The synaptic tagging and capture hypothesis of protein synthesis-dependent long-term potentiation asserts that the induction of synaptic potentiation creates only the potential for a lasting change ...in synaptic efficacy, but not the commitment to such a change. Other neural activity, before or after induction, can also determine whether persistent change occurs. Recent findings, leading us to revise the original hypothesis, indicate that the induction of a local, synapse-specific 'tagged' state and the expression of long-term potentiation are dissociable. Additional observations suggest that there are major differences in the mechanisms of functional and structural plasticity. These advances call for a revised theory that incorporates the specific molecular and structural processes involved. Addressing the physiological relevance of previous in vitro findings, new behavioural studies have experimentally translated the hypothesis to learning and the consolidation of newly formed memories.
It is humbling to think that 30 years have passed since the paper by Collingridge, Kehl and McLennan showing that one of Jeff Watkins most interesting compounds, R-2-amino-5-phosphonopentanoate ...(d-AP5), blocked the induction of long-term potentiation in vitro at synapses from area CA3 of the hippocampus to CA1 without apparent effect on baseline synaptic transmission (Collingridge et al., 1983). This dissociation was one of the key triggers for an explosion of interest in glutamate receptors, and much has been discovered since that collectively contributes to our contemporary understanding of glutamatergic synapses – their biophysics and subunit composition, of the agonists and antagonists acting on them, and their diverse functions in different networks of the brain and spinal cord. It can be fairly said that Collingridge et al.'s (1983) observation was the stimulus that has led, on the one hand, to structural biological work at the atomic scale describing the key features of NMDA receptors that enables their coincidence function to happen; and, on the other, to work with whole animals investigating the contributions that calcium signalling via this receptor can have on rhythmical activities controlled by spinal circuits, memory encoding in the hippocampus (the topic of this article), visual cortical plasticity, sensitization in pain, and other functions. In this article, I lay out how my then interest in long-term potentiation (LTP) as a model of memory enabled me to recognise the importance of Collingridge et al.'s discovery – and how I and my colleagues endeavoured to take things forward in the area of learning and memory. This is in some respects a personal story, and I tell it as such. The idea that NMDA receptor activation is essential for memory encoding, though not for storage, took time to develop and to be accepted. Along the way, there have been confusions, challenges, and surprises surrounding the idea that activation of NMDA receptors can trigger memory. Some of these are described and how they have been addressed and resolved. Last, I touch on some new directions of interest with respect to the functional role of the NMDA receptor in cognition.
This article is part of the Special Issue entitled ‘Glutamate Receptor-Dependent Synaptic Plasticity’.
•A review of research on the role of NMDA receptors in learning and memory.•It documents the initial discovery that blocking NMDA receptors in the hippocampus impairs spatial learning.•It argues that NMDA receptor-dependent synaptic plasticity in the hippocampus is critical for episodic-like memory.•The review covers pharmacological and molecular-genetic studies.
The synaptic plasticity and memory hypothesis asserts that activity-dependent synaptic plasticity is induced at appropriate synapses during memory formation and is both necessary and sufficient for ...the encoding and trace storage of the type of memory mediated by the brain area in which it is observed. Criteria for establishing the necessity and sufficiency of such plasticity in mediating trace storage have been identified and are here reviewed in relation to new work using some of the diverse techniques of contemporary neuroscience. Evidence derived using optical imaging, molecular-genetic and optogenetic techniques in conjunction with appropriate behavioural analyses continues to offer support for the idea that changing the strength of connections between neurons is one of the major mechanisms by which engrams are stored in the brain.
This review, focusing on work using animals, updates a theoretical approach whose aim is to translate neuropsychological ideas about the psychological and anatomical organization of memory into the ...neurobiological domain. It is suggested that episodic-like memory consists of both automatic and controlled components, with the medial temporal mediation of memory encoding including neurobiological mechanisms that are primarily automatic or incidental. These ideas, in the cognitive and behavioral domain, are linked to neurophysiological ideas about cellular consolidation concerning synaptic potentiation, particularly the relationship between protein synthesis-dependent long-term changes and shorter-lasting post-translational mechanisms. Ideas from psychology about mental schemas are considered in relation to the phenomenon of systems consolidation and, specifically, about how prior knowledge can alter the rate at which consolidation occurs. Finally, the hippocampal-neocortical interactions theory is updated in relation to reconsolidation, a process that enables updating of stored memory traces in response to novelty.
When new learning occurs against the background of established prior knowledge, relevant new information can be assimilated into a schema and thereby expand the knowledge base. An animal model of ...this important component of memory consolidation reveals that systems memory consolidation can be very fast. In experiments with rats, we found that the hippocampal-dependent learning of new paired associates is associated with a striking up-regulation of immediate early genes in the prelimbic region of the medial prefrontal cortex, and that pharmacological interventions targeted at that area can prevent both new learning and the recall of remotely and even recently consolidated information. These findings challenge the concept of distinct fast (hippocampal) and slow (cortical) learning systems, and shed new light on the neural mechanisms of memory assimilation into schemas.
Schemas and Memory Consolidation Tse, Dorothy; Langston, Rosamund F; Kakeyama, Masaki ...
