looking for Consolidation with Brain-Imaging Techniques

One difficulty with the concept of gradual memory consolidation is that this idea has depended largely on only one kind of evidence, namely, the evidence of temporally graded retrograde amnesia. Some efforts have been made to find direct evidence for memory consolidation in neuroimaging studies (functional magnetic resonance imaging [fMRI]) that assess medial temporal lobe activity while individuals recollect recent and more remote memories. These studies have yielded mixed results (Ryan et al., 2001; Niki and Luo, 2002; Haist, Bowden Gore, and Mao, 2001; Maguire, Henson, Mummery, and Frith, 2001). A difficulty in interpreting findings obtained with this technique is that the neuroimaging method provides information only about regions where activity correlates with a particular cognitive operation and does not provide information about which regions are essential. Perhaps the medial temporal lobe is very often engaged during memory retrieval but is essential only when recent memories are being retrieved. Or perhaps activation of the medial temporal lobe during recollection of recent and remote events is driven to a large extent by the encoding into long-term memory of the events of the test session, and by the re-encoding of the recollections themselves.

It is notable that work in experimental animals has found activity in the hippocampal region to differ depending on the length of the retention interval. Regional brain activity was mapped in mice tested five days or twenty-five days after learning. Increasing the retention interval from five to twenty-five days resulted in decreased hippocampal activity during retention testing (Bontempi, Laurent-Demir, and Jaffar, 1999). Additional studies in humans and experimental animals using neuroimaging techniques should be of value.

Gradual Memory Consolidation

Another reason that discussion continues about the concept of memory consolidation is that the idea itself is rather vague and depends on mechanisms not yet identified. The central idea is that medial temporal lobe structures direct the gradual establishment of memory representations in the neocortex, and this interaction between the medial temporal lobe and the neocortex embodies the consolidation process. Some researchers have proposed that the hippocampus can serve as a temporary memory store because hippocampal synapses change quickly. The neocortex can store information only gradually as an accumulation of small synaptic changes (McClelland, McNaughton, and O'Reilly, 1995). Consolidation occurs when the hippocampus (and the system to which it belongs) repeatedly activates representations in the neocortex, with the result that the neocortex can eventually support memory independently of the hippocampal system.

Computational considerations have suggested that consolidation is important precisely because it enables the neocortex to slowly incorporate into its representations the regularities of the environment, such as facts about the world (McClelland, McNaughton, and O'Reilly, 1995; O'Reilly and Rudy, 2001). Rapid modification of neocortical representations would lead to instability, for example, if one rapidly introduced into a network the fact that penguins are birds, but cannot fly, when birds are already represented in the network as animals that can fly. In such a case, McClelland and colleagues showed that the performance of the network would be markedly disrupted because the network begins to apply the characteristics of the penguin to other birds.

One proposal is that the hippocampal system stores only a compressed form of the memory but stores sufficient information to activate relevant sites in the neocortex. Consolidation occurs when the neo-cortex is repeatedly activated by the medial temporal lobe, either during rehearsal, reminiscence, or perhaps as a result of spontaneous reactivation during sleep. When activation occurs, gradual and long-lasting changes occur in the connections between the cortical sites. Eventually, these connections become so strong that the medial temporal lobe is not needed to recreate the original representation (see Figure 1).

Conclusion

The idea that memory can consolidate or reorganize after learning in a lengthy process rests largely on the phenomenon of temporally graded retrograde amnesia—namely, the finding in studies of both humans and experimental animals that damage to the medial temporal lobe can impair memories that were acquired recently while sparing more remote memories. These results have suggested that medial temporal lobe structures are required for a limited period after learning, during which time they direct a process of consolidation in the neocortex by gradually binding together the multiple, anatomically separate sites that together represent memory for a whole event.

Efforts to observe consolidation directly in neuroimaging studies have yielded mixed results. Uncertainties also remain concerning whether spatial memory operates by the same rules as nonspatial memory and whether memory for specific events that are unique to time and place consolidate in the same way as facts, which can be repeated in multiple contexts. Computational principles suggest that consolidation occurs because new information must be incorporated gradually into preexisting representations in the neocortex. Simple network models have been constructed that capture these ideas.

See also:GUIDE TO THE ANATOMY OF THE BRAIN: CEREBRAL CORTEX; GUIDE TO THE ANATOMY OF THE BRAIN: HIPPOCAMPUS AND PARAHIPPOCAMPAL REGION; MÜLLER, GEORG ELIAS

Bibliography

Bontempi, B., Laurent-Demir, C., and Jaffar, R. (1999). Time-dependent reorganization of brain circuitry underlying long-term memory storage. Nature 400, 671-675.

