Mechanisms of Memory Reorganization during Retrieval of Acquired Behavioral Experience in Chicks: the Effects of Protein Synthesis Inhibition in the Brain

According to current concepts, memory can be disrupted by administration of protein synthesis inhibitors over a relatively short time period before and after learning. However, data have been obtained indicating that protein synthesis inhibitors can induce amnesia when given long after learning if administration is performed in reminder conditions, i.e., when the animal is presented with one of the environmental components which previously formed the learning situation. The aim of the present work was to confirm the possibility of inducing memory disruption in chicks at late post–learning stages by administering the protein synthesis inhibitor cycloheximide in association with a reminder procedure. Day–old chicks were trained to perform a standard passive avoidance task. Chicks were given cycloheximide (20 g, intracerebrally) 5 min before the reminder procedure, which was performed 2, 24, or 48 h after training. Testing was conducted 0.5, 1, 3, 24, and 48 h after the reminder. Administration of cycloheximide in association with the reminder procedure induced the development of temporary amnesia, whose duration gradually decreased as the interval between training and reminding increased. These data led to the hypothesis that a memory reactivated by a reminder undergoes a process of reorganization and reconsolidation, which depends on the synthesis of new proteins. The quenching of the ability of protein synthesis inhibition during the reminder to disrupt memory demonstrates the existence of a gradual process resulting in consolidation of memory between 2 and 48 h of learning.     

Protein Synthesis Is Required for Induction of Amnesia Elicited by Disruption of the Reconsolidation of Long-Term Memory

Studies on common snails previously trained to an associative skill consisting of rejecting a defined foodstuff addressed the effects of NMDA glutamate receptor antagonists (MK-801 and APV) and protein synthesis inhibitors (cycloheximide and anisomycin) on long-term memory reconsolidation processes. Injections of each of the study compounds before the reminding procedure 24 h after training were found to lead to impairment of the reproduction of the acquired skill, which lasted at least three weeks. Repeat training of these animals to reject the same foodstuff as used in the initial training did not lead to acquisition of the skill. However, simultaneous injections of a protein synthesis inhibitor and an NMDA receptor antagonist (MK-801 + cycloheximide or APV + anisomycin) did not impair the skill. In subsequent experiments, snails received cycloheximide at different times after exposure to MK-801/reminding. Administration of cycloheximide 3 and 6 h after MK-801/reminding led to the development of incomplete amnesia and repeat training of the animals led to rapid restoration of memory. Administration of cycloheximide 9 h after MK-801/reminding evoked the development of stable amnesia characterized by impairment of skill formation on repeat training. We propose that the mechanisms of amnesia induced by the NMDA glutamate receptor antagonist, by analogy with the mechanisms of other long-term adaptive rearrangements of the brain, depend on translation and can be suppressed by inhibitors of translation. The “time window” for the dependence of amnesia induction processes on the synthesis of protein molecules was 6–9 h after exposure to MK-801/reminding.     

Circuit mechanisms underlying memory encoding and retrieval in the long axis of the hippocampal formation

Circuits within the hippocampal formation are active during memory processing. Here we used functional magnetic resonance imaging (fMRI) to examine multiple sites across the long axis of the hippocampal formation while subjects performed different phases of an associative memory task, learning to associate faces with names. Viewing faces and hearing names in isolation resulted in separate hippocampal activation patterns. Pairing faces with names resulted a spatially redistributed activation pattern, rather than a simple summation of the activation patterns resulting from viewing faces and hearing names in isolation. Recalling names when cued with faces reactivated a pattern similar to that found during paired training. Finally, the activation patterns representing faces and names were found to be experience dependent, emerging with repeated exposure. Interpreted in the context of hippocampal anatomy and physiology, these findings reveal hippocampal circuit mechanisms that underlie memory encoding and retrieval.     

