Memory Engrams Research Articles

Hippocampal neurons with stable excitatory connectivity become part of neuronal representations.

Experiences are represented in the brain by patterns of neuronal activity. Ensembles of neurons representing experience undergo activity-dependent plasticity and are important for learning and recall. They are thus considered cellular engrams of memory. Yet, the cellular events that bias neurons to become part of a neuronal representation are largely unknown. In rodents, turnover of structural connectivity has been proposed to underlie the turnover of neuronal representations and also to be a cellular mechanism defining the time duration for which memories are stored in the hippocampus. If these hypotheses are true, structural dynamics of connectivity should be involved in the formation of neuronal representations and concurrently important for learning and recall. To tackle these questions, we used deep-brain 2-photon (2P) time-lapse imaging in transgenic mice in which neurons expressing the Immediate Early Gene (IEG) Arc (activity-regulated cytoskeleton-associated protein) could be permanently labeled during a specific time window. This enabled us to investigate the dynamics of excitatory synaptic connectivity—using dendritic spines as proxies—of hippocampal CA1 (cornu ammonis 1) pyramidal neurons (PNs) becoming part of neuronal representations exploiting Arc as an indicator of being part of neuronal representations. We discovered that neurons that will prospectively express Arc have slower turnover of synaptic connectivity, thus suggesting that synaptic stability prior to experience can bias neurons to become part of representations or possibly engrams. We also found a negative correlation between stability of structural synaptic connectivity and the ability to recall features of a hippocampal-dependent memory, which suggests that faster structural turnover in hippocampal CA1 might be functional for memory.

The role of the dentate gyrus in mnemonic functions

Abstract The hippocampus is decisive for the storage of conscious memories. Current theories suggest that experience-dependent modifications in excitation–inhibition balance enable a select group of neurons to form a new cell association during learning which represents the new memory trace. It was further proposed that particularly GABAergic-inhibitory interneurons have a large impact on population activity in neuronal networks by means of their inhibitory output synapses. They synchronize active principal cells at high frequencies, thereby supporting their binding to cell assemblies to jointly encode information. However, how cell associations emerge in space and time and how interneurons may contribute to this process is still largely unknown. We started to address this fundamental question in the dentate gyrus (DG) as the input gate of the hippocampus, which has an indispensable role in conscious memory formation. We used a combination of in vivo chronic two-photon imaging of population activity in the DG and the hippocampal areas CA1–3 of mice exposed to a virtual reality, in which they perform a goal-oriented spatial memory tasks, with high-density in vivo recordings and multiple whole-cell recordings in acute slice preparations, to determine how memory engrams emerge during learning. We further examine how GABAergic interneurons may contribute to this process. We believe that these lines of research will add to a better understanding on the mechanisms of memory formation in cortical networks.

Contextual Fear Memory Retrieval Is Vulnerable to Hippocampal Noise.

Memory retrieval depends on reactivation of memory engram cells. Inadvertent activation of these cells is expected to cause memory-retrieval failure, but little is known about how noisy activity of memory-irrelevant neurons impacts mnemonic processes. Here, we report that optogenetic nonselective activation of only tens of hippocampal CA1 cells (∼0.01% of the total cells in the CA1 pyramidal cell layer) impairs contextual fear memory recall. Memory recall failure was associated with altered neuronal reactivation in the basolateral amygdala. These results indicate that hippocampal memory retrieval requires strictly regulated activation of a specific neuron ensemble and is easily disrupted by the introduction of noisy CA1 activity, suggesting that reactivating memory engram cells as well as silencing memory-irrelevant neurons are both crucial for memory retrieval.

Incidental auditory learning and memory-guided attention: Examining the role of attention at the behavioural and neural level using EEG

The current study addressed the relation between awareness, attention, and memory, by examining whether merely presenting a tone and audio-clip, without deliberately associating one with other, was sufficient to bias attention to a given side. Participants were exposed to 80 different audio-clips (half included a lateralized pure tone) and told to classify audio-clips as natural (e.g., waterfall) or manmade (e.g., airplane engine). A surprise memory test followed, in which participants pressed a button to a lateralized faint tone (target) embedded in each audio-clip. They also indicated if the clip was (i) old/new; (ii) recollected/familiar; and (iii) if the tone was on left/right/not present when they heard the clip at exposure. The results demonstrate good explicit memory for the clip, but not for tone location. Response times were faster for old than for new clips but did not vary according to the target-context associations. Neuro-electric activity revealed an old-new effect at midline-frontal sites and a difference between old clips that were previously associated with the target tone and those that were not. These results are consistent with the attention-dependent learning hypothesis and suggest that associations were formed incidentally at a neural level (silent memory trace or engram), but these associations did not guide attention at a level that influenced behaviour either explicitly or implicitly.

