Yadin Dudai

Rites of Passage of the Engram: Reconsolidation and the Lingering Consolidation Hypothesis

Memory consolidation refers to the progressive stabilization of items in long-term memory as well as to the memory phase(s) during which this stabilization takes place. The textbook account is that, for each item in memory, consolidation starts and ends just once. In recent years, however, the notion that memories reconsolidate upon their reactivation and hence regain sensitivity to amnestic agents has been revitalized. This issue is of marked theoretical and clinical interest. Here we review the recent literature on reconsolidation and infer, on the basis of the majority of the data, that blockade of reconsolidation does not induce permanent amnesia. Further, in several systems, reconsolidation occurs only in relatively fresh memories. We propose a framework model, which interprets reconsolidation as a manifestation of lingering consolidation, rather than recapitulation of a process that had already come to a closure. This model reflects on the nature of consolidation in general and makes predictions that could guide further research.

The Restless Engram: Consolidations Never End

Memory consolidation is the hypothetical process in which an item in memory is transformed into a long-term form. It is commonly addressed at two complementary levels of description and analysis: the cellular/synaptic level (synaptic consolidation) and the brain systems level (systems consolidation). This article focuses on selected recent advances in consolidation research, including the reconsolidation of long-term memory items, the brain mechanisms of transformation of the content and of cue-dependency of memory items over time, as well as the role of rest and sleep in consolidating and shaping memories. Taken together, the picture that emerges is of dynamic engrams that are formed, modified, and remodified over time at the systems level by using synaptic consolidation mechanisms as subroutines. This implies that, contrary to interpretations that have dominated neuroscience for a while, but similar to long-standing cognitive concepts, consolidation of at least some items in long-term memory may never really come to an end.

The Molecular and Systems Biology of Memory

Learning and memory are two of the most magical capabilities of our mind. Learning is the biological process of acquiring new knowledge about the world, and memory is the process of retaining and reconstructing that knowledge over time. Most of our knowledge of the world and most of our skills are not innate but learned. Thus, we are who we are in large part because of what we have learned and what we remember and forget. In this Review, we examine the molecular, cellular, and circuit mechanisms that underlie how memories are made, stored, retrieved, and lost.

Taste memory: The role of protein synthesis in gustatory cortex

Application of the protein synthesis inhibitor anisomycin to the rat gustatory cortex before and during training impairs conditioned taste aversion (CTA) to saccharin. No behavioral impairment is observed if the inhibitor is applied to an adjacent cortical area or to one cortical hemisphere only. The consumption of saccharin and of total fluid, as well as behavioral recognition of saccharin, is not affected. Preexposure of rats to saccharin several days before training markedly inhibits CTA to that taste. Injection of anisomycin to the gustatory cortex immediately prior to the preexposure period attenuates the latent inhibition. These results suggest that protein synthesis in the gustatory cortex is required for normal acquisition of the memory of taste.

Memory reconsolidation: sensitivity of spatial memory to inhibition of protein synthesis in dorsal hippocampus during encoding and retrieval.

Reconsolidation is a putative neuronal process in which the retrieval of a previously consolidated memory returns it to a labile state that is once again subject to stabilization. This study explored the idea that reconsolidation occurs in spatial memory when animals retrieve memory under circumstances in which new memory encoding is likely to occur. Control studies confirmed that intrahippocampal infusions of anisomycin inhibited protein synthesis locally and that the spatial training protocols we used are subject to overnight protein synthesis-dependent consolidation. We then compared the impact of anisomycin in two conditions: when memory retrieval occurred in a reference memory task after performance had reached asymptote over several days; and after a comparable extent of training of a delayed matching-to-place task in which new memory encoding was required each day. Sensitivity to intrahippocampal anisomycin was observed only in the protocol involving new memory encoding at the time of retrieval.

