The endogenous cannabinoid system controls extinction of aversive memories

Acquisition and storage of aversive memories is one of the basic principles of central nervous systems throughout the animal kingdom. In the absence of reinforcement, the resulting behavioural response will gradually diminish to be finally extinct. Despite the importance of extinction, its cellular mechanisms are largely unknown. The cannabinoid receptor 1 (CB1) and endocannabinoids are present in memory-related brain areas and modulate memory. Here we show that the endogenous cannabinoid system has a central function in extinction of aversive memories. CB1-deficient mice showed strongly impaired short-term and long-term extinction in auditory fear-conditioning tests, with unaffected memory acquisition and consolidation. Treatment of wild-type mice with the CB1 antagonist SR141716A mimicked the phenotype of CB1-deficient mice, revealing that CB1 is required at the moment of memory extinction. Consistently, tone presentation during extinction trials resulted in elevated levels of endocannabinoids in the basolateral amygdala complex, a region known to control extinction of aversive memories. In the basolateral amygdala, endocannabinoids and CB1 were crucially involved in long-term depression of GABA (gamma-aminobutyric acid)-mediated inhibitory currents. We propose that endocannabinoids facilitate extinction of aversive memories through their selective inhibitory effects on local inhibitory networks in the amygdala.     

Time-dependent reorganization of brain circuitry underlying long-term memory storage.

Retrograde amnesia observed following hippocampal lesions in humans and animals is typically temporally graded, with recent memory being impaired while remote memories remain intact, indicating that the hippocampal formation has a time-limited role in memory storage. However, this claim remains controversial because studies involving hippocampal lesions tell us nothing about the contribution of the hippocampus to memory storage if this region was present at the time of memory retrieval. We therefore used non-invasive functional brain imaging using (14C)2-deoxyglucose uptake to examine how the brain circuitry underlying long-term memory storage is reorganized over time in an intact brain. Regional metabolic activity in the brain was mapped in mice tested at different times for retention of a spatial discrimination task. Here we report that increasing the retention interval from 5 days to 25 days resulted in both decreased hippocampal metabolic activity during retention testing and a loss of correlation between hippocampal metabolic activity and memory performance. Concomitantly, a recruitment of certain cortical areas was observed. These results indicate that there is a time-dependent reorganization of the neuronal circuitry underlying long-term memory storage, in which a transitory interaction between the hippocampal formation and the neocortex would mediate the establishment of long-lived cortical memory representations.     

Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval

'New' memories are initially labile and sensitive to disruption before being consolidated into stable long-term memories. Much evidence indicates that this consolidation involves the synthesis of new proteins in neurons. The lateral and basal nuclei of the amygdala (LBA) are believed to be a site of memory storage in fear learning. Infusion of the protein synthesis inhibitor anisomycin into the LBA shortly after training prevents consolidation of fear memories. Here we show that consolidated fear memories, when reactivated during retrieval, return to a labile state in which infusion of anisomycin shortly after memory reactivation produces amnesia on later tests, regardless of whether reactivation was performed 1 or 14 days after conditioning. The same treatment with anisomycin, in the absence of memory reactivation, left memory intact. Consistent with a time-limited role for protein synthesis production in consolidation, delay of the infusion until six hours after memory reactivation produced no amnesia. Our data show that consolidated fear memories, when reactivated, return to a labile state that requires de novo protein synthesis for reconsolidation. These findings are not predicted by traditional theories of memory consolidation.     

Boosting slow oscillations during sleep potentiates memory

There is compelling evidence that sleep contributes to the long-term consolidation of new memories. This function of sleep has been linked to slow (<1 Hz) potential oscillations, which predominantly arise from the prefrontal neocortex and characterize slow wave sleep. However, oscillations in brain potentials are commonly considered to be mere epiphenomena that reflect synchronized activity arising from neuronal networks, which links the membrane and synaptic processes of these neurons in time. Whether brain potentials and their extracellular equivalent have any physiological meaning per se is unclear, but can easily be investigated by inducing the extracellular oscillating potential fields of interest. Here we show that inducing slow oscillation-like potential fields by transcranial application of oscillating potentials (0.75 Hz) during early nocturnal non-rapid-eye-movement sleep, that is, a period of emerging slow wave sleep, enhances the retention of hippocampus-dependent declarative memories in healthy humans. The slowly oscillating potential stimulation induced an immediate increase in slow wave sleep, endogenous cortical slow oscillations and slow spindle activity in the frontal cortex. Brain stimulation with oscillations at 5 Hz--another frequency band that normally predominates during rapid-eye-movement sleep--decreased slow oscillations and left declarative memory unchanged. Our findings indicate that endogenous slow potential oscillations have a causal role in the sleep-associated consolidation of memory, and that this role is enhanced by field effects in cortical extracellular space.     