Amino acid uptake required for long-term memory formation

α-Amino-iso-butyrate (AIB) inhibits long-term, protein synthesis-dependent memory formation by reducing labelled leucine uptake in vivo without affecting leucine incorporation into protein. Unlike the antibiotic cycloheximide, AIB does not block long-term memory formation through inhibition of protein synthesis per se. The behavioural effect of AIB is restricted to times of administration between 5 min before and 5 min after learning a single trial passive avoidance task by day-old chickens. It is concluded that (1) AIB competes with normal amino acids for uptake into cells, and (2) the uptake of amino acids for protein synthesis specific to long-term memory formation takes place in the first few minutes following learning.     

Glucose regulation of memory for reward reduction in young and aged rats

Although baseline blood glucose levels in aged Fischer-344 rats are comparable to those of young rats, the rise in blood glucose in response to training-related stress is substantially attenuated. The diminished response may contribute to increased depletion of extracellular brain glucose levels during training in aged rats; the depletion is blocked and memory is enhanced by systemic injections of glucose. The present experiment examined the role of glucose in regulating memory for reward reduction training. Blood glucose levels exhibited a significant rise after reward reduction trials in young adult but not 2-year-old rats. Although young and aged rats exhibited comparable learning during the day of reward reduction training, aged rats exhibited more rapid forgetting of the learning response. Post-training glucose injections (200 mg/kg, i.p.) facilitated memory formation and slowed the rate of forgetting in young and old rats, consistent with the view that deficiencies in circulating glucose responses to training may contribute to the rapid forgetting evident in aged Fischer-344 rats.     

Neurochemical Mechanisms of Consolidation of Associative Aversive Learning to Food in the Common Snail

Studies of the effects of the protein synthesis inhibitor cycloheximide and serotonin and NMDA glutamate receptor antagonists on the processes of consolidation of the associative skill of rejecting particular foodstuffs were performed in the common snail. The skill was not acquired when animals were trained on the background of cycloheximide. Repeated training of “amnestic” snails to reject the same foodstuff in the absence of the inhibitor also failed to produce learning. Training of snails on the background of the nonselective serotonin receptor antagonist methiothepin or the NMDA glutamate receptor antagonist MK-801 (dizocilpine maleate) did not result in the acquisition of the conditioned reflex to food. However, repeated training led to the rapid formation of the skill. These experiments provide the first evidence that interventions influencing different molecular mechanisms during a single type of training produce either reversible or irreversible impairment of the mechanisms of consolidation of long-term memory. It is suggested that the reversible effect is associated with suppression of reproduction processes, while irreversible impairment was associated with impairments to engram storage. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 94, No. 8, pp. 860–870, August, 2008.     

Recovery of memory in chicks after disruption during learning: The reversibility of amnesia induced by protein synthesis inhibitors

Protein synthesis inhibitors given during learning are known to disrupt memory in various animal species in several models of learning. However, there are suggestions that amnesia induced by protein synthesis inhibitors is not permanent-memory can be recovered by a reminder procedure, i.e., by presenting the animal with one of the components of the external environment which was part of the learning situation. The aim of the present work was to determine the existence of the reminder phenomenon in a well-studied model of single-session training to passive avoidance in chicks. Cycloheximide and anisomycin were used to induce amnesia. Reminder was performed using the aversive taste of methylanthranilate 24 h afte training, and testing was conducted 48 h after training. The results obtained provide evidence that memory disrupted by protein synthesis inhibitors in chicks can be recovered by the reminder procedure. Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 83, No. 11-12, pp. 11–18, November–December, 1997.     