NMDA Receptor and the Tyrosine Phosphorylation of Its 2B Subunit in Taste Learning in the Rat Insular Cortex

We demonstrate that the NMDA receptor is involved in taste learning in the insular cortex of the behaving rat and describe two facets of this involvement. Blockage of the NMDA receptor in the insular cortex by the reversible antagonist APV during training in a conditioned taste aversion (CTA) paradigm impaired CTA memory, whereas blockage of the NMDA receptor in an adjacent cortex or before a retrieval test had no effect. When rats sampled an unfamiliar taste and hence learned about it, either incidentally or in the context of CTA training, the tyrosine phosphorylation of the NMDA receptor subunit 2B (NR2B) in the insular cortex was specifically increased. The level of tyrosine phosphorylation on NR2B was a function of the novelty of the taste stimulus and the quantity of the taste substance consumed, properties that also determined the efficacy of the taste stimulus as a conditioned stimulus in CTA; however, blockage of the NMDA receptor by APV during training did not prevent tyrosine phosphorylation of NR2B. We suggest that tyrosine phosphorylation of NR2B subserves encoding of saliency in the insular cortex during the first hours after an unfamiliar taste is sampled and that this encoding is independent of another, necessary role of NMDA receptors in triggering experience-dependent modifications in the insular cortex during taste learning. Because a substantial fraction of the NR2B protein in the insular cortex seems to be expressed in interneurons, saliency and the tyrosine phosphorylation of NR2B correlated with it may modulate inhibition in cortex.

Molecular bases of long-term memories: a question of persistence

The most distinctive attribute of long-term memory is persistence over time. New studies have uncovered many aspects of the molecular and cellular biology of synaptic plasticity, and the acquisition and consolidation of memory, which are thought to depend on synaptic plasticity. Much less, however, is known about the molecular and cellular biology of long-term memory persistence. Recent findings in the field are construed within the conceptual framework that proposes that consolidation and persistence of long-term memories require modulation of gene expression, which can culminate in synaptic remodeling. Whether modulation of gene expression, and particularly the ensuing morphological plasticity of the synapse, is permissive, causal or sufficient for the materialization and persistence of the long-term trace is, as yet, undetermined. How persistent is persistence? Renewed interest is focused on the possibility that some long-term memories consolidate anew with retrieval, and could, under certain conditions, become transiently shaky in this period of reconsolidation.

Distribution of an α-bungarotoxin-binding cholinergic nicotinic receptor in rat brain

Cholinergic nicotinic receptors in rat brain were demonstrated by the use of the potent nicotinic antagonist [125I]alpha-bungarotoxin [125I]alpha-Btx). Biochemical studies on binding of [125I]alpha-Btx to rat hippocampal homogenates revealed saturable binding sites which are protected by nicotine, D-tuborcurarine and acetylcholine but not by atropine or oxotremorine. The hippocampus and hypothalamus displayed relatively high [125I]alpha-Btx specific binding whereas the cerebellum was devoid of specific binding. Other regions displayed intermediate binding levels. Analysis of the regional distribution of [125I]alpha-Btx binding by autoradiography of frontal brain sections revealed high labeling in the hippocampus, hypothalamic supraoptic, suprachiasmatic and periventricular nuclei, ventral lateral geniculate and the mesencephalic dorsal tegmental nucleus. It is suggested that the limbic forebrain and midbrain structures as well as sensory nuclei are the main nicotinic cholinoceptive structures in the brain.

Reconsolidation of fresh, remote, and extinguished fear memory in medaka: old fears don't die

Long‐term fear memory in the medaka fish (Oryzias latipes) regains transient sensitivity to a consolidation blocker immediately after memory reactivation in retrieval (‘reconsolidation’). Here we show that reconsolidation occurs in fresh long‐term memories but not in remote memories, and that the apparent amnesia induced by blockade of reconsolidation can be reinstated by an unpaired reinforcer, a procedure that has no effect on amnesia induced by blockade of consolidation. Extinction memory also undergoes post‐reactivation reconsolidation, the blockade of which exposes the previously acquired fear. Hence in medaka, the process manifested in reconsolidation seems itself to consolidate; moreover, even when the post‐reactivation application of the consolidation blocker is still able to disrupt the memory, the conditioned fear does not seem to go away permanently.

Enhancement of Consolidated Long-Term Memory by Overexpression of Protein Kinase Mζ in the Neocortex

In rats, overexpression of a persistently active protein kinase C isoform enhances memories long after they have been formed. Memories are more easily disrupted than improved. Many agents can impair memories during encoding and consolidation. In contrast, the armamentarium of potential memory enhancers is so far rather modest. Moreover, the effect of the latter appears to be limited to enhancing new memories during encoding and the initial period of cellular consolidation, which can last from a few minutes to hours after learning. Here, we report that overexpression in the rat neocortex of the protein kinase C isozyme protein kinase Mζ (PKMζ) enhances long-term memory, whereas a dominant negative PKMζ disrupts memory, even long after memory has been formed.