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Neuronal ensembles that hold specific memory (memory engrams) have been identified in the hippocampus, amygdala, or cortex. However, it has been hypothesized that engrams of a specific memory are distributed among multiple brain regions that are functionally connected, referred to as a unified engram complex. Here, we report a partial map of the engram complex for contextual fear conditioning memory by characterizing encoding activated neuronal ensembles in 247 regions using tissue phenotyping in mice. The mapping was aided by an engram index, which identified 117 cFos + brain regions holding engrams with high probability, and brain-wide reactivation of these neuronal ensembles by recall. Optogenetic manipulation experiments revealed engram ensembles, many of which were functionally connected to hippocampal or amygdala engrams. Simultaneous chemogenetic reactivation of multiple engram ensembles conferred a greater level of memory recall than reactivation of a single engram ensemble, reflecting the natural memory recall process. Overall, our study supports the unified engram complex hypothesis for memory storage. Where memories are located in our brains is not well understood. In this paper, the authors demonstrate that memories are spread out throughout multiple brain regions.

Psychedelics are a broad class of drugs defined by their ability to induce an altered state of consciousness 1 , 2 . These drugs have been used for millennia in both spiritual and medicinal contexts, and a number of recent clinical successes have spurred a renewed interest in developing psychedelic therapies 3 – 9 . Nevertheless, a unifying mechanism that can account for these shared phenomenological and therapeutic properties remains unknown. Here we demonstrate in mice that the ability to reopen the social reward learning critical period is a shared property across psychedelic drugs. Notably, the time course of critical period reopening is proportional to the duration of acute subjective effects reported in humans. Furthermore, the ability to reinstate social reward learning in adulthood is paralleled by metaplastic restoration of oxytocin-mediated long-term depression in the nucleus accumbens. Finally, identification of differentially expressed genes in the ‘open state’ versus the ‘closed state’ provides evidence that reorganization of the extracellular matrix is a common downstream mechanism underlying psychedelic drug-mediated critical period reopening. Together these results have important implications for the implementation of psychedelics in clinical practice, as well as the design of novel compounds for the treatment of neuropsychiatric disease. Behavioural electrophysiological and transcriptomic studies in mice show that psychedelic drugs reopen the social reward learning critical period and suggest that this involves reorganization of the extracellular matrix.

Memorization and generalization are complementary cognitive processes that jointly promote adaptive behavior. For example, animals should memorize safe routes to specific water sources and generalize from these memories to discover environmental features that predict new ones. These functions depend on systems consolidation mechanisms that construct neocortical memory traces from hippocampal precursors, but why systems consolidation only applies to a subset of hippocampal memories is unclear. Here we introduce a new neural network formalization of systems consolidation that reveals an overlooked tension—unregulated neocortical memory transfer can cause overfitting and harm generalization in an unpredictable world. We resolve this tension by postulating that memories only consolidate when it aids generalization. This framework accounts for partial hippocampal–cortical memory transfer and provides a normative principle for reconceptualizing numerous observations in the field. Generalization-optimized systems consolidation thus provides new insight into how adaptive behavior benefits from complementary learning systems specialized for memorization and generalization. The authors derive a neural network theory of systems consolidation to assess why some memories consolidate more than others. They propose that brains regulate consolidation to optimize generalization, so only predictable memory components consolidate.

Memory failures are frustrating and often the result of ineffective encoding. One approach to improving memory outcomes is through direct modulation of brain activity with electrical stimulation. Previous efforts, however, have reported inconsistent effects when using open-loop stimulation and often target the hippocampus and medial temporal lobes. Here we use a closed-loop system to monitor and decode neural activity from direct brain recordings in humans. We apply targeted stimulation to lateral temporal cortex and report that this stimulation rescues periods of poor memory encoding. This system also improves later recall, revealing that the lateral temporal cortex is a reliable target for memory enhancement. Taken together, our results suggest that such systems may provide a therapeutic approach for treating memory dysfunction. Memory lapses can occur due to ineffective encoding, but it is unclear if targeted brain stimulation can improve memory performance. Here, authors use a closed-loop system to decode and stimulate periods of ineffective encoding, showing that stimulation of lateral temporal cortex can enhance memory.

The spontaneous replay of patterns of activity related to past experiences and memories is a striking feature of brain activity, as is the coherent activation of sets of brain areas — particularly those comprising the default mode network (DMN) — during rest. We propose that these two phenomena are strongly intertwined and that their potential functions overlap. In the ‘cascaded memory systems model’ that we outline here, we hypothesize that the DMN forms the backbone for the propagation of replay, mediating interactions between the hippocampus and the neocortex that enable the consolidation of new memories. The DMN may also independently ignite replay cascades, which support reactivation of older memories or high-level semantic representations. We suggest that transient cortical activations, inducing long-range correlations across the neocortex, are a key mechanism supporting a hierarchy of representations that progresses from simple percepts to semantic representations of causes and, finally, to whole episodes.Battaglia and colleagues discuss evidence for functional interactions between memory replay and default mode network (DMN) activity and propose an updated model of memory consolidation and retrieval in which the DMN acts as a hub for cascaded replay across the brain.

