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Memory retrieval involves the interaction between external sensory or internally generated cues and stored memory traces (or engrams) in a process termed ‘ecphory’. While ecphory has been examined in human cognitive neuroscience research, its neurobiological foundation is less understood. To the extent that ecphory involves ‘reawakening’ of engrams, leveraging recently developed technologies that can identify and manipulate engrams in rodents provides a fertile avenue for examining retrieval at the level of neuronal ensembles. Here we evaluate emerging neuroscientific research of this type, using cognitive theory as a guiding principle to organize and interpret initial findings. Our Review highlights the critical interaction between engrams and retrieval cues (environmental or artificial) for memory accessibility and retrieval success. These findings also highlight the intimate relationship between the mechanisms important in forming engrams and those important in their recovery, as captured in the cognitive notion of ‘encoding specificity’. Finally, we identify several questions that currently remain unanswered.

Communication and oscillatory synchrony between distributed neural populations are believed to play a key role in multiple cognitive and neural functions. These interactions are mediated by long-range myelinated axonal fiber bundles, collectively termed as white matter. While traditionally considered to be static after development, white matter properties have been shown to change in an activity-dependent way through learning and behavior—a phenomenon known as white matter plasticity. In the central nervous system, this plasticity stems from oligodendroglia, which form myelin sheaths to regulate the conduction of nerve impulses across the brain, hence critically impacting neural communication. We here shift the focus from neural to glial contribution to brain synchronization and examine the impact of adaptive, activity-dependent changes in conduction velocity on the large-scale phase synchronization of neural oscillators. Using a network model based on primate large-scale white matter neuroanatomy, our computational and mathematical results show that such plasticity endows white matter with self-organizing properties, where conduction delay statistics are autonomously adjusted to ensure efficient neural communication. Our analysis shows that this mechanism stabilizes oscillatory neural activity across a wide range of connectivity gain and frequency bands, making phase-locked states more resilient to damage as reflected by diffuse decreases in connectivity. Critically, our work suggests that adaptive myelination may be a mechanism that enables brain networks with ameans of temporal self-organization, resilience, and homeostasis.

Key Points In humans, damage to the medial temporal lobe typically produces temporally-graded retrograde amnesia — a loss of recent memories, but a relative sparing of more remote ones. This has been taken as evidence that the hippocampus has a time-limited role in the storage and retrieval of some forms of memory. This idea forms the central tenet of most contemporary views of system consolidation: the hippocampus acts as a temporary store for new information, but permanent storage depends on a broadly distributed cortical network. The relationship between hippocampal damage and retrograde amnesia has been studied in animal models. The main advantage of this approach is that it allows retrograde amnesia to be studied in a prospective manner — the extent of the lesion can be controlled, as can what is learned and when. As in humans, the typical finding is that disrupting hippocampal function preferentially affects recent, rather than remote, memories. These observations in humans and animal models indicate that memories are reorganized at the system level as they mature. Most contemporary models propose that experience is initially encoded in parallel in hippocampal and cortical networks. Subsequent reactivation of the hippocampal network reinstates activity in different cortical networks. This coordinated replay across hippocampal–cortical networks leads to gradual strengthening of cortico-cortical connections, which eventually allows new memories to become independent of the hippocampus and to be gradually integrated with pre-existing cortical memories. By contrast, multiple trace theory proposes a more permanent role for the hippocampus in some forms of declarative memory. It posits that memories are encoded in hippocampal–cortical networks, and that retrieval of contextually rich episodic memories, as well as spatial detail, always requires the hippocampus. Memory reactivation is the core mechanism in consolidation models. Reactivation of the hippocampal memory trace is thought to lead to the reinstatement of waking patterns of neural activity in the cortex, and subsequent stabilization and refinement of hippocampal–cortical circuits. Gradual remodelling of hippocampal–cortical circuits depends on several rounds of synaptic modification. These changes are initiated in a reactivation-dependent manner, either during online (task-relevant) or offline (sleep or quiet wakefulness) situations, and require the expression of new genes. Imaging studies in rodents have been able to characterize how circuits supporting memories are gradually reorganized over time, to identify sites of permanent storage in the cortex, and to provide evidence for network reorganization at both regional and sub-regional levels. Imaging and pharmacological and anatomical lesion studies have identified the prefrontal cortex as playing a crucial part in processing remote memories. These findings indicate that the prefrontal cortex might have a dual role during recall of remote memories. First, the prefrontal cortex may be important for integrating information from many cortical modules. Second, in the case of successful recall, the prefrontal cortex may exert top-down inhibitory control over hippocampal function to minimize re-encoding of redundant information. A fundamental question in memory research is how our brains can form enduring memories. In humans, memories of everyday life depend initially on the medial temporal lobe system, including the hippocampus. As these memories mature, they are thought to become increasingly dependent on other brain regions such as the cortex. Little is understood about how new memories in the hippocampus are transformed into remote memories in cortical networks. However, recent studies have begun to shed light on how remote memories are organized in the cortex, and the molecular and cellular events that underlie their consolidation.

