Temporally Graded Requirement for Protein Synthesis following Memory Reactivation

AbstractLearning of new information is transformed into long-lasting memory through a process known as consolidation, which requires protein synthesis. Classical theory held that once consolidated, memory was insensitive to disruption. However, old memories that are insensitive to protein synthesis inhibitors can become vulnerable if they are recalled (reactivated). These findings led to a new hypothesis that when an old memory is reactivated, it again becomes labile and, similar to a newly formed memory, requires a process of reconsolidation in order to be maintained. Here, we show that the requirement for protein synthesis of a reactivated memory is evident only when the memory is recent. In fact, memory vulnerability decreases as the time between the original training and the recall increases

Auditory Event-Related P300 Potentials in Rheumatoid Arthritis Patients

The aim of the study was to assess P300 event-related potentials (ERPs) in patients suffering from rheumatoid arthritis (RA) in relation to the duration of illness, degree of disease activity, anatomical and functional stage of the disease, pain intensity, and pain unpleasantness. The cross-sectional study included 53 women with RA (RA group; mean age 50.58 ± 0.93 years) and 27 healthy women (control group, C; 49.41 ± 1.08 years). The intensity and unpleasantness of pain were determined using a visual analog scale (VAS); the functional status was assessed using HAQ (Health Assessment Questionnaire), and the disease activity was estimated using the disease activity scale (DAS28). The P300 waves initiated by auditory stimulations according to the oddball paradigm were recorded from leads Fz and Cz. There were no significant differences between the P300 latencies in both leads. At the same time, the average P300 amplitudes in both leads were found to be considerably lower (P < 0.05) in the RA group compared to the C group. Thus, there is a statistically significant amplitude difference between the P300 cognitive ERPs in RA patients and control subjects.Були досліджені параметри пов’язаних із подією потенціалів (ППП) P300 у пацієнтів, що страждають на ревматоїдний артрит (РА), та зв’язок цих параметрів із тривалістю та інтенсивністю захворювання, анатомічною та функціональною стадіями останнього, інтенсивністю та неприємністю відчуттів болю. У порівняльне дослідження були залучені 53 жінки з РА (група RA, середній вік 50.58 ± ± 0.94 року) та 27 здорових жінок (контрольна група C, 49.41 ± 1.08 року). Інтенсивність та рівень неприємності болю визначали за допомогою візуальної аналогової шкали (VAS), функціональний статус – згідно з опитувальником HAQ, а інтенсивність хвороби – за шкалою DAS28. Потенціали P300 ініціювали акустичною стимуляцією відповідно до oddball-парадигми та відводили від точок Fz та Cz. Усереднені значення латентних періодів хвилі P300 в групах RA та C не демонстрували якихось істотних відмінностей. У той же час усереднені амплітуди P300 в обох кортикальних зонах у групі RA були вірогідно нижчими (P < 0.05), ніж відповідні величини в групі C. Таким чином, існує статистично значуща різниця між характеристиками когнітивного ППП P300 у пацієнтів із ревматоїдним артритом та здорових суб’єктів, що вказує на негативні зміни сенсорного процесінга та уваги, а також когнітивні дисфункції, виниклі під впливом хронічного болю

New Episodic Learning Interferes with the Reconsolidation of Autobiographical Memories

It is commonly assumed that, with time, an initially labile memory is transformed into a permanent one via a process of consolidation. Yet, recent evidence indicates that memories can return to a fragile state again when reactivated, requiring a period of reconsolidation. In the study described here, we found that participants who memorized a story immediately after they had recalled neutral and emotional experiences from their past were impaired in their memory for the neutral (but not for the emotional) experiences one week later. The effect of learning the story depended critically on the preceding reactivation of the autobiographical memories since learning without reactivation had no effect. These results suggest that new learning impedes the reconsolidation of neutral autobiographical memories

Disrupting astrocyte-neuron lactate transfer persistently reduces conditioned responses to cocaine.

A central problem in the treatment of drug addiction is the high risk of relapse often precipitated by drug-associated cues. The transfer of glycogen-derived lactate from astrocytes to neurons is required for long-term memory. Whereas blockade of drug memory reconsolidation represents a potential therapeutic strategy, the role of astrocyte-neuron lactate transport in long-term conditioning has received little attention. By infusing an inhibitor of glycogen phosphorylase into the basolateral amygdala of rats, we report that disruption of astrocyte-derived lactate not only transiently impaired the acquisition of a cocaine-induced conditioned place preference but also persistently disrupted an established conditioning. The drug memory was rescued by L-Lactate co-administration through a mechanism requiring the synaptic plasticity-related transcription factor Zif268 and extracellular signal-regulated kinase (ERK) signalling pathway but not the brain-derived neurotrophic factor (Bdnf). The long-term amnesia induced by glycogenolysis inhibition and the concomitant decreased expression of phospho-ERK were both restored with L-Lactate co-administration. These findings reveal a critical role for astrocyte-derived lactate in positive memory formation and highlight a novel amygdala-dependent reconsolidation process, whose disruption may offer a novel therapeutic target to reduce the long-lasting conditioned responses to cocaine

A Mismatch-Based Model for Memory Reconsolidation and Extinction in Attractor Networks

