Active reversal of motor memories reveals rules governing memory encoding

Learning systems must be able to store memories reliably, yet be able to modify them when new learning is required. At the mechanistic level, new learning may either reverse the cellular events mediating the storage of old memories or mask the old memories with additional cellular changes that preserve the old cellular events in a latent form. Behavioral evidence about whether reversal or masking occurs in a particular circuit can constrain the cellular mechanisms used to store memories. Here we examine these constraints for a simple cerebellum-dependent learning task, motor learning in the vestibulo-ocular reflex (VOR). Learning can change the amplitude of the VOR in two opposite directions. Contrary to previous models about memory encoding by the cerebellum, our results indicate that these behavioral changes are implemented by different plasticity mechanisms, which reverse each other with unequal efficacy.     

Novelty-induced memory transmission between two nonequilibrium neural networks

We treated the interactions between two nonequilibrium neural networks, each of which possesses memories that are different from those of the other. In this respect, we developed a kind of hetero interaction that is a crucial ingredient for assuring communication.We propose a new learning algorithm for assuring different neural activity in both the maintenance of own memories and the learning of other memories (which are different from own memories). We call it novelty-induced learning.     

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.     

Glucocorticoids are necessary for enhancing the acquisition of associative memories after acute stressful experience

Exposure to acute stressful experience can enhance the later ability to acquire new memories about associations between stimuli. This enhanced learning is observed during classical eyeblink conditioning of both hippocampal-dependent and -independent learning. It can be induced within minutes of the stressful event and persists for days. Here we examined the role of the major stress hormones glucocorticoids in the enhancement of learning after stress. In the first two experiments, it was determined that adrenalectomy (ADX), with and without replacement of basal levels of corticosterone, prevented the stress-induced enhancement of trace conditioning, a task that is dependent on the hippocampus for acquisition. In a third experiment, demedullation, which removes the adrenal medulla but leaves the adrenal cortex and corticosterone levels intact, did not affect the enhancement of learning after stress. In a fourth experiment, ADX prevented the stress-induced enhancement of delay conditioning, a hippocampal-independent task. In a final experiment, it was determined that one injection of stress levels of corticosterone enhanced new learning within minutes but not new learning 24 h later. Together these results suggest that endogenous glucocorticoids are necessary and sufficient for transiently enhancing acquisition of new associative memories and necessary but insufficient for persistently enhancing their acquisition after exposure to an acute stressful experience.     

Motor learning

Bilateral damage of the medial temporal lobe system prevents the formation of new declarative memories but leaves intact knowledge that was acquired before damage. For motor learning, no structure has been identified that plays a comparable role for the consolidation of motor memories. The deficits of motor learning are focal and show a similar allocation to the various of motor learning are focal and show a similar allocation to the various sensorimotor subsystems, as do the corresponding non-mnemonic functions. The involvement of sensorimotor circuitries changes during motor learning so that association areas are preferentially activated in the early stages, and cerebello- and striato-motor-cortical loops are preferentially activated in the late stages of motor learning. Recent neuroanatomical and neurophysiological findings on the effects of brain lesions in human and non-human primates are discussed.     

Sleep loss produces false memories

People sometimes claim with high confidence to remember events that in fact never happened, typically due to strong semantic associations with actually encoded events. Sleep is known to provide optimal neurobiological conditions for consolidation of memories for long-term storage, whereas sleep deprivation acutely impairs retrieval of stored memories. Here, focusing on the role of sleep-related memory processes, we tested whether false memories can be created (a) as enduring memory representations due to a consolidation-associated reorganization of new memory representations during post-learning sleep and/or (b) as an acute retrieval-related phenomenon induced by sleep deprivation at memory testing. According to the Deese, Roediger, McDermott (DRM) false memory paradigm, subjects learned lists of semantically associated words (e.g., "night", "dark", "coal",...), lacking the strongest common associate or theme word (here: "black"). Subjects either slept or stayed awake immediately after learning, and they were either sleep deprived or not at recognition testing 9, 33, or 44 hours after learning. Sleep deprivation at retrieval, but not sleep following learning, critically enhanced false memories of theme words. This effect was abolished by caffeine administration prior to retrieval, indicating that adenosinergic mechanisms can contribute to the generation of false memories associated with sleep loss.     

