Amnesic Treatments Research Articles

Memory Integration as a Challenge to the Consolidation/Reconsolidation Hypothesis: Similarities, Differences and Perspectives.

We recently proposed that retrograde amnesia does not result from a disruption of the consolidation/reconsolidation processes but rather to the integration of the internal state induced by the amnesic treatment within the initial memory. Accordingly, the performance disruption induced by an amnesic agent does not result from a disruption of the memory fixation process, but from a difference in the internal state present during the learning phase (or reactivation) and at the later retention test: a case of state-dependency. In the present article, we will review similarities and differences these two competing views may have on memory processing. We will also consider the consequences the integration concept may have on the way memory is built, maintained and retrieved, as well as future research perspectives that such a new view may generate.

P.2.048 - On the synaptic tagging and capture hypothesis and the process of memory reconsolidation

The Synaptic Tagging and Capture (STC) hypothesis proposes that a strong stimulation of a synaptic pathway leads to two dissociable events: (a) local tag setting and (b) the synthesis of diffusible plasticity-related proteins (PRPs) [1]. The PRPs are then “captured” by the tagged synapses allowing the sustenance of long-term potentiation (LTP). Recent behavioral studies suggest that long-term memory (LTM) may also require both synaptic tagging and PRP synthesis in order to persist [2,3]. The studies show that weak events, only able to induce short-term memory (STM), could lead to LTM when the training was associated with parallel stronger experience (i.e. capable of inducing the synthesis of PRPs). Here we investigate whether the process of labilization and reconsolidation of a memory could also involve a mechanism of Synaptic Tagging and Capture. More specifically, for the pilot study presented here (n = 5-8), we aimed to evaluate whether the amnesic effect of the NMDAr inhibitor, MK-801, upon the reactivation of a contextual fear memory (CFC), could be prevented by pairing the event with a strong experience (exposure to novel environment). For that, adult male long-evans rats (200–300g), co-housed in groups of 4 per cage, under a 12 h light/dark cycle and at temperature of 24 C, with water and food ad libitum were used, in accordance to local and national animal care guidelines. On day one, rats were placed in the CFC chamber for 3 min, received 2 foot shocks (0.7 mA 1.5 sec), separated by a 30-sec interval, and after 1 min, rats returned to their home cages. Two days later, animals on the experimental group were exposed to a novel arena (control animals remained on homecages) and one hour later were reexposed to the CFC context (5 min). MK-801 or Saline was injected intraperitoneally (1mg/kg) immediately after. On the next day, all animals were exposed once more to the CFC context (4 min) in order to assess memory expression. The aversive response (freezing) were recorded during all sessions and used as the memory index. Two-way ANOVA revealed marginal effect of drug (p = 0.08; Saline x MK-801), a significant effect of group (p= 0.02; Control x Novelty) and no interaction (p = 0.22; Drug x Group). Further analysis with Tukey post-hoc revealed a significant difference between the animals not exposed to novelty and treated with MK-801, and those treated with MK-801 as well, but previously exposed to novelty (p = 0.03). The results are still preliminary, but indicate that the exposure to a novel experience (supposedly capable of inducing PRPs synthesis in Hippocampus) is able to prevent the effects associated to amnesic treatment after the reactivation of a contextual fear memory. This associative phenomenon could be the first step suggesting the involvement of a Synaptic Tagging and Capture mechanism in process of memory labilization and reconsolidation.

Who is the boss? Individual recognition memory and social hierarchy formation in crayfish.

Under laboratory conditions, crayfish establish hierarchical orders through agonistic encounters whose outcome defines the dominant one and one, or more, submissive animals. These agonistic encounters are ritualistic, based on threats, pushes, attacks, grabs, and avoidance behaviors that include retreats and escape responses. Agonistic behavior in a triad of unfamiliar, size-matched animals is intense on the first day of social interaction and the intensity fades on daily repetitions. The dominant animal keeps its status for long periods, and the submissive ones seem to remember 'who the boss is'. It has been assumed that animals remember and recognize their hierarchical status by urine signals, but the putative substance mediating this recognition has not been reported. The aim of this work was to characterize this hierarchical recognition memory. Triads of unfamiliar crayfish (male animals, size and weight-matched) were faced during standardized agonistic protocols for five consecutive days to analyze memory acquisition dynamics (Experiment 1). In Experiment 2, dominant crayfish were shifted among triads to disclose whether hierarchy depended upon individual recognition memory or recognition of status. The maintenance of the hierarchical structure without behavioral reinforcement was assessed by immobilizing the dominant animal during eleven daily agonistic encounters, and considering any shift in the dominance order (Experiment 3). Standard amnesic treatments (anisomycin, scopolamine or cold-anesthesia) were given to all members of the triads immediately after the first interaction session to prevent individual recognition memory consolidation and evaluate its effect on the hierarchical order (Experiment 4). Acquisition of hierarchical recognition occurs at the first agonistic encounter and agonistic behavior gradually diminishes in the following days; animals keep their hierarchical order despite the inability of the dominant crayfish to attack the submissive ones. Finally, blocking of protein synthesis or muscarinic receptors and cold anesthesia impair memory consolidation. These findings suggest that agonistic encounters induces the acquisition of a robust and lasting social recognition memory in crayfish.

