Reconsolidation reconsidered

Some of the considerations that led to a consolidation interpretation of retrograde amnesia (RA), which states that RA results from the disruption of memory processing and storage when neural activity is interrupted by a brain insult, are reviewed here. The time-dependent gradient of memory loss (i.e., new memories are more vulnerable to amnesia than old memories) that characterizes RA seemed to fit nicely with the notion of a cascade of cellular events occurring during the immediate post-acquisition period that would transform a labile representation into a more stable form (i.e., consolidate the memory). However, a variety of observations came to challenge the storage-disruption model, and among these was the finding of amnesia for old but reactivated memories. A recent study by Nader, Schafe, and LeDoux (2000) provides an important analytic extension of the work on “reconsolidation” by showing that inhibition of protein synthesis in the lateral and basal nuclei of the amygdala immediately following the reactivation of old memory will induce retrograde amnesia. We offer a retrieval-oriented conceptualization to account for the temporal gradient and the “reconsolidation” phenomena.     

The many faces of amnesia

Results from studies of retrograde amnesia provide much of the evidence for theories of memory consolidation. Retrograde amnesia gradients are often interpreted as revealing the time needed for the formation of long-term memories. The rapid forgetting observed after many amnestic treatments, including protein synthesis inhibitors, and the parallel decay seen in long-term potentiation experiments are presumed to reveal the duration of short-term memory processing. However, there is clear and consistent evidence that the time courses obtained in these amnesia experiments are highly variable within and across experiments and treatments. The evidence is inconsistent with identification of basic temporal properties of memory consolidation. Alternative views include modulation of memory and emphasize the roles that hormones and neurotransmitters have in regulating memory formation. Of related interest, converging lines of evidence suggest that inhibitors of protein synthesis and of other biochemical processes act on modulators of memory formation rather than on mechanisms of memory formation. Based on these findings, memory consolidation and reconsolidation studies might better be identified as memory modulation and "remodulation" studies. Beyond a missing and perhaps unattainable time constant of memory consolidation, some current views of memory consolidation assume that memories, once formed, are generally unmodifiable. It is this perspective that appears to have led to the recent interest in memory reconsolidation. But the view adopted here is that memories are continually malleable, being updated by new experiences and, at the same time, altering the memories of later experiences. Studies of memory remodulation offer promise of understanding the neurobiological bases by which new memories are altered by prior experiences and by which old memories are altered by new experiences.     

Retrograde amnesia in patients with hippocampal, medial temporal, temporal lobe, or frontal pathology

There is considerable controversy concerning the theoretical basis of retrograde amnesia (R.A.). In the present paper, we compare medial temporal, medial plus lateral temporal, and frontal lesion patients on a new autobiographical memory task and measures of the more semantic aspects of memory (famous faces and news events). Only those patients with damage extending beyond the medial temporal cortex into the lateral temporal regions showed severe impairment on free recall remote memory tasks, and this held for both the autobiographical and the more semantic memory tests. However, on t-test analysis, the medial temporal group was impaired in retrieving recent autobiographical memories. Within the medial temporal group, those patients who had combined hippocampal and parahippocampal atrophy (H+) on quantified MRI performed somewhat worse on the semantic tasks than those with atrophy confined to the hippocampi (H-), but scores were very similar on autobiographical episodic recall. Correlational analyses with regional MRI volumes showed that lateral temporal volume was correlated significantly with performance on all three retrograde amnesia tests. The findings are discussed in terms of consolidation, reconsolidation, and multiple trace theory: We suggest that a widely distributed network of regions underlies the retrieval of past memories, and that the extent of lateral temporal damage appears to be critical to the emergence of a severe remote memory impairment.     

人类记忆再巩固研究现状及临床应用

巩固的记忆被提取后,进入不稳定状态,再重新稳定下来,这个过程称为记忆再巩固。本文首先阐述人类记忆再巩固主要研究方法和经典范式,梳理记忆再巩固在人类恐惧记忆和情景记忆两个方面的相关研究,并从认知神经科学角度整理记忆再巩固的加工机制。然后总结记忆再巩固应用于创伤性应激障碍和药物成瘾等心理障碍临床治疗的相关文献。最后本文提出未来研究的方向和建议,希冀对人类记忆再巩固的理论研究和临床应用提供新思路。     

Choline reverses scopolamine-induced memory impairment by improving memory reconsolidation

It is widely known that pre-training systemic administration of the muscarinic antagonist scopolamine (SCP) (0.5mg/kg, i.p.) leads to anterograde memory impairment in retention tests. The administration of the α(7)-nicotinic receptor agonist choline (Ch) in the dorsal hippocampus (0.8μg/hippocampus) immediately after memory reactivation allowed recovery from scopolamine-induced memory impairment. This effect of Ch was time-dependent, and retention performance was not affected in drug-treated mice that were not subjected to memory reactivation, suggesting that the performance effects are not due to non-specific effects of the drug. The effects of Ch also depended on the age of the reactivated memory. Altogether, our results suggest that Ch exerts its effects by modulating memory reconsolidation, and that the memory impairment induced by low doses of SCP is a memory expression failure and not a storage deficit. Therefore, reconsolidation, among other functions, might serve to change memory expression in later tests. Summarizing, our results open new avenues about the behavioral significance and the physiological functions of memory reconsolidation, providing new strategies for recovering memories from some types of amnesia.     

