Infusion of protein synthesis inhibitors in the entorhinal cortex blocks consolidation but not reconsolidation of object recognition memory

Memory consolidation and reconsolidation require the induction of protein synthesis in some areas of the brain. Here, we show that infusion of the protein synthesis inhibitors anisomycin, emetine and cycloheximide in the entorhinal cortex immediately but not 180 min or 360 min after training in an object recognition learning task hinders long-term memory retention without affecting short-term memory or behavioral performance. Inhibition of protein synthesis in the entorhinal cortex after memory reactivation involving either a combination of familiar and novel objects or two familiar objects does not affect retention. Our data suggest that protein synthesis in the entorhinal cortex is necessary early after training for consolidation of object recognition memory. However, inhibition of protein synthesis in this cortical region after memory retrieval does not seem to affect the stability of the recognition trace.     

De novo mRNA synthesis is required for both consolidation and reconsolidation of fear memories in the amygdala

Memory consolidation is the process by which newly learned information is stabilized into long-term memory (LTM). Considerable evidence indicates that retrieval of a consolidated memory returns it to a labile state that requires it to be restabilized. Consolidation of new fear memories has been shown to require de novo RNA and protein synthesis in the lateral nucleus of the amygdala (LA). We have previously shown that de novo protein synthesis in the LA is required for reconsolidation of auditory fear memories. One key question is whether protein synthesis during reconsolidation depends on already existing mRNAs or on synthesis of new mRNAs in the amygdala. In the present study, we examined the effect of mRNA synthesis inhibition during consolidation and reconsolidation of auditory fear memories. We first show that intra-LA infusion of two different mRNA inhibitors dose-dependently impairs long-term memory but leaves short-term memory (STM) intact. Next, we show that intra-LA infusion of the same inhibitors dose-dependently blocks post-reactivation long-term memory (PR-LTM), whereas post-reactivation short-term memory (PR-STM) is left intact. Furthermore, the same treatment in the absence of memory reactivation has no effect. Together, these results show that both consolidation and reconsolidation of auditory fear memories require de novo mRNA synthesis and are equally sensitive to disruption of de novo mRNA synthesis in the LA.     

Dual trace theory and the consolidation of long-term memory

Retention functions were determined for four Ss for recognition memory of letters at 14 different delays from 3 sec to 5 min and two levels of storage load (1 and 6 letter lists), the retention interval being filled with backward counting. Memory strength retention functions were fit extremely well by assuming that two traces, short-term memory and long-term memory, are operative in this type of memory task. Only the short-term memory trace appears to be present during the first 8 or 10 sec of the retention interval, and this short-term trace decays exponentially with a time constant in the vicinity of 10 sec. Long-term memory is subject to a consolidation process which does not begin until about 10 sec after the study period and which is substantially complete at about 30 sec after the study period. Storage load has a very large effect on the degree of acquisition (learning) for both short and long-term traces, but storage load appears to have only a moderate effect or no effect on the decay rate of the short-term trace. There is some suggestion that the duration of the consolidation phase is shortened by an increase in storage load.     

记忆再巩固的时间动态性及其生物学机制

记忆巩固需经觉醒状态下的信息编码和睡眠状态下的巩固阶段两个过程。记忆再巩固理论认为记忆巩固是一个需要多次反复巩固的过程,即使已巩固的记忆也会在提取激活后变得不稳定, 需经再巩固才能重返稳定状态, 此过程需要新的蛋白质的合成。记忆再巩固具有较强的时间特征, 发生在记忆巩固之后, 依赖于蛋白质降解的去稳定化阶段和依赖于蛋白质合成的记忆再稳定阶段, 所持续的时间窗为6 h。不同类型的记忆是否引发记忆再巩固或消退行为, 取决于提取试次暴露所持续时间的长短。     

On the role of hippocampal protein synthesis in the consolidation and reconsolidation of object recognition memory