The timing of learning before night-time sleep differentially affects declarative and procedural long-term memory consolidation in adolescents

Sleep after learning has been shown to foster the consolidation of new memories. However, fundamental questions on the best timing of learning before night-time sleep persist. We tested the hypothesis that learning directly prior to night-time sleep compared to 7.5 hrs prior to night-time sleep provides better conditions for the consolidation of declarative and procedural memories. Fifty healthy female adolescents (aged 16-17 years) were trained on a declarative word-pair and a procedural finger-tapping task at 3 pm (afternoon group, n = 25) or at 9 pm (evening group, n = 25), followed by a sleep laboratory night. Retrieval was assessed 24 hours and 7 days after initial training. Subjects trained in the afternoon showed a significantly elevated retention rate of word-pairs compared to subjects trained in the evening after 24 hours, but not after 7 days. In contrast, off-line gains in finger-tapping performance were significantly higher in subjects trained in the evening compared to those trained in the afternoon after both retention intervals. The observed enhanced consolidation of procedural memories after training in the evening fits to current models of sleep-related memory consolidation. In contrast, the higher retention of declarative memories after encoding in the afternoon is surprising, appeared to be less robust and needs further investigation.     

Disrupting reconsolidation of drug memories reduces cocaine-seeking behavior

Maladaptive memories that associate environmental stimuli with the effects of drugs of abuse are known to be a major cause of relapse to, and persistence of, a drug addictive habit. However, memories may be disrupted after their acquisition and consolidation by impairing their reconsolidation. Here, we show that infusion of Zif268 antisense oligodeoxynucleotides into the basolateral amygdala, prior to the reactivation of a well-learned memory for a conditioned stimulus (CS)-cocaine association, abolishes the acquired conditioned reinforcing properties of the drug-associated stimulus and thus its impact on the learning of a new cocaine-seeking response. Furthermore, we show that reconsolidation of CS-fear memories also requires Zif268 in the amygdala. These results demonstrate that appetitive CS-drug memories undergo reconsolidation in a manner similar to aversive memories and that this amygdala-dependent reconsolidation can be disrupted to reduce the impact of drug cues on drug seeking.     

Sequence Skill Acquisition and Off-Line Learning in Normal Aging

It is well known that certain cognitive abilities decline with age. The ability to form certain new declarative memories, particularly memories for facts and events, has been widely shown to decline with advancing age. In contrast, the effects of aging on the ability to form new procedural memories such as skills are less well known, though it appears that older adults are able to acquire some new procedural skills over practice. The current study examines the effects of normal aging on procedural memory more closely by comparing the effects of aging on the encoding or acquisition stage of procedural learning versus its effects on the consolidation, or between-session stage of procedural learning. Twelve older and 14 young participants completed a sequence-learning task (the Serial Reaction Time Task) over a practice session and at a re-test session 24 hours later. Older participants actually demonstrated more sequence skill during acquisition than the young. However, older participants failed to show skill improvement at re-test as the young participants did. Age thus appears to have a differential effect upon procedural learning stages such that older adults'' skill acquisition remains relatively intact, in some cases even superior, compared to that of young adults, while their skill consolidation may be poorer than that of young adults. Although the effect of normal aging on procedural consolidation remains unclear, aging may actually enhance skill acquisition on some procedural tasks.     