Posthypnotic amnesia for a first romantic relationship: Forgetting the entire relationship versus forgetting selected events

This experiment investigated the impact of suggestion focus on posthypnotic amnesia (PHA) for memories of a first romantic relationship. During hypnosis, high and low hypnotisable participants recalled specific memories from this period in response to 10 cue phrases (Elicitation). They then received a PHA suggestion that targeted either the entire period or specific memories from that period. Participants' explicit memory was indexed by cued recall after PHA was administered (memories recalled to "old" and "new" cues; Recall 1) and after it was cancelled (Recall 2). A social judgement task indexed dissociations between implicit and explicit memory. PHA had the greatest impact on highs', but not lows', memory performance (in terms of memories recalled to old cues, recall latency, and qualitative memory ratings) when the suggestion targeted the entire period rather than specific events. We discuss these findings in terms of the parameters of PHA's influence on memory, its value for exploring the nature and structure of autobiographical memory, and its utility as a laboratory analogue of functional amnesia.     

A neuropsychological study of fact memory and source amnesia

We investigated the ability of amnesic patients to learn new facts (e.g., Angel Falls is located in Venezuela) and also to remember where and when the facts were learned (i.e., source memory). To assess the susceptibility of fact and source memory to retrograde amnesia, patients prescribed electroconvulsive therapy were presented facts prior to the first treatment and were tested after their second treatment. All amnesic patients exhibited marked fact memory impairment. In addition, some amnesic patients exhibited source amnesia (i.e., they recalled a few facts but then could not remember where or when those facts had been learned). Source amnesia was unrelated to the severity of the memory deficit itself, because patients who exhibited source amnesia recalled as many facts as the patients who did not. These results show that the deficit in amnesia includes an impairment in acquiring and retaining new facts. Source amnesia can also occur, but it is dissociable from impaired recall and recognition and appears to reflect difficulty in remembering the specific context in which information is acquired. The findings are discussed in terms of their significance for how memory is organized.     

Remote Memory Function and Dysfunction in Korsakoff’s Syndrome

Korsakoff's syndrome (KS) is a pervasive disorder of memory characterized by both anterograde and retrograde amnesia. Although retrograde memory impairment in KS has been less frequently studied, the status of remote memory in KS has been tested across a number of different tasks that measure knowledge of public information (e.g., famous faces/news events), general semantic information (e.g., vocabulary words), personal semantic information (e.g., facts about oneself), and autobiographical events (e.g., events from one's personal past). In each of these domains, Korsakoff patients demonstrate remote memory impairments that can extend back many years or decades. In addition, a majority of studies report that the extensive remote memory impairment in KS is temporally graded, with relative preservation of memories from childhood and early adulthood. The current paper reviews published experimental studies of remote memory in KS, with particular attention paid to (a) the selectivity of the deficit with respect to the age of the memory and (b) the relationship of memory impairment to underlying neuropathology. We discuss the significance of the reported pattern and extent of remote memory impairment with respect to theories about the nature of the underlying cognitive deficits in KS.     

Disrupting reconsolidation: pharmacological and behavioral manipulations

We previously demonstrated that disrupting reconsolidation by pharmacological manipulations "deleted" the emotional expression of a fear memory in humans. If we are to target reconsolidation in patients with anxiety disorders, the disruption of reconsolidation should produce content-limited modifications. At the same time, the fear-erasing effects should not be restricted to the feared cue itself considering that fear generalization is a main characteristic of anxiety disorders. In Experiment I and Experiment I(b), we addressed these issues using a within-subject differential startle fear conditioning paradigm and a test of fear generalization. In Experiment II, we tested whether a behavioral approach targeting the reconsolidation through extinction learning was also effective in weakening the original fear memory. A behavioral procedure is evidently preferred over drug manipulations provided that similar effects can be obtained. Here, the extinction procedure subsequent to retrieval did not "erase" the emotional expression of the fear memory as the retrieval techniques (i.e., reminder shocks and reacquisition) unveiled a return of the startle fear response to the fear-relevant stimuli. In contrast, β-adrenergic receptor blockade during reconsolidation selectively deleted the fear-arousing aspects of the memory (i.e., startle fear response) along with its category-related information. The pharmacological manipulation rendered the core memory trace too weak to observe fear generalization after successful reacquisition. Hence, relearning following the disruption of reconsolidation seems to be qualitatively different from initial learning. Our findings demonstrate that disrupting reconsolidation by pharmacological manipulations, although selective, undermines the generalization of fear, a key feature of anxiety disorders.     