Upon retrieval, consolidated memories are again rendered vulnerable to the action of metabolic blockers, notably protein synthesis inhibitors. This has led to the hypothesis that memories are reconsolidated at the time of retrieval, and that this depends on protein synthesis. Ample evidence indicates that the hippocampus plays a key role both in the consolidation and reconsolidation of different memories. Despite this fact, at present there are no studies about the consequences of hippocampal protein synthesis inhibition in the storage and post-retrieval persistence of object recognition memory. Here we report that infusion of the protein synthesis inhibitor anisomycin in the dorsal CA1 region immediately or 180 min but not 360 min after training impairs consolidation of long-term object recognition memory without affecting short-term memory, exploratory behavior, anxiety state, or hippocampal functionality. When given into CA1 after memory reactivation in the presence of familiar objects, ANI did not affect further retention. However, when administered into CA1 immediately after exposing animals to a novel and a familiar object, ANI impaired memory of both of them. The amnesic effect of ANI was long-lasting, did not happen after exposure to two novel objects, following exploration of the context alone, or in the absence of specific stimuli, suggesting that it was not reversible but was contingent on the reactivation of the consolidated trace in the presence of a salient, behaviorally relevant novel cue. Our results indicate that hippocampal protein synthesis is required during a limited post-training time window for consolidation of object recognition memory and show that the hippocampus is engaged during reconsolidation of this type of memory, maybe accruing new information into the original trace.     

Rapid, Labile, and Protein Synthesis– Independent Short-Term Memory in Conditioned Taste Aversion

Short-term memory is a rapid, labile, and protein-synthesis-independent phase of memory. The existence of short-term memory in conditioned taste aversion (CTA) learning has not been demonstrated formally. To determine the earliest time at which a CTA is expressed, we measured intraoral intake of sucrose at 15 min, 1 hr, 6 hr, or 48 h after contingent pairing of an intraoral infusion of 5% sucrose (6.6 ml over 6 min) and toxic lithium chloride injection (76 mg/kg). Rats were implanted with intraoral catheters to allow presentation of taste solutions at arbitrary times. Intraoral intake was measured under conditions of long-delay, single-trial learning typical of CTA. Rats decreased intraoral intake of sucrose at 15 min after contingent pairing of sucrose and LiCl, but not after noncontingent LiCl or sucrose. Thus CTA learning can be expressed rapidly. To determine if short-term CTA memory is labile and decays in the absence of long-term memory, we measured intraoral intake of sucrose after pairing sucrose with low doses of LiCl. Rats received an intraoral infusion of 5% sucrose (6 ml/6 min); 30 min later LiCl was injected at three different doses (19, 38, or 76 mg/kg). A second intraoral infusion of sucrose was administered 15 min, 1 hr, 3 hr, 4.5 hr, 6 hr, or 48 hr later. The formation of long-term CTA memory was dependent on the dose of LiCl paired with sucrose during acquisition. Low doses of LiCl induced a CTA that decayed within 6 hr after pairing. Central administration of the protein synthesis inhibitor cycloheximide prior to LiCl injection blocked long-term CTA expression at 6 and 48 hr, but not short-term CTA expression at 1 hr. Thus, short-term memory for CTA learning exists that is acquired rapidly and independent of protein synthesis, but labile in the absence of long-term memory formation.     

Cognitive approaches to the development of short-term memory

The capacity to retain information for brief periods of time increases dramatically during the childhood years. The increases in temporary storage of speech-based material that take place in the period spanning the pre-school years and adolescence reflect complex changes in many of the different component processes, including perceptual analysis, construction and maintenance of a memory trace, retention of order information, rehearsal, retrieval and redintegration. Another crucial capacity that undergoes a similar striking development is complex working memory, the ability to manipulate and store material simultaneously. Possible sources of age-related changes in working memory include increases in processing efficiency and attentional capacity, and task-switching. These two short-term memory systems might play significant but distinct roles in supporting the acquisition of knowledge and skills during childhood. Whereas phonological short-term memory is linked specifically with the learning of the phonological structures of new words, complex working memory appears to support processing and learning in a wide range of contexts, in both childhood and adulthood.     