Cipolotti, L., Shallice T., Chan, D., Fox, N., Scahill, R., Harrison, G., Stevens, J., and Rudge, P. (2001). Long-term retrograde amnesia: The crucial role of the hippocampus. Neuropsychologia 39, 151-172.

Haist, F., Bowden Gore, J., and Mao, H. (2001). Consolidation of human memory over decades revealed by functional magnetic resonance imaging. Nature Neuroscience 11, 1,139-1,145.

Knowlton, B. J., and Fanselow, M. S. (1998). The hippocampus, consolidation and on-line memory. Current Opinion in Neurobiology 8, 293-296.

Maguire, E. A., Henson, R. N. A., Mummery, C. J., and Frith, C. D. (2001). Activity in prefrontal cortex, not hippocampus, varies parametrically with the increasing remoteness of memories. NeuroReport 12, 441-444.

McClelland, J. L., McNaughton, B. L., and O'Reilly, R. C. (1995). Why there are complementary learning systems in the hippocampus and neocortex: Insights from the successes and failures of connectionist models of learning and memory. Psychological Review, 419-437.

Müller, G. E., and Pilzecker, A. (1900). Experimentelle beitrage zur lehre vom Gedachtniss. Zeitschrift fur Psychologie, Erganzungsband 1, 1-300.

Nadel, L., and Moscovitch, M. (1997). Memory consolidation, retrograde amnesia and the hippocampal complex. Current Opinion in Neurobiology 7, 217-227.

Niki, K., and Luo, J. (2002). An fMRI study on the time-limited role of the medial temporal lobe in long-term topographical autobiographical memory. Journal of Cognitive Neuroscience 14, 500-507.

O'Reilly, R. C., and Rudy, J. W. (2001). Conjunctive representations in learning and memory: Principles of cortical and hippocampal function. Psychology Review 108, 311-345.

Ramos, J. M. J. (1998). Retrograde amnesia for spatial information: A dissociation between intra and extramaze cues following hippocampus lesions in rats. European Journal of Neuroscience 10, 3,295-3,301.

Reed, J. M., and Squire, L. R. (1997). Impaired recognition memory in patients with lesions limited to the hippocampal formation. Behavioral Neuroscience 111, 667-675.

Rempel-Clower, N., Zola, S. M., Squire L. R., and Amaral, D. G. (1996). Three cases of enduring memory impairment following bilateral damage limited to the hippocampal formation. Journal of Neuroscience 16, 5,233-5,255.

Ryan, L., Nadel L., Keil K., Putnam K., Schnyer D., Trouard T., and Moscovitch, M. (2001). Hippocampal complex and retrieval of recent and very remote autobiographical memories: Evidence from functional magnetic resonance imaging in neurologically intact people. Hippocampus 11, 707-714.

Scoville, W. B., and Milner, B. (1957). Loss of recent memory after bilateral hippocampal lesions. Journal of Neurology, Neurosurgery, and Psychiatry 20, 11-21.

Squire, L., and Kandel, E. R. (1999). Memory: From mind to molecules. New York: Scientific American Library.

Squire, L. R., and Alvarez, P. (1995). Retrograde amnesia and memory consolidation: A neurobiological perspective. Current Opinion in Neurobiology 5, 169-177.

Squire, L. R., Clark, R. E., and Knowlton, B. J. (2001). Retrograde amnesia. Hippocampus 11, 50-55.

Squire, L. R., and Zola-Morgan, S. (1991). The medial temporal lobe memory system. Science 253, 1,380-1,386.

Sutherland, R. J., Weisend, M. P., Mumby, D., Astur, R. S., Hanlon, F. M., Koerner, A., Thomas, M. J., Wu, Y., Moses, S. N., Cole, C., Hamilton, D. A., and Hoesing, J. M. (2001). Retrograde amnesia after hippocampal damage: Recent versus remote memories in two tasks. Hippocampus 11, 27-42.

Teng, E., and Squire, L. R. (1999). Memory for places learned long ago is intact after hippocampal damage. Nature 400, 675-677.

Zola-Morgan, S., Squire, L. R., and Amaral, D. G. (1986). Human amnesia and the medial temporal region: Enduring memory impairment following a bilateral lesion limited to field CA1 of the hippocampus. Journal of Neuroscience 6, 2,950-2,967.

Larry R.Squire