Retrograde amnesia: forgetting back

Recently, the field of animal memory research has seen a resurgence of interest in the mechanisms underlying retrograde amnesia (RA) and in the use of RA as a technique for studying memory processes. A recent report from a major neuroscience lab, which demonstrated RA for an old reactivated memory, revitalized the debate regarding the widely accepted memory-consolidation theory of RA. Here, we discuss a number of the characteristics of RA and consider the findings that led to the development of the memory-consolidation hypothesis, as well as those suggesting an alternative retrieval-deficit explanation.     

Long-term memory for instrumental responses does not undergo protein synthesis-dependent reconsolidation upon retrieval

Recent evidence indicates that certain forms of memory, upon recall, may return to a labile state requiring the synthesis of new proteins in order to preserve or reconsolidate the original memory trace. While the initial consolidation of "instrumental memories" has been shown to require de novo protein synthesis in the nucleus accumbens, it is not known whether memories of this type undergo protein synthesis-dependent reconsolidation. Here we show that low doses of the protein synthesis inhibitor anisomycin (ANI; 5 or 20 mg/kg) administered systemically in rats immediately after recall of a lever-pressing task potently impaired performance on the following daily test sessions. We determined that the nature of this impairment was attributable to conditioned taste aversion (CTA) to the sugar reinforcer used in the task rather than to mnemonic or motoric impairments. However, by substituting a novel flavored reinforcer (chocolate pellets) prior to the administration of doses of ANI (150 or 210 mg/kg) previously shown to cause amnesia, a strong CTA to chocolate was induced sparing any aversion to sugar. Importantly, when sugar was reintroduced on the following session, we found that memory for the task was not significantly affected by ANI. Thus, these data suggest that memory for a well-learned instrumental response does not require protein synthesis-dependent reconsolidation as a means of long-term maintenance.     

Cycloheximide produces amnesia for extinction and reconsolidation in an appetitive odor discrimination task in rats

A considerable literature has shown deficits in memory resulting from the administration of protein synthesis inhibitors; however, most of the past literature in this field has focused on acquisition of new memory using aversively-motivated tasks. The effect of protein synthesis inhibition on appetitive learning and memory as well as extinction is less clear. The present study employed an appetitive odor discrimination paradigm to examine the effects of acute cycloheximide administration (1 mg/kg) on reconsolidation and extinction.Male, Long-Evans adult rats were trained to discriminate between two odors (i.e., cocoa and cinnamon) and then received extinction trials following an intraperitoneal injection of cycloheximide or vehicle. Twenty-four hours later, rats were tested via one non-reinforced test trial. Results showed amnesia for extinction as well as original training (i.e., correct odor choice) in cycloheximide-injected rats in this appetitive task, while vehicle-injected controls showed good memory for extinction. These data add to a growing literature showing the importance of protein synthesis inhibition for extinction and reconsolidation in appetitive learning and memory.     

逆行性遗忘、额叶与远期记忆的组织

通过对一例严重记忆障碍合并额叶损伤病人的逆行性遗忘的分析,对远期记忆的组织特点进行了探讨。被试的额叶功能受损较为明显。除顺行性遗忘外,患者的逆行性遗忘也较为严重。对病人进行的逆行性遗忘检测包括：著名人物测验、著名事件、一般知识测验和自传性记忆测验等。被试对著名人物、著名事件的回忆和再认成绩、以及有关个人的情节和语义记忆成绩均较低,但没有典型的随时间下降的趋势,而是呈平直斜率;患者儿童期的自传性记忆和公众事件记忆也受损。这两个特点均与内侧颞叶一间脑系统损伤的特点不同,提示额叶参与了远期记忆的提取等过程。     

Reconsolidation: a brief history, a retrieval view, and some recent issues

This review briefly traces some of the history of the phenomenon of what has come to be called "reconsolidation." The early findings of retrograde amnesia for an old but reactivated memory led to several interesting but largely behaviorally oriented studies. With only a few sporadic exceptions, research in the area languished until about 2000, when several articles caught the attention of the neuroscience community and led to a number of studies examining the phenomenon at several different levels of analysis. We consider several of the current issues generated by those studies, present a retrieval based model that may account for some findings, and indicate some possible new directions on this topic.     

Growth points in research on memory and hippocampus.

