ReviewMolecular mechanisms of memory acquisition, consolidation and retrieval
Introduction
Memory, as measured by changes in an animal's behavior some time after learning, reflects many processes including acquisition, consolidation, retention, retrieval and performance. Molecular accounts of memory have focused mainly on the mechanisms that underlie acquisition. This emphasis is due, in large part, to the success of cellular models of learning, including forms of synaptic plasticity such as long-term potentiation (LTP). Although there are many unanswered questions about the role of LTP as a cellular mechanism of memory storage [1], it is clear that the study of LTP has provided a way to identify and characterize molecular mechanisms that potentially underlie memory storage [2]. On a molecular level, studies of LTP in hippocampal area CA1 have focused on the NMDA receptor and intracellular signaling events downstream of Ca2+ influx through the NMDA receptor (Fig. 1). In this review, we explore recent advances in some of the neural systems and molecular processes that may mediate acquisition, consolidation and retrieval of memories for spatial learning and fear conditioning. We also explore some of the ways that memories change after they have been retrieved during reconsolidation and extinction.
The use of pharmacological, genetic and lesion approaches has helped to define the brain systems and molecular processes important for different stages of memory, as illustrated by contextual fear conditioning (Fig. 2). Memory acquisition occurs as the animal learns an association between a context and a shock. During consolidation, which can last from minutes to days, this memory is moved from a labile to a more fixed state. During retrieval, the animal is returned to the conditioning context, where memory for the context–shock association is assessed. It can be quite difficult to isolate experimentally the different stages of memory because experimental techniques potentially affect two or more stages of memory, depending on the time course of the manipulations (Fig. 2). Short-lived treatments, however, can isolate consolidation independent of acquisition or retrieval. Advances in conditional genetic systems and reversible lesion techniques are bringing the time windows of these manipulations more in line with traditional pharmacological approaches 3., 4..
Section snippets
Acquisition: the importance of temporal relations
Many neurobiological experiments examining the mechanisms that underlie associative learning have focused on delayed fear conditioning, in which a neutral conditioned stimulus (CS), such as a tone, is presented just before a footshock unconditioned stimulus (US). At the systems level, lesions of the amygdala block conditioned freezing to both the context and the tone, but lesions of the hippocampus block freezing to only the context [5]. Recent experiments have investigated the molecular
Consolidation: memory modulation and storage
One of the hallmarks of long-term memory storage is that newly learned information is sensitive to disruption after acquisition, a property that gives rise to the phenomenon of retrograde amnesia [12]. This labile state following training suggests that a period of consolidation occurs that may last for hours or even days. Memories can be impaired or enhanced during the consolidation period, suggesting that this labile state may have evolved as a way to allow memory to be integrated with new
Retrieval: distinct molecular mechanisms?
During a test for memory, a stimulus is presented and the subject must remember what it learned previously about that stimulus. There are various neurobiological and behavioral theories about the mechanisms that underlie this retrieval process 31., 32., 33.. Analyses of retrieval are faced with the challenge of disentangling the effects of a manipulation on retrieval from its effects on performance of the behavioral task, a problem that might be particularly difficult in studies of the
Beyond retrieval: extinction and reconsolidation
Retrieval tests result not only in reactivating the memory from acquisition, but also in establishing new memories for the events that occur during the retrieval tests themselves. During retrieval trials in contextual fear conditioning, an animal is placed into the context in the absence of shock (Fig. 2). These types of trials constitute extinction trials, which result in the diminishment of fear evoked by the context as the animal learns that the context no longer predicts shock. Many
Conclusions
The use of systems, pharmacological, biochemical and genetic methods has done much to define the nature of learning and how it is modified during the processes of consolidation, retrieval, reconsolidation and extinction. As shown in Fig. 1, the molecular mechanisms of acquisition have been extensively studied, largely on the basis of our knowledge of the intracellular signaling pathways activated by the NMDA receptor. A key challenge for the field is to determine whether the processes of
Acknowledgements
Our research is supported by grants from the Merck Foundation, the National Institutes of Health, the University of Pennsylvania Research Foundation, the Packard Foundation and the Whitehall Foundation to T Abel, and by a National Research Service Award postdoctoral fellowship and a National Institutes of Health neuropsychopharmacology training grant to KM Lattal. We thank Jessica Cardin, Tom Gould and Noreen O'Connor-Abel for their comments.
References and recommended reading
Papers of particular interest, published within the annual period of review,have been highlighted as:
• of special interest
•• of outstanding interest
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