The processes of memory reconsolidation and extinction have received increasing attention in recent experimental research, as their potential clinical applications begin to be uncovered. A number of studies suggest that amnestic drugs injected after reexposure to a learning context can disrupt either of the two processes, depending on the behavioral protocol employed. Hypothesizing that reconsolidation represents updating of a memory trace in the hippocampus, while extinction represents formation of a new trace, we have built a neural network model in which either simple retrieval, reconsolidation or extinction of a stored attractor can occur upon contextual reexposure, depending on the similarity between the representations of the original learning and reexposure sessions. This is achieved by assuming that independent mechanisms mediate Hebbian-like synaptic strengthening and mismatch-driven labilization of synaptic changes, with protein synthesis inhibition preferentially affecting the former. Our framework provides a unified mechanistic explanation for experimental data showing (a) the effect of reexposure duration on the occurrence of reconsolidation or extinction and (b) the requirement of memory updating during reexposure to drive reconsolidation

Repeated Labilization-Reconsolidation Processes Strengthen Declarative Memory in Humans

The idea that memories are immutable after consolidation has been challenged. Several reports have shown that after the presentation of a specific reminder, reactivated old memories become labile and again susceptible to amnesic agents. Such vulnerability diminishes with the progress of time and implies a re-stabilization phase, usually referred to as reconsolidation. To date, the main findings describe the mechanisms associated with the labilization-reconsolidation process, but little is known about its functionality from a biological standpoint. Indeed, two functions have been proposed. One suggests that destabilization of the original memory after the reminder allows the integration of new information into the background of the original memory (memory updating), and the other suggests that the labilization-reconsolidation process strengthens the original memory (memory strengthening). We have previously reported the reconsolidation of human declarative memories, demonstrating memory updating in the framework of reconsolidation. Here we deal with the strengthening function attributed to the reconsolidation process. We triggered labilization-reconsolidation processes successively by repeated presentations of the proper reminder. Participants learned an association between five cue-syllables and their respective response-syllables. Twenty-four hours later, the paired-associate verbal memory was labilized by exposing the subjects to one, two or four reminders. The List-memory was evaluated on Day 3 showing that the memory was improved when at least a second reminder was presented in the time window of the first labilization-reconsolidation process prompted by the earlier reminder. However, the improvement effect was revealed on Day 3, only when at least two reminders were presented on Day2 and not as a consequence of only retrieval. Therefore, we propose central concepts for the reconsolidation process, emphasizing its biological role and the parametrical constrains for this function to be operative

Advanced paternal age effects in neurodevelopmental disorders?review of potential underlying mechanisms

Multiple epidemiological studies suggest a relationship between advanced paternal age (APA) at conception and adverse neurodevelopmental outcomes in offspring, particularly with regard to increased risk for autism and schizophrenia. Conclusive evidence about how age-related changes in paternal gametes, or age-independent behavioral traits affect neural development is still lacking. Recent evidence suggests that the origins of APA effects are likely to be multidimensional, involving both inherited predisposition and de novo events. Here we provide a review of the epidemiological and molecular findings to date. Focusing on the latter, we present the evidence for genetic and epigenetic mechanisms underpinning the association between late fatherhood and disorder in offspring. We also discuss the limitations of the APA literature. We propose that different hypotheses relating to the origins of the APA effects are not mutually exclusive. Instead, multiple mechanisms likely contribute, reflecting the etiological complexity of neurodevelopmental disorders

The CB1 receptor antagonist AM251 impairs reconsolidation of pavlovian fear memory in the rat basolateral amygdala

We have investigated the requirement for signaling at CB1 receptors in the reconsolidation of a previously consolidated auditory fear memory, by infusing the CB1 receptor antagonist AM251, or the FAAH inhibitor URB597, directly into the basolateral amygdala (BLA) in conjunction with memory reactivation. AM251 disrupted memory restabilization, but only when administered after reactivation. URB597 produced a small, transient enhancement of memory restabilization when administered after reactivation. The amnestic effect of AM251 was rescued by coadministration of the GABAA receptor antagonist bicuculline at reactivation, indicating that the disruption of reconsolidation was mediated by altered GABAergic transmission in the BLA. These data show that the endocannabinoid system in the BLA is an important modulator of fear memory reconsolidation and that its effects on memory are mediated by an interaction with the GABAergic system. Thus, targeting the endocannabinoid system may have therapeutic potential to reduce the impact of maladaptive memories in neuropsychiatric disorders such as posttraumatic stress disorder.This work was conducted within the Behavioural and Clinical Neuroscience Institute, a joint initiative funded by the Wellcome Trust and the UK Medical Research Council, in the Department of Psychology at the University of Cambridge. This work was funded by a UK Medical Research Council programme grant (no. G1002231) awarded to BJE and ALM. PR was supported by a Department of Physiology and Pharmacology Fellowship at the Sapienza University of Rome, and an Italian Society of Pharmacology Fellowship. ALM is the Ferreras-Willetts Fellow in Neuroscience at Downing College, Cambridge. The manuscript was partly prepared while ALM was an Erskine Visiting Cambridge Fellow at the University of Canterbury, Christchurch, New Zealand