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According to the Causal Theory of Memory (CTM), remembering a particular past event requires a causal connection between that event and its subsequent representation in memory, specifically, a connection sustained by a memory trace. The CTM is the default view of memory in contemporary philosophy, but debates persist over what the involved memory traces must be like. Martin and Deutscher (Philos Rev 75:161-196, 1966) argued that the CTM required memory traces to be structural analogues of past events. Bernecker (Memory: A philosophical study. Oxford University Press, Oxford, 2010) and Michaelian (Philos Psychol 24:323-342, 2011), contemporary CTM proponents, reject structural analogues in favor of memory traces as distributed patterns of event features. The proposals are understood as distinct accounts of how memory traces represent past events. But there are two distinct questions one could ask about a trace's representational features. One might ask how memory traces, qua mental representations, have their semantic properties. Or, what makes memory traces, qua mental representations of memories, distinct from other mental representations. Proponents of the CTM, both past and present, have failed to keep these two questions distinct. The result is a serious but unnoticed problem for the CTM in its current form. Distributed memory traces are incompatible with the CTM. Such traces do not provide a way to track the causal history of individual memories, as the CTM requires. If memory traces are distributed patterns of event features, as Bernecker and Michaelian each claim, then the CTM cannot be right.

Research on episodic memory has established that spontaneous eye movements occur to spaces associated with retrieved information even if those spaces are blank at the time of retrieval. Although it has been claimed that such looks to \"nothing\" can function as facilitatory retrieval cues, there is currently no conclusive evidence for such an effect. In the present study, we addressed this fundamental issue using four direct eye manipulations in the retrieval phase of an episodic memory task: (a) free viewing on a blank screen, (b) maintaining central fixation, (c) looking inside a square congruent with the location of the to-be-recalled objects, and (d) looking inside a square incongruent with the location of the to-be-recalled objects. Our results provide novel evidence of an active and facilitatory role of gaze position during memory retrieval and demonstrate that memory for the spatial relationship between objects is more readily affected than memory for intrinsic object features.

In the brain, neuronal gene expression is dynamically changed in response to neuronal activity. In particular, the expression of immediate-early genes (IEGs) such as egr-1, c-fos, and Arc is rapidly and selectively upregulated in subsets of neurons in specific brain regions associated with learning and memory formation. IEG expression has therefore been widely used as a molecular marker for neuronal populations that undergo plastic changes underlying formation of long-term memory. In recent years, optogenetic and pharmacogenetic studies of neurons expressing c-fos or Arc have revealed that, during learning, IEG-positive neurons encode and store information that is required for memory recall, suggesting that they may be involved in formation of the memory trace. However, despite accumulating evidence for the role of IEGs in synaptic plasticity, the molecular and cellular mechanisms associated with this process remain unclear. In this review, we first summarize recent literature concerning the role of IEG-expressing neuronal ensembles in organizing the memory trace. We then focus on the physiological significance of IEGs, especially Arc, in synaptic plasticity, and describe our hypotheses about the importance of Arc expression in various types of input-specific circuit reorganization. Finally, we offer perspectives on Arc function that would unveil the role of IEG-expressing neurons in the formation of memory traces in the hippocampus and other brain areas.

A brief wakeful rest after new verbal learning enhances memory for several minutes. In the research reported here, we explored the possibility of extending this rest-induced memory enhancement over much longer periods. Participants were presented with two stories; one story was followed by a 10-min period of wakeful resting, and the other was followed by a 10-min period during which participants played a spot-the-difference game. In Experiment 1, wakeful resting led to significant enhancement of memory after a 15- to 30-min period and also after 7 days. In Experiment 2, this striking enhancement of memory 7 days after learning was demonstrated even when no retrievals were imposed in the interim. The degree to which people can remember prose after 7 days is significantly affected by the cognitive activity that they engage in shortly after new learning takes place. We propose that wakeful resting after new learning allows new memory traces to be consolidated better and hence to be retained for much longer.

When new learning occurs against the background of established prior knowledge, relevant new information can be assimilated into a schema and thereby expand the knowledge base. An animal model of this important component of memory consolidation reveals that systems memory consolidation can be very fast. In experiments with rats, we found that the hippocampal-dependent learning of new paired associates is associated with a striking up-regulation of immediate early genes in the prelimbic region of the medial prefrontal cortex, and that pharmacological interventions targeted at that area can prevent both new learning and the recall of remotely and even recently consolidated information. These findings challenge the concept of distinct fast (hippocampal) and slow (cortical) learning systems, and shed new light on the neural mechanisms of memory assimilation into schemas.