Newly generated dentate granule cells in the hippocampus at 4 weeks after their 'birth' are more plastic than existing neurons. The authors use a combined retroviral and optogenetic approach to show that silencing these 4-week-old cells, but not cells of other ages, impaired retrieval of hippocampal memory. Accumulating evidence suggests that global depletion of adult hippocampal neurogenesis influences its function and that the timing of the depletion affects the deficits. However, the behavioral roles of adult-born neurons during their establishment of projections to CA3 pyramidal neurons remain largely unknown. We used a combination of retroviral and optogenetic approaches to birth date and reversibly control a group of adult-born neurons in adult mice. Adult-born neurons formed functional synapses on CA3 pyramidal neurons as early as 2 weeks after birth, and this projection to the CA3 area became stable by 4 weeks in age. Newborn neurons at this age were more plastic than neurons at other stages. Notably, we found that reversibly silencing this cohort of ∼4-week-old cells after training, but not cells of other ages, substantially disrupted retrieval of hippocampal memory. Our results identify a restricted time window for adult-born neurons essential in hippocampal memory retrieval.

The formation of long-lasting memories requires coordinated changes in gene expression and protein synthesis. Although many studies implicate DNA modifications (DNA methylation, histone modifications) in memory formation, the contributions of RNA modifications remain largely unexplored. Here we investigated the role of mRNA methylation in hippocampal-dependent memory formation in mice. RNA modifications are highly dynamic and readily reversible. Methyltransferases add a methyl group to mRNA while demethylases remove methyl groups. Here we focused on examining the role of the best characterized RNA demethylase, FTO (fat mass and obesity-associated) in memory. We observed that FTO is expressed in the nuclei, dendrites and near dendritic spines of mouse dorsal hippocampal CA1 neurons. Next, we found that contextual fear conditioning transiently (0.5 h) decreased Fto levels in these neurons, with the largest decrease in FTO observed near synapses. The decrease in FTO observed shortly after contextual fear conditioning suggests that FTO normally constrains memory formation. To directly test this, we artificially decreased FTO levels in dorsal hippocampus of otherwise normal (wild-type) mice by microinjecting before training a single herpes simplex virus (HSV) vector expressing either CRISPR/Cas9 or shRNA targeted against Fto. Decreasing FTO using either method specifically enhanced contextual fear memory. Together, these results show the importance of FTO during memory formation and, furthermore, implicate mRNA modification and epi-transcriptomics as novel regulators of memory formation.