Commentary: Rehebbilitating Memory.

Commentary: Rehebbilitating Memory.

Integration of New Information with Active Memory Accounts for Retrograde Amnesia: A Challenge to the Consolidation/Reconsolidation Hypothesis?

This study provides evidence challenging the traditional consolidation/reconsolidation hypotheses that have dominated the literature over the past 50 years. Based on amnesia studies, that hypothesis states that active (i.e., new and reactivated) memories are similarly labile and (re)established in a time-dependent manner within the brain through processes that require de novo protein synthesis. Our data show that new/reactivated memories can be formed without protein synthesis and that amnesia can be induced by drugs that do not affect protein synthesis. We propose that amnesia results from memory integration of the internal state produced by the drug that is subsequently necessary for retrieval of the memory. This interpretation gives a dynamic view of memory, rapidly stored and easily updated when active.

Neonatal representation of odour objects: distinct memories of the whole and its parts.

Extraction of relevant information from highly complex environments is a prerequisite to survival. Within odour mixtures, such information is contained in the odours of specific elements or in the mixture configuration perceived as a whole unique odour. For instance, an AB mixture of the element A (ethyl isobutyrate) and the element B (ethyl maltol) generates a configural AB percept in humans and apparently in another species, the rabbit. Here, we examined whether the memory of such a configuration is distinct from the memory of the individual odorants. Taking advantage of the newborn rabbit's ability to learn odour mixtures, we combined behavioural and pharmacological tools to specifically eliminate elemental memory of A and B after conditioning to the AB mixture and evaluate consequences on configural memory of AB. The amnesic treatment suppressed responsiveness to A and B but not to AB. Two other experiments confirmed the specific perception and particular memory of the AB mixture. These data demonstrate the existence of configurations in certain odour mixtures and their representation as unique objects: after learning, animals form a configural memory of these mixtures, which coexists with, but is relatively dissociated from, memory of their elements. This capability emerges very early in life.

Intense emotional experiences and enhanced training prevent memory loss induced by post-training amnesic treatments administered to the striatum, amygdala, hippocampus or substantia nigra

Most of the work related to the neurobiological basis of memory has been guided by the memory consolidation theory, which was derived from the seminal work of Miiller and Pilzecker that was published over a century ago. This theory proposes that the transfer from short- to long-term memory is mediated by a process called consolidation,and while consolidation is taking place, the information to be stored is in a labile state. A great deal of experimentation has given strong support to this proposal,as it has been found repeatedly that interference with neural activity shortly after a learning experience impedes durable retention of that experience. A growing body of evidence, however, indicates that intense emotional experiences prevent memory loss induced by amnesic treatments,even when these treatments are administered intracerebrally shortly after the learning experience. This evidence implies that the memory consolidation theory cannot account for long-term memory formation when neural activity is disrupted while consolidation should be taking place, and it calls for new hypotheses to account for these findings.

Extinction procedure induces pruning of dendritic spines in CA1 hippocampal field depending on strength of training in rats.

Numerous reports indicate that learning and memory of conditioned responses are accompanied by genesis of dendritic spines in the hippocampus, although there is a conspicuous lack of information regarding spine modifications after behavioral extinction. There is ample evidence that treatments that typically produce amnesia become innocuous when animals are submitted to a procedure of enhanced training. We now report that extinction of inhibitory avoidance (IA), trained with relatively low foot-shock intensities, induces pruning of dendritic spines along the length of the apical dendrites of hippocampal CA1 neurons. When animals are trained with a relatively high foot-shock there is a high resistance to extinction, and pruning in the proximal and medial segments of the apical dendrite are seen, while spine count in the distal dendrite remains normal. These results indicate that pruning is involved in behavioral extinction, while maintenance of spines is a probable mechanism that mediates the protecting effect against amnesic treatments produced by enhanced training.