Standard models of episodic memory focus on hippocampal–parahippocampal interactions, with the neocortex supplying sensory information and providing a final repository of mnemonic representations. However, recent advances have shown that other regions make distinct and equally critical contributions to memory. In particular, there is growing evidence that the anterior thalamic nuclei have a number of key cognitive functions that support episodic memory. In this article, we describe these findings and argue for a core, tripartite memory system, comprising a ‘temporal lobe’ stream (centred on the hippocampus) and a ‘medial diencephalic’ stream (centred on the anterior thalamic nuclei) that together act on shared cortical areas. We demonstrate how these distributed brain regions form complementary and necessary partnerships in episodic memory formation.Accumulating evidence indicates that the anterior thalamic nuclei make important contributions to cognition. Aggleton and O’Mara review these findings and propose that the anterior thalamic nuclei, hippocampus and cortex act together to support episodic memory function.

The function of rapid eye movement (REM) sleep remains unclear. By examining how REM sleep affects synapses in the mouse cortex, the authors show that REM sleep is fundamental to brain development, learning and memory consolidation by selectively pruning and maintaining newly formed synapses via dendritic calcium spike-dependent mechanisms. The functions and underlying mechanisms of rapid eye movement (REM) sleep remain unclear. Here we show that REM sleep prunes newly formed postsynaptic dendritic spines of layer 5 pyramidal neurons in the mouse motor cortex during development and motor learning. This REM sleep-dependent elimination of new spines facilitates subsequent spine formation during development and when a new motor task is learned, indicating a role for REM sleep in pruning to balance the number of new spines formed over time. Moreover, REM sleep also strengthens and maintains newly formed spines, which are critical for neuronal circuit development and behavioral improvement after learning. We further show that dendritic calcium spikes arising during REM sleep are important for pruning and strengthening new spines. Together, these findings indicate that REM sleep has multifaceted functions in brain development, learning and memory consolidation by selectively eliminating and maintaining newly formed synapses via dendritic calcium spike-dependent mechanisms.

The authors demonstrate that activity patterns in the default network during unguided spoken recollection of real-world events were similar between individuals recalling the same specific events. Patterns were altered between perception and recall in a systematic manner across brains. These results reveal a common spatial organization for memory representations. Our lives revolve around sharing experiences and memories with others. When different people recount the same events, how similar are their underlying neural representations? Participants viewed a 50-min movie, then verbally described the events during functional MRI, producing unguided detailed descriptions lasting up to 40 min. As each person spoke, event-specific spatial patterns were reinstated in default-network, medial-temporal, and high-level visual areas. Individual event patterns were both highly discriminable from one another and similar among people, suggesting consistent spatial organization. In many high-order areas, patterns were more similar between people recalling the same event than between recall and perception, indicating systematic reshaping of percept into memory. These results reveal the existence of a common spatial organization for memories in high-level cortical areas, where encoded information is largely abstracted beyond sensory constraints, and that neural patterns during perception are altered systematically across people into shared memory representations for real-life events.

Remote memories depend on coordinated activity in the hippocampus and frontal cortices, but the timeline of these interactions is debated. Astrocytes sense and modify neuronal activity, but their role in remote memory is scarcely explored. We expressed the Gi-coupled designer receptor hM4Di in CA1 astrocytes and discovered that astrocytic manipulation during learning specifically impaired remote, but not recent, memory recall and decreased activity in the anterior cingulate cortex (ACC) during retrieval. We revealed massive recruitment of ACC-projecting CA1 neurons during memory acquisition, which was accompanied by the activation of ACC neurons. Astrocytic Gi activation disrupted CA3 to CA1 communication in vivo and reduced the downstream response in the ACC. In behaving mice, it induced a projection-specific inhibition of CA1-to-ACC neurons during learning, which consequently prevented ACC recruitment. Finally, direct inhibition of CA1-to-ACC-projecting neurons spared recent and impaired remote memory. Our findings suggest that remote memory acquisition involves projection-specific functions of astrocytes in regulating CA1-to-ACC neuronal communication.Kol et al. show that the foundation of remote memory is formed during acquisition by the massive recruitment of ACC-projecting CA1 neurons. Remote memory acquisition involves projection-specific effects of astrocytes on CA1-to-ACC neuronal communication.

Although every life event is unique, there are considerable commonalities across events. However, little is known about whether or how the brain flexibly represents information about different event components at encoding and during remembering. Here, we show that different cortico-hippocampal networks systematically represent specific components of events depicted in videos, both during online experience and during episodic memory retrieval. Regions of an Anterior Temporal Network represented information about people, generalizing across contexts, whereas regions of a Posterior Medial Network represented context information, generalizing across people. Medial prefrontal cortex generalized across videos depicting the same event schema, whereas the hippocampus maintained event-specific representations. Similar effects were seen in real-time and recall, suggesting reuse of event components across overlapping episodic memories. These representational profiles together provide a computationally optimal strategy to scaffold memory for different high-level event components, allowing efficient reuse for event comprehension, recollection, and imagination. How the brain builds memories from the complex, dynamic experiences that make up everyday life remains poorly understood. Here, the authors show that memories for lifelike events are supported by stable representations of people, contexts, and situations that can be flexibly recombined into unique, specific instances.