Inhibition of adenovirus multiplication by metabolic inhibitors

Summary Under conditions of one-step growth the multiplication of adenovirus 19 in HeLa cells was inhibited by 7 inhibitors of DNA synthesis (see Table 1), by cycloheximide, streptovitacin A, actinomycin D and mitomycin D. The inhibition involved the formation of infectious virus and of capsid proteins. The viral CPE was not inhibited by inhibitors of DNA synthesis; cycloheximide, streptovitacin and actinomycin inhibited the CPE with viral multiplicities up to 2. With medium doses of IUdR and BUdR the formation of infectious virus was inhibited with almost normal formation of capsid proteins. A selective formation of group-specific CF antigen was also observed under a number of conditions. The inhibitory effect of several drugs was reversible on removal. A reversion of the inhibition mediated by amethopterin, fluoruracil and FUdR was achieved only by addition of thymidine. No reversion was seen after removal of actinomycin. Deoxycytidine had an antagonistic effect against the inhibition mediated by cytosine arabinoside, when added 8 to 22 hours after the drug.The time during the replication cycle until which the inhibitors are fully effective was found to be 8 to 10 hours for inhibitors of DNA synthesis, 12 hours for actinomycin and 14 hours for cycloheximide and streptovitacin. This inhibition time was largely independent of inhibitor doses and viral multiplicity. When inhibitors were added during the exponential rise of viral activity, cycloheximide and streptovitacin stopped the further rise. Cycloheximide and actinomycin also stopped the progression of viral CPE. Apparently continuous protein synthesis is required for both viral maturation and viral CPE. Eor cycloheximide two inhibitor-sensitive periods (early proteins from 6 hpi, structural proteins from 14 hpi) were distinguished, while the period of synthesis of viral DNA lasted from 8 to 18 hours.Aided by a grant from the Deutsche Forschungsgemeinschaft.     

Chronic lithium treatment magnifies learning in rats

Recent electrophysiological work shows that chronic lithium treatment increases long-term potentiation (LTP) in neurons of the hippocampus, and LTP is thought to be the major neurophysiological basis for the development of learning and memory. This suggests that lithium might enhance learning and memory. Available studies have mainly assessed memory using aversive conditioning paradigms, but very little is available on the effect of lithium on learning. Since lithium may diminish anxiety or negative affect in adult rats, which would hinder aversive learning, the present study used three different positive reinforcement spatial cognitive tasks to determine whether chronic lithium affects learning. Each task differed in complexity, in the type of learning required, and in the reward received. For 4 weeks prior to, and throughout all learning assessments, rats had continual access to lithium chow or to a control chow diet. After 4 weeks’ access to their designated chow diet, rats began conditioning in the hole-board spatial discrimination or T-maze delayed alternation tasks in a counterbalanced fashion. They immediately began conditioning in the opposite task once completing the first. This was then followed with social place-preference conditioning, after 24-h isolation from their home-cage social partner. Chronic lithium increased learning in all three paradigms, regardless of the reward received. Indeed, both food and social interaction supported enhanced learning. Thus the learning effect was not merely due to an effect of lithium on food palatability. Importantly, clinically relevant serum lithium levels were evidenced at the time of testing. Lithium also marginally enhanced memory as well. Thus chronic lithium treatment may improve learning and memory in Alzheimer’s disease, and do so not only by blocking the formation of beta-amyloid and neurofibrillary tangles as suggested by previous research, but also by enhancing mechanisms involved in basal learning and memory formation, such as hippocampal synaptic plasticity.     

大鼠海马结构在空间辨别性学习记忆时突触素表达的变化

目的:探讨空间辨别性学习记忆活动与突触可塑性的关系。方法:用免疫组织化学方法对具有空间辨别性学习记忆功能的模型大鼠与对照组大鼠海马结构内突触素I的表达进行对比研究。结果:(1)对照组大鼠海马结构内未见明显的突触素颗粒产物;在模型组,经水迷宫训练1周的大鼠海马切片上见到齿状回、CA4和CA3区出现深染的颗粒分布,CA2和CA1区颗粒较少;训练2周的大鼠海马结构内的染色显示颗粒与训练1周的比较无明显差异,但染色加深;(2)模型组大鼠的突触素反应产物的光密度值明显大于对照组(P＜0.05);模型组大鼠海马结构内突触素光密度值在训练的1~2周内随训练时间增加而增加,训练2~3周则增加不明显;模型组大鼠海马结构CA3、CA4区和齿状回突触素反应产物的光密度值较CA1和CA2区的大,差异有显著(P＜0.05)。结论:(1)大鼠经水迷宫训练获得空间辨别性学习记忆功能时在海马结构内有新突触形成;(2)海马结构的CA3、CA4区和齿状回与空间辨别性学习记忆的关系密切。     