Modulation of fear memory by retrieval and extinction: a clue for memory deconsolidation

Memories are fragile and easily forgotten at first, but after a consolidation period of hours to weeks, are inscribed in our brains as stable traces, no longer vulnerable to conventional amnesic treatments. Retrieval of a memory renders it labile, akin to the early stages of consolidation. This phenomenon has been explored as memory reactivation, in the sense that the memory is temporarily 'deconsolidated', allowing a short time window for amnesic intervention. This window closes again after reconsolidation, which restores the stability of the memory. In contrast to this 'transient deconsolidation' and the short-spanned amnesic effects of consolidation blockers, some specific treatments can disrupt even consolidated memory, leading to apparent amnesia. We propose the term 'amnesic deconsolidation' to describe such processes that lead to disruption of consolidated memory and/or consolidated memory traces. We review studies of these 'amnesic deconsolidation' treatments that enhance memory extinction, alleviate relapse, and reverse learning-induced plasticity. The transient deconsolidation that memory retrieval induces and the amnesic deconsolidation that these regimes induce both seem to dislodge a component that stabilizes consolidated memory. Characterizing this component, at both molecular and network levels, will provide a key to developing clinical treatments for memory-related disorders and to defining the consolidated memory trace.

A Bridge Over Troubled Water: Reconsolidation as a Link Between Cognitive and Neuroscientific Memory Research Traditions

There are two research traditions on dynamic memory processes. In cognitive psychology, the malleable nature of long-term memory has been extensively documented. Distortions, such as the misinformation effect or hindsight bias, illustrate that memories can be easily changed, often without their owner taking notice. On the other hand, effects like hypermnesia demonstrate that memory might be more reliable than these distortions suggest. In the neuroscience field, similar observations were obtained mostly from animal studies. Research on memory consolidation suggested that memories become progressively resistant to amnesic treatments over time, but the reconsolidation phenomenon showed that this stability can be transiently lifted when these memories are reactivated, i.e., retrieved. Surprisingly, both research traditions have not taken much notice of each others' advances in understanding memory dynamics. We apply concepts developed in neuroscience to phenomena revealed in cognitive psychology to illustrate how these twins separated at birth may be reunited again.

Kin recognition loss following anesthesia in beetle larvae (Aleochara bilineata, Coleoptera, Staphylinidae)

Kin recognition is a complex cognitive process, where an individual should detect a phenotypic cue and compare it to an internal template, which might be genetically determined (i.e., innate or acquired). Kin recognition mechanisms will depend on whether previous encounters with kin are possible or not to form the individual internal template. When relatives have never met before, kin recognition is supposed to rely on recognition alleles (which allows the innate recognition of relatives bearing them), or on self-referent phenotype matching (the individual has formed a template using its own phenotype and recognizes as kin individuals which match it closely enough). Although self-referent phenotype matching is in theory the more likely explanation, it has not been possible so far to exclude experimentally the recognition alleles' hypothesis. Here, we report that kin recognition in the solitary parasitoid larvae of Aleochara bilineata (Coleoptera; Staphylinidae) is suppressed following carbon dioxide anesthesia or chill-coma, both treatments known to cause a temporary amnesia. Treated larvae superparasitize indifferently hosts parasitized either by siblings or by non-kin larvae, while untreated larvae avoid hosts occupied by siblings. The two types of anesthesia thus suppress kin recognition, but their global effect on larvae is different. Chill-coma suppresses the ability to distinguish parasitized from unparasitized hosts and reduces parasitism rate, suggesting an aspecific impairment of sensory receptors or cognition. However, carbon dioxide narcosis only impairs kin recognition, strongly suggesting that an intact memory is necessary for kin recognition to take place. Although this study does not address the recognition alleles' hypothesis per se, our results strongly support a self-referent phenotype matching mechanism. On the whole, kin recognition in A. bilineata larvae is effective through short-term memory, because it is affected by amnesic treatments.

Enhanced inhibitory avoidance learning prevents the long-term memory-impairing effects of cycloheximide, a protein synthesis inhibitor

Interference with activity of numerous cerebral structures produces memory deficiencies; in many instances, however, when animals are over-trained such interference becomes innocuous. Systemic administration of protein synthesis inhibitors impairs long-term retention; this effect has been interpreted to mean that protein synthesis is required for memory consolidation, though little is known about the effect of protein synthesis inhibitors on memory of enhanced learning in the rat. To further analyze the protective effect of enhanced learning against amnesic treatments, groups of Wistar rats were trained in a one-trial step-through inhibitory avoidance task, using different intensities of foot-shock during training. Cycloheximide (CXM; 2.8 mg/kg), an inhibitor of protein synthesis, was injected either 30 min before training or immediately after training. Twenty-four hours after training retention latencies were recorded. Our data showed that both pre- and post-training administration of CXM produced amnesia in those groups that had been trained with relatively low foot-shock intensities, but no impairment in retention was observed when relatively high intensities of foot-shock were administered. These and similar results lead us to conclude that protein synthesis inhibitors may interfere with memory consolidation, but their effect disappears when animals are submitted to an enhanced learning experience, calling into question the idea that protein synthesis is required for memory consolidation.