Science (American Association for the Advancement of Science),
04/2007, Volume:
316, Issue:
5821
Journal Article
Peer reviewed
Open access
Memory encoding occurs rapidly, but the consolidation of memory in the neocortex has long been held to be a more gradual process. We now report, however, that systems consolidation can occur ...extremely quickly if an associative "schema" into which new information is incorporated has previously been created. In experiments using a hippocampal-dependent paired-associate task for rats, the memory of flavor-place associations became persistent over time as a putative neocortical schema gradually developed. New traces, trained for only one trial, then became assimilated and rapidly hippocampal-independent. Schemas also played a causal role in the creation of lasting associative memory representations during one-trial learning. The concept of neocortical schemas may unite psychological accounts of knowledge structures with neurobiological theories of systems memory consolidation.
The retention of episodic-like memory is enhanced, in humans and animals, when something novel happens shortly before or after encoding. Using an everyday memory task in mice, we sought the neurons ...mediating this dopamine-dependent novelty effect, previously thought to originate exclusively from the tyrosine-hydroxylase-expressing (TH
) neurons in the ventral tegmental area. Here we report that neuronal firing in the locus coeruleus is especially sensitive to environmental novelty, locus coeruleus TH
neurons project more profusely than ventral tegmental area TH
neurons to the hippocampus, optogenetic activation of locus coeruleus TH
neurons mimics the novelty effect, and this novelty-associated memory enhancement is unaffected by ventral tegmental area inactivation. Surprisingly, two effects of locus coeruleus TH
photoactivation are sensitive to hippocampal D
/D
receptor blockade and resistant to adrenoceptor blockade: memory enhancement and long-lasting potentiation of synaptic transmission in CA1 ex vivo. Thus, locus coeruleus TH
neurons can mediate post-encoding memory enhancement in a manner consistent with possible co-release of dopamine in the hippocampus.
Rapid place encoding by hippocampal neurons, as reflected by place-related firing, has been intensely studied, whereas the substrates that translate hippocampal place codes into behavior have ...received little attention. A key point relevant to this translation is that hippocampal organization is characterized by functional-anatomical gradients along the septotemporal axis: Whereas the ability of hippocampal neurons to encode accurate place information declines from the septal to temporal end, hippocampal connectivity to prefrontal and subcortical sites that might relate such place information to behavioral-control processes shows an opposite gradient. We examined in rats the impact of selective lesions to relevant parts of the hippocampus on behavioral tests requiring place learning (watermaze procedures) and on in vivo electrophysiological models of hippocampal encoding (long-term potentiation LTP, place cells). We found that the intermediate hippocampus is necessary and largely sufficient for behavioral performance based on rapid place learning. In contrast, a residual septal pole of the hippocampus, although displaying intact electrophysiological indices of rapid information encoding (LTP, precise place-related firing, and rapid remapping), failed to sustain watermaze performance based on rapid place learning. These data highlight the important distinction between hippocampal encoding and the behavioral performance based on such encoding, and suggest that the intermediate hippocampus, where substrates of rapid accurate place encoding converge with links to behavioral control, is critical to translate rapid (one-trial) place learning into navigational performance.
Three experiments investigated the role in memory processing of dopamine (DA) afferents to the hippocampus (HPC) that arise from the ventral tegmental area. One hypothesis is that D(1)/D(5) receptor ...activation in HPC is necessary for the encoding of novel, episodic-like information; the other is that DA activation ensures the greater temporal persistence of transient hippocampal memory traces. Rats (n = 35) were trained, in separate experiments using an episodic-like memory task, to learn six paired associates (PAs) in an "event arena" involving a repeated association between specific flavors of food and locations in space. After 6 weeks of training, rats had learned a "schema" such that two new paired associates could be acquired in a single trial in one session (episodic-like memory). We show that encoding of novel PAs is sensitive to intrahippocampal microinfusion of the NMDA antagonist d-AP-5. Experiment 1 established that intrahippocampal infusion of the D(1)/D(5) dopaminergic antagonist SCH23390 R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride before encoding of new PAs caused impaired memory 24 h later but that SCH23390 had no effect on the later memory of previously established PAs. Experiment 2 established that SCH23390 modulated the persistence of new memories over time (30 min vs 24 h) rather than affecting initial encoding. Experiment 3 revealed that the impact of SCH23390 was not mediated by state dependence nor had an effect on memory retrieval. These findings support the second hypothesis and establish that persistent, long-term memory of rapid, hippocampal-mediated acquisition of new paired associates requires activation of D(1)/D(5) receptors in HPC at or around the time of encoding.
The current neuroscience of memory takes on board the remarkable achievements of molecular neurobiology and merges them with findings from systems neuroscience and cognitive psychology. This results ...in a highly dynamic depiction of the memory trace, appreciating its restlessness and incessant assimilation into accumulating knowledge. With an armamentarium of amazing methodologies at hand, and more around the corner, we still lack dictionaries of neuronal codes, able to translate spatiotemporal patterns of brain activity into behavioral tokens. But the path to getting there continues to fascinate, to be accompanied by fresh challenges and new approaches.
With a wealth of new technologies and a diversity of systems, we have a clearer picture of the mechanisms that contribute to learning and memory and yet many questions remain. Yadin Dudai and Richard Morris review how the science of memory has evolved in the last 25 years.
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