Distinct consolidation outcomes in a visuomotor adaptation task: Off-line leaning and persistent after-effect

Consolidation is a time-dependent process responsible for the storage of information in long-term memory. As such, it plays a crucial role in motor learning. In two experiments, we sought to determine whether one’s performance influences the outcome of the consolidation process. We used a visuomotor adaptation task in which the cursor moved by the participants was rotated 30° clockwise. Thus, participants had to learn a new internal model to compensate for the rotation of the visual feedback. The results indicated that when participants showed good adaptation in the first session, consolidation resulted in a persistent after-effect in a no-rotation transfer test; they had difficulty returning to their normal no-rotation internal model. However, when participants showed poor adaptation in the first session, consolidation led to significant off-line learning (between sessions improvement) but labile after-effects. These observations suggest that distinct consolidation outcomes (off-line learning and persistent after-effect) may occur depending on the learner’s initial performance.     

Evidence for recovery of fear following immediate extinction in rats and humans

Fear responses can be eliminated through extinction, a procedure involving the presentation of fear-eliciting stimuli without aversive outcomes. Extinction is believed to be mediated by new inhibitory learning that acts to suppress fear expression without erasing the original memory trace. This hypothesis is supported mainly by behavioral data demonstrating that fear can recover following extinction. However, a recent report by Myers and coworkers suggests that extinction conducted immediately after fear learning may erase or prevent the consolidation of the fear memory trace. Since extinction is a major component of nearly all behavioral therapies for human fear disorders, this finding supports the notion that therapeutic intervention beginning very soon after a traumatic event will be more efficacious. Given the importance of this issue, and the controversy regarding immediate versus delayed therapeutic interventions, we examined two fear recovery phenomena in both rats and humans: spontaneous recovery (SR) and reinstatement. We found evidence for SR and reinstatement in both rats and humans even when extinction was conducted immediately after fear learning. Thus, our data do not support the hypothesis that immediate extinction erases the original memory trace, nor do they suggest that a close temporal proximity of therapeutic intervention to the traumatic event might be advantageous.     

行为干预情绪记忆再巩固：从实验室到临床转化

重新激活已经储存的记忆会重返暂时不稳定的状态, 需要经历重新稳定, 称为记忆再巩固。在这期间可以通过多种行为手段破坏、强化或更新原始记忆痕迹, 这为开发一种革命性的情绪记忆障碍治疗方法开辟了道路。然而, 即使在简单的实验模型中引发记忆再巩固的条件也是复杂的, 这给临床转化带来了困难与挑战。未来研究可以设置更具生态效应的基础模型, 寻求引发以及干预再巩固的最佳方式, 从神经生理、细胞分子层面进一步深化其内在机理研究。     

注意和记忆对孤独症儿童词汇发展滞后的影响

孤独症语言障碍的表现之一是词汇发展滞后, 可能与其注意和记忆损伤有关。当前研究结果表明, 孤独症儿童在学习词汇时难以利用社会注意提供的有效信息, 且其注意易受到无关刺激干扰, 这可能导致其形成的物体-词汇的联结不稳定, 影响其进一步将这种联结整合到心理词典并保存在记忆中。未来研究应探究联合注意影响孤独症儿童词汇学习的发展轨迹和机制, 儿童的词汇知识对其词汇记忆的影响, 并关注自然场景中孤独症儿童的词汇学习过程和个体差异。     

The dynamics of memory: context-dependent updating

Understanding the dynamics of memory change is one of the current challenges facing cognitive neuroscience. Recent animal work on memory reconsolidation shows that memories can be altered long after acquisition. When reactivated, memories can be modified and require a restabilization (reconsolidation) process. We recently extended this finding to human episodic memory by showing that memory reactivation mediates the incorporation of new information into existing memory. Here we show that the spatial context plays a unique role for this type of memory updating: Being in the same spatial context during original and new learning is both necessary and sufficient for the incorporation of new information into existing episodic memories. Memories are automatically reactivated when subjects return to an original learning context, where updating by incorporating new contents can occur. However, when in a novel context, updating of existing memories does not occur, and a new episodic memory is created instead.     