New insights in human memory interference and consolidation

Learning new facts and skills in succession can be frustrating because no sooner has new knowledge been acquired than its retention is being jeopardized by learning another set of skills or facts. Interference between memories has recently provided important new insights into the neural and psychological systems responsible for memory processing. For example, interference not only occurs between the same types of memories, but can also occur between different types of memories, which has important implications for our understanding of memory organization. Converging evidence has begun to reveal that the brain produces interference independently from other aspects of memory processing, which suggests that interference may have an important but previously overlooked function. A memory's initial susceptibility to interference and subsequent resistance to interference after its acquisition has revealed that memories continue to be processed 'off-line' during consolidation. Recent work has demonstrated that off-line processing is not limited to just the stabilization of a memory, which was once the defining characteristic of consolidation; instead, off-line processing can have a rich diversity of effects, from enhancing performance to making hidden rules explicit. Off-line processing also occurs after memory retrieval when memories are destabilized and then subsequently restabalized during reconsolidation. Studies are beginning to reveal the function of reconsolidation, its mechanistic relationship to consolidation and its potential as a therapeutic target for the modification of memories.     

Motor learning: spare the rod to benefit the child?

A new study has found that individuals who were rewarded while they learned a motor task performed it much better one month later than those who were punished or received nothing. Long-term memories depend on events experienced during learning.     

New experiences enhance coordinated neural activity in the hippocampus

The acquisition of new memories for places and events requires synaptic plasticity in the hippocampus, and plasticity depends on temporal coordination among neurons. Spatial activity in the hippocampus is relatively disorganized during the initial exploration of a novel environment, however, and it is unclear how neural activity during the initial stages of learning drives synaptic plasticity. Here we show that pairs of CA1 cells that represent overlapping novel locations are initially more coactive and more precisely coordinated than are cells representing overlapping familiar locations. This increased coordination occurs specifically during brief, high-frequency events (HFEs) in the local field potential that are similar to ripples and is not associated with better coordination of place-specific neural activity outside of HFEs. As novel locations become more familiar, correlations between cell pairs decrease. Thus, hippocampal neural activity during learning has a unique structure that is well suited to induce synaptic plasticity and to allow for rapid storage of new memories.     

Dynamics of memory representations in networks with novelty-facilitated synaptic plasticity

The ability to associate some stimuli while differentiating between others is an essential characteristic of biological memory. Theoretical models identify memories as attractors of neural network activity, with learning based on Hebb-like synaptic modifications. Our analysis shows that when network inputs are correlated, this mechanism results in overassociations, even up to several memories "merging" into one. To counteract this tendency, we introduce a learning mechanism that involves novelty-facilitated modifications, accentuating synaptic changes proportionally to the difference between network input and stored memories. This mechanism introduces a dependency of synaptic modifications on previously acquired memories, enabling a wide spectrum of memory associations, ranging from absolute discrimination to complete merging. The model predicts that memory representations should be sensitive to learning order, consistent with recent psychophysical studies of face recognition and electrophysiological experiments on hippocampal place cells. The proposed mechanism is compatible with a recent biological model of novelty-facilitated learning in hippocampal circuitry.     

Amnesia,memory and brain systems.

Bilateral damage to either the medial temporal lobe or the diencephalic midline causes an amnesic syndrome, i.e. a global impairment in the ability to acquire new memories regardless of sensory modality, and a loss of some memories, especially recent ones, from the period before amnesia began. The memory deficit can occur against a background of intact intellectual and perceptual functions. Two themes have been prominent in recent work. First, the amnesic syndrome is narrower than once believed in the sense that a number of learning and memory abilities are preserved (e.g. skill and habit learning, simple forms of conditioning and the phenomenon of priming). Second, the brain system damaged in amnesia has only a temporary role in memory. As time passes after learning, memory is reorganized and consolidated within neocortex, such that eventually medial temporal lobe and diencephalic structures are not needed for storage or retrieval.     

Proteomics of multiprotein complexes: answering fundamental questions in neuroscience

Proteomics tools offer new ways to analyse networks of proteins that control important neurobiological phenomena such as learning and memory. In this review, we discuss how a combined proteomic, pharmacological and genetic approach reveals that multiprotein complexes process neural information and encode memories. Simultaneous analysis of multiple proteins enables the development of new concepts and approaches for neuroscience research.     