We present an overview of two of our on-going projects relating processes in the hippocampus to memory. We are trying to understand why retrograde amnesia occurs after damage to the hippocampus. Our experiments establish the generality of several new retrograde amnesia phenomena that are at odds with the consensus view of the role of the hippocampus in memory. We show in many memory tasks that complete damage to the hippocampus produces retrograde amnesia that is equivalent for recent and remote memories. Retrograde amnesia affects a much wider range of memory tasks than anterograde amnesia. Normal hippocampal processes can interfere with retention of a long-term memory stored outside the hippocampus. We conclude that the hippocampus competes with nonhippocampal systems during memory encoding and retrieval. Finally, we outline a project to understand and manipulate adult hippocampal neurogenesis in order to repair damaged hippocampal circuitry to recover lost cognitive functions.     

Consolidation theory and retrograde amnesia in humans

Recent research on the cognitive dysfunctions experienced by human anmesic patients indicates that very long term (multidecade) changes may occur in memory.Flat retrograde amnesia (RA), consisting of a uniform memory deficit for information from all preamnesia time periods, indicates a simple, monolithic retrieval problem, whereasgraded RA, with greater memory deficits for information from recent as opposed to remote time periods, suggests the presence of a gradual long-term encoding, or consolidation, process. An evaluation of 247 outcomes from 61 articles provides strong evidence of graded RA across different cerebral injuries, materials, and test procedures, as well as in measures of both absolute and relative (patient vs. control) performance. Future conceptualizations of human memory should address the possibility that memories increase in resistance to forgetting, or reduction in trace fragility, across many decades.     

Preserved ability to recognize keywords related to remote events in the absence of retrieval of relevant knowledge: a case of postencephalitic amnesia

We describe a case of severe anterograde and retrograde amnesia resulting from herpes simplex encephalitis. Magnetic resonance imaging revealed pathological changes in the bilateral hippocampi, parahippocampal gyri, fusiform gyri, medial temporal poles, posterior part of the cingulate gyri, and insula. The patient showed severe amnesia for autobiographical episodic memory in relation to events that had occurred throughout her life, but temporally graded amnesia for autobiographical semantic memory, and severe amnesia without a temporal gradient for public events and famous people. However, using a multiple-choice method, she showed a high level of accuracy when choosing keywords related to public or personal events, although this did not prompt her recollection of the events. An important indication of these results is that, even with severe retrograde amnesia, memories of past events are not completely lost. We propose that an event may be stored in a fragmented form, consisting of many components, and that normal recall of an event may require recombination or reconstruction of these components.     

对人类不良记忆的修饰：来自记忆再巩固的证据

已经巩固的长时记忆被再次提取后, 进入一个记忆的不稳定期, 在此过程中, 记忆可被更新、强化、削弱甚至抹除, 这个过程称为再巩固。人类不良记忆再巩固研究揭示记忆激活后口服普萘洛尔(propranolol)或进行消退训练可削弱或抹除不良情绪记忆, 此过程中涉及杏仁核、海马、前额叶皮层等脑区的参与及其构成的神经环路的调控。当前临床上利用再巩固原理可通过药物治疗、行为干预或无创脑部刺激的方法改变不良记忆。然而, 由于其形成过程复杂并受多种因素影响, 未来研究应尽可能模拟临床中人类不良记忆形成的复杂环境, 深入探讨再巩固“边界问题”, 推动实验室研究向临床应用的转化。     

Traumatic memories of war veterans: not so special after all

Several authors have argued that traumatic experiences are processed and remembered in a qualitatively different way from neutral events. To investigate this issue, we interviewed 121 Croatian war veterans diagnosed with posttraumatic stress disorder (PTSD) about amnesia, intrusions (i.e., flashbacks and nightmares), and the sensory qualities of their most horrific war memories. Additionally, they completed a self-report scale measuring dissociative experiences. In contrast to what one would expect on the basis of theories emphasizing the special status of traumatic memories, amnesia, and high frequency intrusions were not particularly typical for our sample of traumatized individuals. Moreover, traumatic memories were not qualitatively different from neutral memories with respect to their stability and sensory qualities. The severity of PTSD symptoms was not significantly correlated with dissociative experiences. Our findings do not support the existence of special memory mechanisms that are unique to experiencing traumatic events.     

Reactivation-dependent amnesia in Pavlovian approach and instrumental transfer

The theory of memory reconsolidation relates to the hypothesized restabilisation process that occurs following the reactivation of a memory through retrieval. Thus the demonstration of reactivation-dependent amnesia for a previously acquired memory is a prerequisite for showing that such a memory undergoes reconsolidation. Here we show that the appetitive Pavlovian representations that underlie Pavlovian approach and Pavlovian-instrumental transfer are destabilized following their retrieval. This reactivation-dependent amnesia demonstrates that the general motivational or incentive properties of appetitive conditioned stimuli, as well as their conditioned reinforcing properties, can be reduced by blocking memory reconsolidation.