Playing counter-strike versus running: The impact of leisure time activities and cortisol on intermediate-term memory in male students

The everyday life of students is characterized by hours of learning in order to pass exams. After learning they tend to opt for an occupation that provides them with a great deal of entertainment. It is obvious that it would be advantageous if the chosen activity had a positive impact on memory consolidation. Due to the circumstance that such activities can lead to stress and that memory is affected by stress we wanted to look at these coherences. We examined the effect of two different common leisure time activities on cortisol and memory to be able to formulate recommendations for society. For this purpose, a group was tested before and after playing a violent computer game while the second group was tested before and after running. In addition, a control group was set up. Salivary cortisol was measured at the beginning, during, and at the end of the experiment.Our data demonstrates that running increases cortisol levels and, performed immediately after a learning period, facilitates memorization of neutral information. In contrast, playing a violent computer game tends to impair memorization.The results of the present study have practical implications for the choice of recreational activities in the context of learning.     

Contextual modulation of memory consolidation

We investigate olfactory memory consolidation in honeybees. Three experiments are reported that include 1024 animals in 28 experimental groups. After one pairing of odorant and sucrose reward, retention is typically nonmonotonic with a minimum 3 min after conditioning. This corresponds to the “Kamin effect” in vertebrates; the postminimum rise in retention is usually interpreted as reflecting memory consolidation. First, we test for the generality of this effect across four different odorants. The postminimum rise in retention was reproducibly observed for 1-hexanol but not for 1-octanol, limonene, or geraniol. Second, we investigate whether previous learning about the training context modulates subsequent memory consolidation. On the day before training, a reward was applied either upon placement into the future training context for 1 min, halfway during exposure or just before removal from the context. In the latter group, the 3-min minimum in retention was eliminated; thus, in that group, forward pairings of context and reward (i.e., context exposure begins before reward is applied) lead to an associative context memory that can modulate subsequent olfactory memory consolidation. Third, we found no evidence for a modulation of olfactory memory consolidation by pre-exposure to the odorant.     

Developmental study of multiple memory stages in the cuttlefish, Sepia officinalis

The inhibition of predatory behavior observed during the "prawn-in-the-tube" procedure has been extensively used in studies of cuttlefish learning. The present study examines the effect of age on the conditioning of this response in the cuttlefish, Sepia officinalis. Data show that a significant increase in acquisition performance occurs between 15 and 21 days of age. The retention curves in 8- and 15-day-old cuttlefish show a monotonic memory process, presumably reflecting the presence of only short-term memory. In 21-day-old cuttlefish, there are two distinct processes which could be a labile short-term memory, and a subsequent intermediate memory. These mnesic systems seem to become more effective over the course of post-embryonic development. Moreover, the retention curves obtained in the oldest cuttlefish (30- and 90-day-old) bear a close resemblance to that observed in adults. These behavioral findings will allow further work on the cellular and molecular mechanisms of learning and memory in the cuttlefish.     

Mapping of olfactory memory circuits: region-specific c-fos activation after odor-reward associative learning or after its retrieval

Although there is growing knowledge about intracellular mechanisms underlying neuronal plasticity and memory consolidation and reconsolidation after retrieval, information concerning the interaction among brain areas during formation and retrieval of memory is relatively sparse and fragmented. Addressing this question requires simultaneous monitoring of activity in multiple brain regions during learning, the post-acquisition consolidation period, and retrieval and subsequent reconsolidation. Immunoreaction to the immediate early gene c-fos is a powerful tool to mark neuronal activation of specific populations of neurons. Using this method, we are able to report, for the first time, post-training activation of a network of closely related brain regions, particularly in the frontal cortex and the basolateral amygdala (BLA), that is specific to the learning of an odor-reward association. On the other hand, retrieval of a well-established associative memory trace does not seem to differentially activate the same regions. The amygdala, in particular, is not engaged after retrieval, whereas the lateral habenula (LHab) shows strong activation that is restricted to animals having previously learned the association. Although intracellular mechanisms may be similar during consolidation and reconsolidation, this study indicates that different brain circuits are involved in the two processes, at least with respect to a rapidly learned olfactory task.     