Graded persistent activity in entorhinal cortex neurons

Working memory represents the ability of the brain to hold externally or internally driven information for relatively short periods of time. Persistent neuronal activity is the elementary process underlying working memory but its cellular basis remains unknown. The most widely accepted hypothesis is that persistent activity is based on synaptic reverberations in recurrent circuits. The entorhinal cortex in the parahippocampal region is crucially involved in the acquisition, consolidation and retrieval of long-term memory traces for which working memory operations are essential. Here we show that individual neurons from layer V of the entorhinal cortex-which link the hippocampus to extensive cortical regions-respond to consecutive stimuli with graded changes in firing frequency that remain stable after each stimulus presentation. In addition, the sustained levels of firing frequency can be either increased or decreased in an input-specific manner. This firing behaviour displays robustness to distractors; it is linked to cholinergic muscarinic receptor activation, and relies on activity-dependent changes of a Ca2+-sensitive cationic current. Such an intrinsic neuronal ability to generate graded persistent activity constitutes an elementary mechanism for working memory.     

Role for a cortical input to hippocampal area CA1 in the consolidation of a long-term memory

A dialogue between the hippocampus and the neocortex is thought to underlie the formation, consolidation and retrieval of episodic memories, although the nature of this cortico-hippocampal communication is poorly understood. Using selective electrolytic lesions in rats, here we examined the role of the direct entorhinal projection (temporoammonic, TA) to the hippocampal area CA1 in short-term (24 hours) and long-term (four weeks) spatial memory in the Morris water maze. When short-term memory was examined, both sham- and TA-lesioned animals showed a significant preference for the target quadrant. When re-tested four weeks later, sham-lesioned animals exhibited long-term memory; in contrast, the TA-lesioned animals no longer showed target quadrant preference. Many long-lasting memories require a process called consolidation, which involves the exchange of information between the cortex and hippocampus. The disruption of long-term memory by the TA lesion could reflect a requirement for TA input during either the acquisition or consolidation of long-term memory. To distinguish between these possibilities, we trained animals, verified their spatial memory 24 hours later, and then subjected trained animals to TA lesions. TA-lesioned animals still exhibited a deficit in long-term memory, indicating a disruption of consolidation. Animals in which the TA lesion was delayed by three weeks, however, showed a significant preference for the target quadrant, indicating that the memory had already been adequately consolidated at the time of the delayed lesion. These results indicate that, after learning, ongoing cortical input conveyed by the TA path is required to consolidate long-term spatial memory.     

Sleep-dependent memory consolidation

The concept of 'sleeping on a problem' is familiar to most of us. But with myriad stages of sleep, forms of memory and processes of memory encoding and consolidation, sorting out how sleep contributes to memory has been anything but straightforward. Nevertheless, converging evidence, from the molecular to the phenomenological, leaves little doubt that offline memory reprocessing during sleep is an important component of how our memories are formed and ultimately shaped.     

Recovery of learning and memory is associated with chromatin remodelling

Neurodegenerative diseases of the central nervous system are often associated with impaired learning and memory, eventually leading to dementia. An important aspect in pre-clinical research is the exploration of strategies to re-establish learning ability and access to long-term memories. By using a mouse model that allows temporally and spatially restricted induction of neuronal loss, we show here that environmental enrichment reinstated learning behaviour and re-established access to long-term memories after significant brain atrophy and neuronal loss had already occurred. Environmental enrichment correlated with chromatin modifications (increased histone-tail acetylation). Moreover, increased histone acetylation by inhibitors of histone deacetylases induced sprouting of dendrites, an increased number of synapses, and reinstated learning behaviour and access to long-term memories. These data suggest that inhibition of histone deacetylases might be a suitable therapeutic avenue for neurodegenerative diseases associated with learning and memory impairment, and raises the possibility of recovery of long-term memories in patients with dementia.     

What can false memory tell us about memory impairments in Alzheimer’s disease?