Hippocampal Lesions Impair Rapid Learning of a Continuous Spatial Alternation Task

The hippocampus is essential for the formation of memories for events, but the specific features of hippocampal neural activity that support memory formation are not yet understood. The ideal experiment to explore this issue would be to monitor changes in hippocampal neural coding throughout the entire learning process, as subjects acquire and use new episodic memories to guide behavior. Unfortunately, it is not clear whether established hippocampally-dependent learning paradigms are suitable for this kind of experiment. The goal of this study was to determine whether learning of the W-track continuous alternation task depends on the hippocampal formation. We tested six rats with NMDA lesions of the hippocampal formation and four sham-operated controls. Compared to controls, rats with hippocampal lesions made a significantly higher proportion of errors and took significantly longer to reach learning criterion. The effect of hippocampal lesion was not due to a deficit in locomotion or motivation, because rats with hippocampal lesions ran well on a linear track for food reward. Rats with hippocampal lesions also exhibited a pattern of perseverative errors during early task experience suggestive of an inability to suppress behaviors learned during pretraining on a linear track. Our findings establish the W-track continuous alternation task as a hippocampally-dependent learning paradigm which may be useful for identifying changes in the neural representation of spatial sequences and reward contingencies as rats learn and apply new task rules.     

Neuronal leucine-rich repeat protein 4 functions in hippocampus-dependent long-lasting memory

Neuronal leucine-rich repeat proteins (NLRRs) are type I transmembrane proteins and expressed in neuronal tissues, but their function remains unknown. Here, we describe the identification and characterization of a new member of the NLRR family, NLRR4, and its potential role in long-lasting memory. We generated NLRR4-deficient (NLRR4(-/-)) mice and found that they showed impaired memory retention. In hippocampus-dependent learning tasks, NLRR4(-/-) mice were able to learn and maintain the memories for one day but unable to retain the memories for four days after learning. In contrast, in a hippocampus-independent task, NLRR4(-/-) mice were able to retain the memory normally for at least seven days. These results suggest that NLRR4 plays a key role in hippocampus-dependent long-lasting memory.     

Proteomics of multiprotein complexes: answering fundamental questions in neuroscience

Proteomics tools offer new ways to analyse networks of proteins that control important neurobiological phenomena such as learning and memory. In this review, we discuss how a combined proteomic, pharmacological and genetic approach reveals that multiprotein complexes process neural information and encode memories. Simultaneous analysis of multiple proteins enables the development of new concepts and approaches for neuroscience research.     

Parallels between cerebellum- and amygdala-dependent conditioning

Recent evidence from cerebellum-dependent motor learning and amygdala-dependent fear conditioning indicates that, despite being mediated by different brain systems, these forms of learning might use a similar sequence of events to form new memories. In each case, learning seems to induce changes in two different groups of neurons. Changes in the first class of cells are induced very rapidly during the initial stages of learning, whereas changes in the second class of cells develop more slowly and are resistant to extinction. So, anatomically distinct cell populations might contribute differentially to the initial encoding and the long-term storage of memory in these two systems.     

Offline persistence of memory-related cerebral activity during active wakefulness

Much remains to be discovered about the fate of recent memories in the human brain. Several studies have reported the reactivation of learning-related cerebral activity during post-training sleep, suggesting that sleep plays a role in the offline processing and consolidation of memory. However, little is known about how new information is maintained and processed during post-training wakefulness before sleep, while the brain is actively engaged in other cognitive activities. We show, using functional magnetic resonance imaging, that brain activity elicited during a new learning episode modulates brain responses to an unrelated cognitive task, during the waking period following the end of training. This post-training activity evolves in learning-related cerebral structures, in which functional connections with other brain regions are gradually established or reinforced. It also correlates with behavioral performance. These processes follow a different time course for hippocampus-dependent and hippocampus-independent memories. Our experimental approach allowed the characterization of the offline evolution of the cerebral correlates of recent memories, without the confounding effect of concurrent practice of the learned material. Results indicate that the human brain has already extensively processed recent memories during the first hours of post-training wakefulness, even when simultaneously coping with unrelated cognitive demands.