Effects of protein synthesis inhibitors during reactivation of associative memory in the common snail induces reversible and irreversible amnesia

The effects of protein synthesis inhibitors on the reactivation of an associative skill consisting of refusing a particular food by common snails were studied. Animals were given single injections of a protein synthesis inhibitor (cycloheximide at 0.6 mg/snail or anisomycin at 0.4 mg) 24 h after three days of training, and were then presented with a “reminding” stimulus (the “conditioned reflex” food-banana) and tested for retention of the skill. Observations revealed an impairment of reproduction of the acquired skill 2.5 h after the “reminder, ” with spontaneous restoration at 4.5–5.5 h. Other snails were given single 1.8-mg doses of cycloheximide or three 0.6-mg doses with intervals of 2 h. “Reminders” were presented after each injection. In these conditions, impairment of reproduction of the conditioned reflex also appeared 2.5 h after the first “reminder, ” though amnesia lasted at least 30 days and repeat training of the animals produced only partial recovery of the skill. Thus, we have provided the first demonstration that recovery of a long-term memory “trace” on exposure to relatively low doses of protein synthesis inhibitors produces transient and short-lived amnesia, lasting 2–3 h, while long-term, irreversible amnesia occurrs after longer-lasting or more profound suppression of protein synthesis. These results suggest that the “reminding” process induces reconsolidation of the “ initial” memory, suppression of which by protein synthesis inhibitors leads to “erasure” of the memory “trace” and impairs consolidation on repeat training. __________ Translated from Rossiiskii Fiziologicheskii Zhurnal imeni I. M. Sechenova, Vol. 92, No. 9, 1058–1068. September, 2006.     

Long-term retention explained by a model of short-term learning in the adaptive control of reaching

Extensive theoretical, psychophysical, and neurobiological work has focused on the mechanisms by which short-term learning develops into long-term memory. Better understanding of these mechanisms may lead to the ability to improve the efficiency of training procedures. A key phenomenon in the formation of long-term memory is the effect of over learning on retention-discovered by Ebbinghaus in 1885: when the initial training period in a task is prolonged even beyond what is necessary for good immediate recall, long-term retention improves. Although this over learning effect has received considerable attention as a phenomenon in psychology research, the mechanisms governing this process are not well understood, and the ability to predict the benefit conveyed by varying degrees of over learning does not yet exist. Here we studied the relationship between the duration of an initial training period and the amount of retention 24 h later for the adaptation of human reaching arm movements to a novel force environment. We show that in this motor adaptation task, the amount of long-term retention is predicted not by the overall performance level achieved during the training period but rather by the level of a specific component process in a multi-rate model of short-term memory formation. These findings indicate that while multiple learning processes determine the ability to learn a motor adaptation, only one provides a gateway to long-term memory formation. Understanding the dynamics of this key learning process may allow for the rational design of training and rehabilitation paradigms that maximize the long-term benefit of each session.     

Theta oscillations during holeboard training in rats: different learning strategies entail different context-dependent modulations in the hippocampus

A functional connection between theta rhythms, information processing, learning and memory formation is well documented by studies focusing on the impact of theta waves on motor activity, global context or phase coding in spatial learning. In the present study we analyzed theta oscillations during a spatial learning task and assessed which specific behavioral contexts were connected to changes in theta power and to the formation of memory. Therefore, we measured hippocampal dentate gyrus theta modulations in male rats that were allowed to establish a long-term spatial reference memory in a holeboard (fixed pattern of baited holes) in comparison to rats that underwent similar training conditions but could not form a reference memory (randomly baited holes). The first group established a pattern specific learning strategy, while the second developed an arbitrary search strategy, visiting increasingly more holes during training. Theta power was equally influenced during the training course in both groups, but was significantly higher when compared to untrained controls. A detailed behavioral analysis, however, revealed behavior- and context-specific differences within the experimental groups. In spatially trained animals theta power correlated with the amounts of reference memory errors in the context of the inspection of unbaited holes and exploration in which, as suggested by time frequency analyses, also slow wave (delta) power was increased. In contrast, in randomly trained animals positive correlations with working memory errors were found in the context of rearing behavior. These findings indicate a contribution of theta/delta to long-lasting memory formation in spatially trained animals, whereas in pseudo trained animals theta seems to be related to attention in order to establish trial specific short-term working memory. Implications for differences in neuronal plasticity found in earlier studies are discussed.     