Memory consolidation and reconsolidation in an invertebrate model: The role of the GABAergic system

Consolidation theory assumes that memories are labile during a limited time window after acquisition, but as time passes, memories become stable and resistant to amnesic agents. However, the vision of immutable memories after consolidation has been challenged. Thus, after the presentation of a reminder, the reactivated old memories become labile and again susceptible to amnesic treatments. This process implies a re-stabilization phase, usually referred to as reconsolidation.Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter both in the Central nervous system (CNS) and in the periphery. A considerable amount of evidence has arisen from different studies regarding the role of the GABAA receptor in diverse behavioral paradigms and tasks. Here, we investigate the role of the GABAergic system on both memory consolidation and reconsolidation phases by using the memory paradigm of the crab Chasmagnathus. In order to achieve such a goal, we design pharmacological-behavioral experiments, which include the administration of classic agonist (muscimol) and antagonist (bicuculline) of the mammals GABAA receptors. The current results show that the systemic administration of muscimol impairs the consolidation and reconsolidation processes. In contrast, the administration of bicuculline improves the consolidation and reconsolidation processes. Furthermore, the co-administration of both drugs blocks the agonist amnesic effect on the consolidation phase.The ubiquity of the neurotransmitter and its receptors in the animal taxa allows us to use the classic agonist-and-antagonist administration procedure in this invertebrate. Thus, all the results reported in this paper can be judged as a result of the modulation exerted by the functional state of the GABAergic system in the CNS.To conclude, the results obtained in this report with an invertebrate model represent additional evidences supporting the view that some molecular mechanisms subserving different memory phases could be the basic tools employed by phylogenetically disparate animals.

Acquisition and retention of enhanced active avoidance are unaffected by interference with serotonergic activity

Pre-training administration of p-chloroamphetamine (PCA) produces reliable deficits of avoidance learning. When animals are trained in inhibitory avoidance with relatively high foot-shock intensities, other amnesic treatments have no effect. The present experiment was conducted to determine if this protective effect of high foot shock is also observed after administration of PCA (10 mg/kg, i.p., injected 7 days before training; this dose produces a lesion of central serotonin neurons). Rats were trained in active avoidance (a single 20-trial session), administering shocks of 0.6, 0.8, 1.0, or 1.4 mA to independent groups of rats. When compared to saline-injected groups trained with the same intensities, PCA produced a significant learning deficit in the low foot-shock groups, but not in the high foot-shock animals. These results indicate that the dose of PCA administered, which is known to deplete cerebral serotonin, does not interfere with acquisition and retention of enhanced active avoidance training.

Transient Disruption of Fear-Related Memory by Post-Retrieval Inactivation of Gastrin-Releasing Peptide or N-Methyl-D-Aspartate Receptors in the Hippocampus

Molecular accounts of memory consolidation suggest that new learning generates persistent synaptic modifications through activation of an extensive set of neuronal receptors and intracellular signal transduction pathways, accompanied by RNA and protein synthesis. This traditional cellular consolidation theory has been challenged by evidence that reactivation of a previously consolidated memory might render this memory again susceptible to disruption by amnesic treatments, a process generally referred to as reconsolidation. Current evidence indicates that reconsolidation can be disrupted by administration of a variety of pharmacological agents after memory reactivation. Previous studies have indicated that the gastrin-releasing preferring type of bombesin receptor (GRPR) and the N-methyl-D-aspartate glutamate receptor (NMDAR) in the rat hippocampus are involved in consolidation of inhibitory avoidance (IA), a fear-related memory task. We show here that blockade of hippocampal GRPRs or NMDARs after memory reactivation temporarily disrupts memory retention. Post-retrieval intra-hippocampal infusion of the GRPR antagonist RC-3095 or the NMDAR antagonist aminophosphonopentanoic acid (AP5) produced an impairment of IA performance tested 2 days after training in rats. However, this impairment was transient and recovered to levels of control rats in a subsequent test 3 days after training. The drug effects were only present after memory reactivation and not in its absence. These findings provide evidence that GRPR or NMDAR inactivation after retrieval can impair fear memory.