The range of memory impairments associated with Alzheimer’s disease (AD) has been a focus for psychological and clinical re-searchers for many years. In addition to investigations of AD patients’ veridical memory using traditional recognition memory tasks, a number of recent studies have focused on false memories to reveal the underlying causes of memory impairment in AD. Studies comparing illusory memories between AD patients and healthy older people have revealed various differences in memory deficits between the development of AD and the typical aging processes. Here, we review 3 types of memory illusions tested in AD patients: associative memory illusions, fluency-based false memories and source memory errors. By comparing AD patients with healthy older adults, we sought to analyze the mechanisms underlying AD-related memory impairments at different stages of memory processing, including encoding, retrieval and monitoring. This comparison revealed that AD patients exhibit an impaired ability to establish and utilize gist representations at the encoding stage and impairments in processing on the basis of familiarity and recollection at the retrieval stage. Consequently, patients with AD have access to less information when making memory judgments. As a result, they become more susceptible to the effects of item fluency, which can be manipulated during the retrieval stage. Furthermore, with impaired source memory monitoring abilities, the capacity of AD patients to suppress memory illusions is compromised. Based on these findings, we propose that the study of false memories constitute a critical tool for elucidating the memory impairments involved in AD. Further explorations of these memory impairments will have practical significance for the diagnosis and treatment of AD in the future.     

乘除形态学联想记忆及其性能分析

形态学联想记忆是一类新颖的人工神经网络,但是它的异联想记忆效果较差.针对这个问题,基于互补的思想,提出一种形态学联想记忆方法,称为乘除形态学联想记忆.文中分析了乘除形态学联想记忆方法完全回忆记忆的条件及其噪声性质.分析和实验表明,这种方法对异联想效果显著,并具有一定的抗噪声鲁棒性,在一些情况下,能够取得更好的异联想效果.     

Long-term plasticity in hippocampal place-cell representation of environmental geometry

The hippocampus is widely believed to be involved in the storage or consolidation of long-term memories. Several reports have shown short-term changes in single hippocampal unit activity during memory and plasticity experiments, but there has been no experimental demonstration of long-term persistent changes in neuronal activity in any region except primary cortical areas. Here we report that, in rats repeatedly exposed to two differently shaped environments, the hippocampal-place-cell representations of those environments gradually and incrementally diverge; this divergence is specific to environmental shape, occurs independently of explicit reward, persists for periods of at least one month, and transfers to new enclosures of the same shape. These results indicate that place cells may be a neural substrate for long-term incidental learning, and demonstrate the long-term stability of an experience-dependent firing pattern in the hippocampal formation.     

Glutamate-receptor-mediated encoding and retrieval of paired-associate learning

Paired-associate learning is often used to examine episodic memory in humans. Animal models include the recall of food-cache locations by scrub jays and sequential memory. Here we report a model in which rats encode, during successive sample trials, two paired associates (flavours of food and their spatial locations) and display better-than-chance recall of one item when cued by the other. In a first study, pairings of a particular foodstuff and its location were never repeated, so ensuring unique 'what-where' attributes. Blocking N-methyl-d-aspartate receptors in the hippocampus--crucial for the induction of certain forms of activity-dependent synaptic plasticity--impaired memory encoding but had no effect on recall. Inactivating hippocampal neural activity by blocking alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors impaired both encoding and recall. In a second study, two paired associates were trained repeatedly over 8 weeks in new pairs, but blocking of hippocampal AMPA receptors did not affect their recall. Thus we conclude that unique what-where paired associates depend on encoding and retrieval within a hippocampal memory space, with consolidation of the memory traces representing repeated paired associates in circuits elsewhere.     

Opposite effects of fear conditioning and extinction on dendritic spine remodelling

It is generally believed that fear extinction is a form of new learning that inhibits rather than erases previously acquired fear memories. Although this view has gained much support from behavioural and electrophysiological studies, the hypothesis that extinction causes the partial erasure of fear memories remains viable. Using transcranial two-photon microscopy, we investigated how neural circuits are modified by fear learning and extinction by examining the formation and elimination of postsynaptic dendritic spines of layer-V pyramidal neurons in the mouse frontal association cortex. Here we show that fear conditioning by pairing an auditory cue with a footshock increases the rate of spine elimination. By contrast, fear extinction by repeated presentation of the same auditory cue without a footshock increases the rate of spine formation. The degrees of spine remodelling induced by fear conditioning and extinction strongly correlate with the expression and extinction of conditioned fear responses, respectively. Notably, spine elimination and formation induced by fear conditioning and extinction occur on the same dendritic branches in a cue- and location-specific manner: cue-specific extinction causes formation of dendritic spines within a distance of two micrometres from spines that were eliminated after fear conditioning. Furthermore, reconditioning preferentially induces elimination of dendritic spines that were formed after extinction. Thus, within vastly complex neuronal networks, fear conditioning, extinction and reconditioning lead to opposing changes at the level of individual synapses. These findings also suggest that fear memory traces are partially erased after extinction.     