Dysregulation of the fear system is at the core of many psychiatric disorders. Much progress has been made in uncovering the neural basis of fear learning through studies in which associative emotional memories are formed by pairing an initially neutral stimulus (conditioned stimulus, CS; e.g., a tone) to an unconditioned stimulus (US; e.g., a shock). Despite recent advances, the question of how to persistently weaken aversive CS-US associations, or dampen traumatic memories in pathological cases, remains a major dilemma. Two paradigms (blockade of reconsolidation and extinction) have been used in the laboratory to reduce acquired fear. Unfortunately, their clinical efficacy is limited: Reconsolidation blockade typically requires potentially toxic drugs, and extinction is not permanent. Here, we describe a behavioral design in which a fear memory in rats is destabilized and reinterpreted as safe by presenting an isolated retrieval trial before an extinction session. This procedure permanently attenuates the fear memory without the use of drugs.

Although reconsolidation opens up new avenues to erase excessive fear memory, subtle boundary conditions put constraints on retrieval-induced plasticity. Reconsolidation may only take place when memory reactivation involves an experience that engages new learning (prediction error). Thus far, it has not been possible to determine the optimal degree of novelty required for destabilizing the memory. The occurrence of prediction error could only be inferred from the observation of a reconsolidation process itself. Here, we provide a noninvasive index of memory destabilization that is independent from the occurrence of reconsolidation. Using this index, we show in humans that prediction error is (i) a necessary condition for reconsolidation of associative fear memory and (ii) determined by the interaction between original learning and retrieval. Insight into the process of memory updating is crucial for understanding the optimal and boundary conditions on reconsolidation and provides a clear guide for the development of reconsolidation-based treatments.

Memories become labile when recalled. In humans and rodents alike, reactivated fear memories can be attenuated by disrupting reconsolidation with extinction training. Using functional brain imaging, we found that, after a conditioned fear memory was formed, reactivation and reconsolidation left a memory trace in the basolateral amygdala that predicted subsequent fear expression and was tightly coupled to activity in the fear circuit of the brain. In contrast, reactivation followed by disrupted reconsolidation suppressed fear, abolished the memory trace, and attenuated fear-circuit connectivity. Thus, as previously demonstrated in rodents, fear memory suppression resulting from behavioral disruption of reconsolidation is amygdala-dependent also in humans, which supports an evolutionarily conserved memory-update mechanism.

Although formation and stabilization of long-lasting associative memories are thought to require time-dependent coordinated hippocampal-cortical interactions, the underlying mechanisms remain unclear. Here, we present evidence that neurons in the rat cortex must undergo a \"tagging process\" upon encoding to ensure the progressive hippocampal-driven rewiring of cortical networks that support remote memory storage. This process was AMPA- and N-methyl-D-aspartate receptor-dependent, information-specific, and capable of modulating remote memory persistence by affecting the temporal dynamics of hippocampal-cortical interactions. Post-learning reinforcement of the tagging process via time-limited epigenetic modifications resulted in improved remote memory retrieval. Thus, early tagging of cortical networks is a crucial neurobiological process for remote memory formation whose functional properties fit the requirements imposed by the extended time scale of systems-level memory consolidation.

The retrosplenial cortex (RSC) is part of a network of interconnected cortical, hippocampal, and thalamic structures harboring spatially modulated neurons. The RSC contains head direction cells and connects to the parahippocampal region and anterior thalamus. Manipulations of the RSC can affect spatial and contextual tasks. A considerable amount of evidence implicates the role of the RSC in spatial navigation, but it is unclear whether this structure actually encodes or stores spatial information. We used a transgenic mouse in which the expression of green fluorescent protein was under the control of the immediate early gene c-fos promoter as well as time-lapse two-photon in vivo imaging to monitor neuronal activation triggered by spatial learning in the Morris water maze. We uncovered a repetitive pattern of cell activation in the RSC consistent with the hypothesis that during spatial learning an experience-dependent memory trace is formed in this structure. In support of this hypothesis, we also report three other observations. First, temporary RSC inactivation disrupts performance in a spatial learning task. Second, we show that overexpressing the transcription factor CREB in the RSC with a viral vector, a manipulation known to enhance memory consolidation in other circuits, results in spatial memory enhancements. Third, silencing the viral CREB-expressing neurons with the allatostatin system occludes the spatial memory enhancement. Taken together, these results indicate that the retrosplenial cortex engages in the formation and storage of memory traces for spatial information.