Retrieval failure versus memory loss in experimental amnesia: definitions and processes.

For at least 40 years, there has been a recurring argument concerning the nature of experimental amnesia, with one side arguing that amnesic treatments interfere with the formation of enduring memories and the other side arguing that these treatments interfere with the expression of memories that were effectively encoded. The argument appears to stem from a combination of (1) unclear definitions and (2) real differences in the theoretical vantages that underlie the interpretation of relevant data. Here we speak to how the field might avoid arguments that are definitional in nature and how various hypotheses fare in light of published data. Existing but often overlooked data favor very rapid (milliseconds) synaptic consolidation, with experimental amnesia reflecting, at least in part, deficits in retrieval rather than in the initial storage of information.

Aversive memory reactivation engages in the amygdala only some neurotransmitters involved in consolidation

Consolidation refers to item stabilization in long-term memory. Retrieval renders a consolidated memory sensitive, and a "reconsolidation" process has been hypothesized to keep the original memory persistent. Some authors could not detect this phenomenon. Here we show that retrieved contextual fear memory is vulnerable to amnesic treatments and that the amygdala is critically involved. Cholinergic and histaminergic systems seem to modulate only consolidation, whereas cannabinoids are involved in both consolidation and reactivation. The lability of retrieved memory affords opportunities to treat disorders such as phobias, post-traumatic stress, or chronic pain, and these results help searching for appropriate therapeutic targets.

Interpretations of retrograde amnesia: old problems redux.

Recent evidence indicates that an old memory reactivated by cueing becomes labile and vulnerable to an amnesic treatment. Although the 'reconsolidation' concept derived from these findings challenges the traditional consolidation theory, here we argue that the new concept suffers from some of the same limitations as the earlier model. We propose an alternative retrieval-based theory that accommodates the recent data, as well as other puzzling related observations.

The interplay of learning and anxiety in the elevated plus-maze.

In naive rats benzodiazepines have clear anxiolytic effects in the elevated plus-maze, but in rats with previous plus-maze experience benzodiazepines are ineffective. This phenomenon does not depend on the drug state on trial 1 or on the inter-trial interval and generalises across mazes of different material; it is dependent on experience of the open arm. The phenomenon of "one-trial tolerance" to the anxiolytic effect of benzodiazepines is not seen in other animal tests; and there is no equivalent phenomenon of "one-trial withdrawal" or of tolerance to anxiogenic effects in the plus-maze. The phenomenon is not seen in unhandled rats, in rats given longer trials in the plus-maze, or in those given an amnesic treatment on trial 1. It is suggested that during the first 5 min in the elevated plus-maze the rats are acquiring a fear of heights and it is this phobic anxiety state that is measured during the second 5-min trial. Thus the nature of the anxiety generated by the maze is different on trials 1 and 2. The results of a factor analysis study confirm this conclusion.

Potential cognition‐enhancing properties of S 9977 in three moenls of amnesia in the mouse

AbstractThe effects of S 9977 (1,3,7‐trimethyl 8‐[3‐(4‐diethylaminocarbonyl‐l‐piperazinyl) 1‐propyl]‐3,7‐dihydro(1H)2,6‐purinedione hydrochloride) on the amnesias induced by scopolamine, diazepam, and electroconvulsive shock (ECS) were studied in a passive avoidance procedure in the mouse. Amnesia was induced by injecting scopolamine or diazepam (1 mg/kg i.p.) 30 min before or ECS administered immediately after the first session (S1) of the passive avoidance task. S 9977 was studied in a dose range of 0.0312–16 mg/kg administered p.o. 60 min before S1. Retention was measured 24 hr later (S2) in the absence of any treatment. S 9977 was also investigated after repeated administration (twice daily for 3 days and then 60 min before acquisition on the 4th day) using the scopolamine‐induced amnesia model. Additional experiments investigated the interactions of the compound with the major behavioral effects of the amnesic treatments, namely scopolamine‐induced hyperactivity (activity meter test), diazepam‐induced release of punished behavior (four plates test), and ECS‐induced convulsion. S 9977 at low doses (0.0312–0.5 mg/kg p.o.) clearly attenuated the memory deficits induced by the three amnesic treatments after acute treatment and no tolerance was observed after repeated treatment in the scopolamine model. S 9977 did not affect either scopolamine‐induced hyperactivity, diazepam‐induced release of punished behavior, or ECS‐induced convulsions. These results point to the specificity of S 9977's antiamnesic activity and suggest that it might be a useful agent for the treatment of memory deficits of different origins in humans. © 1992 Wiley‐Liss, Inc.