记忆巩固效力研究述评

睡眠的记忆巩固在多大程度上取决于学习材料的类型、学习与提取测验的类型以及睡眠的不同特征？弱编码联系、外显编码的记忆相对于强编码联系、内隐编码的记忆提高得更多;慢波睡眠巩固陈述性记忆而快速眼动睡眠巩固程序性和情绪性记忆;陈述性记忆的提高来自相当短的睡眠时间,程序性记忆的提高似乎更多地取决于学习后当天的睡眠时间长度。     

Learning-related feedforward inhibitory connectivity growth required for memory precision

In the adult brain, new synapses are formed and pre-existing ones are lost, but the function of this structural plasticity has remained unclear. Learning of new skills is correlated with formation of new synapses. These may directly encode new memories, but they may also have more general roles in memory encoding and retrieval processes. Here we investigated how mossy fibre terminal complexes at the entry of hippocampal and cerebellar circuits rearrange upon learning in mice, and what is the functional role of the rearrangements. We show that one-trial and incremental learning lead to robust, circuit-specific, long-lasting and reversible increases in the numbers of filopodial synapses onto fast-spiking interneurons that trigger feedforward inhibition. The increase in feedforward inhibition connectivity involved a majority of the presynaptic terminals, restricted the numbers of c-Fos-expressing postsynaptic neurons at memory retrieval, and correlated temporally with the quality of the memory. We then show that for contextual fear conditioning and Morris water maze learning, increased feedforward inhibition connectivity by hippocampal mossy fibres has a critical role for the precision of the memory and the learned behaviour. In the absence of mossy fibre long-term potentiation in Rab3a(-/-) mice, c-Fos ensemble reorganization and feedforward inhibition growth were both absent in CA3 upon learning, and the memory was imprecise. By contrast, in the absence of adducin 2 (Add2; also known as β-adducin) c-Fos reorganization was normal, but feedforward inhibition growth was abolished. In parallel, c-Fos ensembles in CA3 were greatly enlarged, and the memory was imprecise. Feedforward inhibition growth and memory precision were both rescued by re-expression of Add2 specifically in hippocampal mossy fibres. These results establish a causal relationship between learning-related increases in the numbers of defined synapses and the precision of learning and memory in the adult. The results further relate plasticity and feedforward inhibition growth at hippocampal mossy fibres to the precision of hippocampus-dependent memories.     

即刻早期基因Arc/Arg3.1的表达及其与学习记忆关系概述

Arc/Arg3.1基因为即刻早期基因(Immediate-early genes,IEGs)中的一种,相对于其他作为转录因子的IEGs,Arc/Arg3.1是可以直接作为效应因子的细胞结构元件.Arc/Arg3.1基因在神经元的突触可塑性方面起重要的作用,如果它的蛋白表达受阻则会损坏LTP的维持,从而损坏长期记忆的巩固.就Arc/Arg3.1基因的序列克隆与表达及其与学习记忆之间关系的研究进展进行了阐述.     

建立小鼠学习记忆损伤模型的方法学研究

目的 通过避暗和Morris水迷宫实验研究建立小鼠学习记忆损伤模型的有效方法。方法 分别在小鼠避暗电击训练之前20 min腹腔注射东莨菪碱1 mg/kg体质量,电击训练结束之后立即皮下注射亚硝酸钠90 mg/kg和下次电击测试之前15 min给小鼠灌服35%乙醇0.1 mL/10 g,建立记忆获得、记忆巩固和记忆再现障碍模型,测定各组小鼠在电击训练后6 h、24 h、30 h、48 h后的避暗潜伏期、错误次数和探头次数等多项指标,评价三种记忆障碍模型方法各指标的敏感性和最适测试时间。小鼠分别腹腔注射东莨菪碱1 mg/kg和灌服35%乙醇0.1 mL/10 g造成学习记忆损伤,通过Morris水迷宫定位航行试验和空间探索试验用于测试实验动物对空间位置感和方向感(空间定位)的学习记忆能力,建立空间学习记忆障碍小鼠模型的评价方法。结果 避暗实验显示：和空白组比较,东莨菪碱造成记忆获得障碍模型小鼠在电击训练之后6 h、24 h避暗潜伏期明显缩短,错误次数也明显增多(P0.05)。结论 避暗实验中使用东莨菪碱、亚硝酸钠构建小鼠记忆获得障碍和记忆巩固模型时应在造模后24 h和30 h检测相应指标;乙醇造成的记忆再现障碍模型,应在电击训练24 h后,在下次测试之前15 min给小鼠灌服乙醇后检测,指标以避暗潜伏期、错误次数和探头次数为宜。Morris水迷宫实验提示东莨菪碱能够损害小鼠空间学习记忆,可以作为构建小鼠空间学习记忆障碍模型的药物,乙醇并不能建立小鼠的空间记忆障碍模型。     