The role of telencephalic NMDA receptors in avoidance learning in goldfish (Carassius auratus)

Studies with goldfish (Carassius auratus) have suggested that N-methyl-D-aspartate (NMDA) receptors are concentrated most densely in the telencephalon, a simple structure homologous to the limbic structure of higher vertebrates. The present study investigated the amnestic effects of microinjections of the NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP5) to the goldfish telencephalon on avoidance conditioning. Results showed that microinjections of D-AP5 before training impaired avoidance learning at doses that did not impair performance processes. High-performance liquid chromatography measurements showed that D-AP5 was detected only in the telencephalon following microinjections. Thus, D-AP5 impaired avoidance learning through its interaction with telencephalic NMDA receptors in goldfish. Furthermore, microinjections of D-AP5 to the goldfish telencephalon immediately following training did not impair memory consolidation of avoidance conditioning.     

噪声对大鼠学习记忆中海马区NOS阳性神经元表达的影响

目的：拟在白噪声下观察对大鼠学习记忆的影响及海马区NOS的变化，探讨噪声所致大鼠学习记忆下降的机制。方法：44只SD大鼠，其中20只随机分两组，分别在持续80dB(A)白噪声和无噪声的环境下，在Y—迷宫中进行空间辨别学习记忆训练，了解噪声对大鼠学习记忆的影响，另24只大鼠随机分三组：噪声训练组、正常训练组和噪声观察组，以同样的方法训练，用免疫组化的方法观察持续噪声对海马区NOS阳性神经元表达变化。结果：噪声能降低大鼠学习记忆能力，而且海马区NOS阳性神经元较正常对照组的数量及染色强度显著降低。结论：噪声降低海马区神经元活性，NOS的合成减少，抑制海马习得性长时程突触增强，影响记忆的获得与保持，延迟短时记亿向长时记忆的转化。     

The effect of two types of memory training on subjective and objective memory performance in healthy individuals aged 55 years and older: a randomized controlled trial

The objective of the study was to examine the effectiveness of two types of memory training (collective and individual), compared to control (waiting list), on memory performance. Participants were 139 community-dwelling older individuals recruited through media advertisements asking for people with subjective memory complaints to participate in a study. Data were collected at baseline, and at 1 week and 4 months after the intervention. Training efficacy was assessed using measures of subjective and objective memory performance. After the intervention, participants in the collective training group reported more stability in memory functioning and had fewer feelings of anxiety and stress about memory functioning. In addition, positive effects were found on objective memory functioning. Compared with the other two groups, the collective training group participants had an improved recall of a previously learned word list. Compared to controls, participants in the individual training group reported fewer feelings of anxiety and stress in relation to memory functioning.     

Comparison of the effects of early handling and early deprivation on conditioned stimulus, context, and spatial learning and memory in adult rats

Effects of manipulations of the rat pup-dam relationship on affective learning and memory in adulthood have received scant systematic investigation. The authors previously described how early handling (EH; 15 min isolation/day) and early deprivation (ED; 4 hr isolation/day) exert similar effects on spontaneous adult affect (open-field behavior, acoustic startle, endocrine stress response) relative to nonhandling (NH; C. R. Pryce, D. Bettschen, N. I. Bahr, & J. Feldon, 2001). The present study demonstrates that both EH and ED adults exhibit enhanced active avoidance relative to NH adults. Fear-conditioned context and conditioned stimulus (CS) freezing were unaffected in both EH and ED, but stress hormone responses to the CS were reduced in EH males and ED females relative to NH. In the water maze, ED adults exhibited enhanced spatial learning and memory relative to NH.