睡眠对知觉与动作序列内隐学习离线巩固效应的影响

离线阶段发生的学习被称为离线巩固, 即在最初获得知识之后, 即使没有额外的练习, 其记忆痕迹也会保持稳定或提高。有研究初步探究了睡眠对知觉和动作序列内隐学习离线巩固的影响, 然而, 这些研究未能实现知觉序列与动作序列的完全分离, 序列类型是否调节睡眠对内隐序列学习离线巩固的影响仍需进一步探讨。此外, 既往外显学习的研究发现相对于简单的序列, 复杂的序列更容易从睡眠中获益, 表现出基于睡眠的离线巩固效应。睡眠对知觉序列与动作序列内隐学习离线巩固的影响是否会受到序列复杂程度的调节尚不明确。为此, 本研究在完全分离知觉序列和动作序列的情况下, 通过3个实验操纵序列的长度及结构, 设置3种不同复杂程度的序列规则, 考察了这一问题。结果发现, 对于动作序列, 序列规则复杂程度较低时, 无论是否经过睡眠都会发生离线巩固效应, 而当动作序列规则较为复杂时, 只有经历睡眠才会引起离线巩固效应; 对于知觉序列, 无论何种难易程度的规则, 均未发生离线巩固效应。上述结果表明内隐序列知识基于睡眠的离线巩固会受到序列类型及序列复杂程度的调节, 这为内隐学习的离线巩固争论提供了新的视角。     

Post-training, but not post-reactivation, administration of amphetamine and anisomycin modulates Pavlovian conditioned approach

The psychostimulant, amphetamine (AMPH), and the protein synthesis inhibitor, anisomycin (ANI), have been shown to modulate the consolidation and reconsolidation of several types of learning. To determine whether Pavlovian conditioned approach (PCA) is modulated in a similar manner, we examined the effects of post-training and post-reactivation administration of both AMPH and ANI on memory for PCA. Male Long-Evans rats received PCA training sessions during which presentations of a CS+ were followed by sucrose delivery. AMPH (1 mg/kg, s.c.) injected immediately but not 6h after the first training session enhanced PCA behavior. ANI (150 mg/kg, s.c.) injected immediately but not 3h after the first training session impaired PCA behavior. This impairment was not due to the development of a conditioned taste aversion. To examine whether PCA can also be modulated by post-reactivation administration of AMPH and ANI, rats were given an injection of AMPH, ANI, or vehicle immediately after a memory reactivation session. Upon testing, the behavior of both the AMPH- and the ANI-treated rats was unaffected. This result remained consistent when the experiment was repeated with changes to various behavioral parameters (i.e., amount of training, length of memory reactivation). These findings indicate that AMPH and ANI act during the post-training but not the post-reactivation period to enhance and impair, respectively, the learning of PCA. This suggests that the consolidation of PCA can be modulated in a manner comparable to other types of learned associations, but once learned, the memory appears to be relatively robust and stable.     

Behavioral interference and C/EBPbeta expression in the insular-cortex reveal a prolonged time period for taste memory consolidation

Memory consolidation is defined as the time window during which the memory trace is susceptible to behavioral, electrical, or pharmacological interventions. Here, we presented rats with two novel tastes at consecutive time intervals. Clear interference was evident when a novel taste formed the second taste input whereby, surprisingly, the time window for interference was found to last more than 10 h. In addition, we detected an increase of C/EBPbeta protein expression in the gustatory cortex 18 h after novel taste learning. This modulation was attenuated by a subsequent novel taste. Our findings reveal temporal constraints and a lingering nature of taste memory consolidation.