A polymer/semiconductor write-once read-many-times memory

Organic devices promise to revolutionize the extent of, and access to, electronics by providing extremely inexpensive, lightweight and capable ubiquitous components that are printed onto plastic, glass or metal foils. One key component of an electronic circuit that has thus far received surprisingly little attention is an organic electronic memory. Here we report an architecture for a write-once read-many-times (WORM) memory, based on the hybrid integration of an electrochromic polymer with a thin-film silicon diode deposited onto a flexible metal foil substrate. WORM memories are desirable for ultralow-cost permanent storage of digital images, eliminating the need for slow, bulky and expensive mechanical drives used in conventional magnetic and optical memories. Our results indicate that the hybrid organic/inorganic memory device is a reliable means for achieving rapid, large-scale archival data storage. The WORM memory pixel exploits a mechanism of current-controlled, thermally activated un-doping of a two-component electrochromic conducting polymer.     

Repetitive motor learning induces coordinated formation of clustered dendritic spines in vivo

Many lines of evidence suggest that memory in the mammalian brain is stored with distinct spatiotemporal patterns. Despite recent progresses in identifying neuronal populations involved in memory coding, the synapse-level mechanism is still poorly understood. Computational models and electrophysiological data have shown that functional clustering of synapses along dendritic branches leads to nonlinear summation of synaptic inputs and greatly expands the computing power of a neural network. However, whether neighbouring synapses are involved in encoding similar memory and how task-specific cortical networks develop during learning remain elusive. Using transcranial two-photon microscopy, we followed apical dendrites of layer 5 pyramidal neurons in the motor cortex while mice practised novel forelimb skills. Here we show that a third of new dendritic spines (postsynaptic structures of most excitatory synapses) formed during the acquisition phase of learning emerge in clusters, and that most such clusters are neighbouring spine pairs. These clustered new spines are more likely to persist throughout prolonged learning sessions, and even long after training stops, than non-clustered counterparts. Moreover, formation of new spine clusters requires repetition of the same motor task, and the emergence of succedent new spine(s) accompanies the strengthening of the first new spine in the cluster. We also show that under control conditions new spines appear to avoid existing stable spines, rather than being uniformly added along dendrites. However, succedent new spines in clusters overcome such a spatial constraint and form in close vicinity to neighbouring stable spines. Our findings suggest that clustering of new synapses along dendrites is induced by repetitive activation of the cortical circuitry during learning, providing a structural basis for spatial coding of motor memory in the mammalian brain.     

Structural basis of long-term potentiation in single dendritic spines

Dendritic spines of pyramidal neurons in the cerebral cortex undergo activity-dependent structural remodelling that has been proposed to be a cellular basis of learning and memory. How structural remodelling supports synaptic plasticity, such as long-term potentiation, and whether such plasticity is input-specific at the level of the individual spine has remained unknown. We investigated the structural basis of long-term potentiation using two-photon photolysis of caged glutamate at single spines of hippocampal CA1 pyramidal neurons. Here we show that repetitive quantum-like photorelease (uncaging) of glutamate induces a rapid and selective enlargement of stimulated spines that is transient in large mushroom spines but persistent in small spines. Spine enlargement is associated with an increase in AMPA-receptor-mediated currents at the stimulated synapse and is dependent on NMDA receptors, calmodulin and actin polymerization. Long-lasting spine enlargement also requires Ca2+/calmodulin-dependent protein kinase II. Our results thus indicate that spines individually follow Hebb's postulate for learning. They further suggest that small spines are preferential sites for long-term potentiation induction, whereas large spines might represent physical traces of long-term memory.