Memory is coded by patterns of neural activity in distinct circuits. Therefore, it should be possible to reverse engineer a memory by artificially creating these patterns of activity in the absence of a sensory experience. In olfactory conditioning, an odor conditioned stimulus (CS) is paired with an unconditioned stimulus (US; for example, a footshock), and the resulting CS–US association guides future behavior. Here we replaced the odor CS with optogenetic stimulation of a specific olfactory glomerulus and the US with optogenetic stimulation of distinct inputs into the ventral tegmental area that mediate either aversion or reward. In doing so, we created a fully artificial memory in mice. Similarly to a natural memory, this artificial memory depended on CS–US contingency during training, and the conditioned response was specific to the CS and reflected the US valence. Moreover, both real and implanted memories engaged overlapping brain circuits and depended on basolateral amygdala activity for expression.Pairing an odor conditioned stimulus (CS) with an unconditioned stimulus (US) induces memory formation. Vetere et al. replace the real CS and US with direct optogenetic stimulation of the brain and create a fully artificial odor memory in mice.

Collections of cells called engrams are thought to represent memories. Although there has been progress in identifying and manipulating single engrams, little is known about how multiple engrams interact to influence memory. In lateral amygdala (LA), neurons with increased excitability during training outcompete their neighbors for allocation to an engram. We examined whether competition based on neuronal excitability also governs the interaction between engrams. Mice received two distinct fear conditioning events separated by different intervals. LA neuron excitability was optogenetically manipulated and revealed a transient competitive process that integrates memories for events occurring closely in time (coallocating overlapping populations of neurons to both engrams) and separates memories for events occurring at distal times (disallocating nonoverlapping populations to each engram).

Throughout life, new neurons are continuously added to the dentate gyrus. As this continuous addition remodels hippocampal circuits, computational models predict that neurogenesis leads to degradation or forgetting of established memories. Consistent with this, increasing neurogenesis after the formation of a memory was sufficient to induce forgetting in adult mice. By contrast, during infancy, when hippocampal neurogenesis levels are high and freshly generated memories tend to be rapidly forgotten (infantile amnesia), decreasing neurogenesis after memory formation mitigated forgetting. In precocial species, including guinea pigs and degus, most granule cells are generated prenatally. Consistent with reduced levels of postnatal hippocampal neurogenesis, infant guinea pigs and degus did not exhibit forgetting. However, increasing neurogenesis after memory formation induced infantile amnesia in these species.

The dentate gyrus (DG) is important for encoding contextual memories, but little is known about how a population of DG neurons comes to encode and support a particular memory. One possibility is that recruitment into an engram depends on a neuron's excitability. Here, we manipulated excitability by overexpressing CREB in a random population of DG neurons and examined whether this biased their recruitment to an engram supporting a contextual fear memory. To directly assess whether neurons overexpressing CREB at the time of training became critical components of the engram, we examined memory expression while the activity of these neurons was silenced. Chemogenetically (hM4Di, an inhibitory DREADD receptor) or optogenetically (iC++, a light-activated chloride channel) silencing the small number of CREB-overexpressing DG neurons attenuated memory expression, whereas silencing a similar number of random neurons not overexpressing CREB at the time of training did not. As post-encoding reactivation of the activity patterns present during initial experience is thought to be important in memory consolidation, we investigated whether post-training silencing of neurons allocated to an engram disrupted subsequent memory expression. We found that silencing neurons 5 min (but not 24 h) following training disrupted memory expression. Together these results indicate that the rules of neuronal allocation to an engram originally described in the lateral amygdala are followed in different brain regions including DG, and moreover, that disrupting the post-training activity pattern of these neurons prevents memory consolidation.

Long-term memories are thought to depend upon the coordinated activation of a broad network of cortical and subcortical brain regions. However, the distributed nature of this representation has made it challenging to define the neural elements of the memory trace, and lesion and electrophysiological approaches provide only a narrow window into what is appreciated a much more global network. Here we used a global mapping approach to identify networks of brain regions activated following recall of long-term fear memories in mice. Analysis of Fos expression across 84 brain regions allowed us to identify regions that were co-active following memory recall. These analyses revealed that the functional organization of long-term fear memories depends on memory age and is altered in mutant mice that exhibit premature forgetting. Most importantly, these analyses indicate that long-term memory recall engages a network that has a distinct thalamic-hippocampal-cortical signature. This network is concurrently integrated and segregated and therefore has small-world properties, and contains hub-like regions in the prefrontal cortex and thalamus that may play privileged roles in memory expression.