Memory: It’s Not a Lie if You Believe It

Memories are crucial for making accurate predictions about our environment. New research suggests that, in the face of limited perceptual evidence, our brains quickly form generalized contextual memory engrams that can be refined based on future, confirmatory or misleading, experience.

Hippocampal Negative Memory Engrams and Stress Susceptibility

Hippocampal Negative Memory Engrams and Stress Susceptibility

An update on memory formation and retrieval: An engram-centric approach.

We explore here that memory loss observed in the early stage of Alzheimer's disease (AD) is a disorder of memory retrieval, instead of a storage impairment. This engram-centric explanation aims to enlarge the conceptual frame of memory as an emergent behavior of the brain and to propose a new treatment strategy for memory retrieval in dementia-AD. The conventional memory hypothesis suggests that memory is stored as multiple traces in hippocampal neurons but recent evidence indicates that there are specialized memory engrams responsible for the storage and the retrieval of different memory types. There are specialized memory engram neurons for each memory type and when information will be stored as a memory arrives in the hippocampus through afferent neurons finds its neuron according to the excitability states of engram neurons. The excitability level in engram neurons seems like a code canalizing the interactions between engrams and information. Therefore, to enhance the excitability of memory engram neurons improves memory loss observed in AD. In addition, we suggest that the hippocampus creates an index for information stored in memory engram cells in specialized regions for different types of memory, instead of storing all information; and different anatomic locations of engram cells and their roles in memory retrieval point out that memory could be an emergent behavior of the brain, and the interaction between serotonin fluctuation and engram neurons could be neural underpinnings of terminal lucidity. The major challenge for this engram-centric memory retrieval model is the translation from bench to patient, specifically the delivery of optogenetic tools in patients. Engram neurons can be specifically activated by optogenetic tools, but optogenetics is an invasive technique which requires optic fiber implantation into the brain. In addition, light can overheat the tissue and thus induce damage in tissue. Furthermore, light is a foreign object and its direct implantation into the brain may cause neuroinflammation, the main trigger of neurodegenerative diseases. Therefore, to test the engram hypothesis in human, new tools to allow specific engram activation should be discovered.

The cellular and molecular basis of in vivo synaptic plasticity in rodents.

Plasticity within the neuronal networks of the brain underlies the ability to learn and retain new information. The initial discovery of synaptic plasticity occurred by measuring synaptic strength in vivo, applying external stimulation and observing an increase in synaptic strength termed long-term potentiation (LTP). Many of the molecular pathways involved in LTP and other forms of synaptic plasticity were subsequently uncovered in vitro. Over the last few decades, technological advances in recording and imaging in live animals have seen many of these molecular mechanisms confirmed in vivo, including structural changes both pre- and postsynaptically, changes in synaptic strength, and changes in neuronal excitability. A well-studied aspect of neuronal plasticity is the capacity of the brain to adapt to its environment, gained by comparing the brains of deprived and experienced animals in vivo, and in direct response to sensory stimuli. Multiple in vivo studies have also strongly linked plastic changes to memory by interfering with the expression of plasticity and by manipulating memory engrams. Plasticity in vivo also occurs in the absence of any form of external stimulation, i.e., during spontaneous network activity occurring with brain development. However, there is still much to learn about how plasticity is induced during natural learning and how this is altered in neurological disorders.

Retrograde and anterograde contextual fear amnesia induced by selective elimination of layer IV-Va neurons in the granular retrosplenial cortex (A29).

Differences in cytoarchitectural organization and connectivity distinguishes granular (or area 29, A29) and dysgranular (or area 30, A30) subdivisions of the retrosplenial cortex (RSC). Although increasing evidence supports the participation of RSC in contextual fear learning and memory, the contribution of each RSC subdivision remains unknown. Here we used orchiectomized rats and intraperitoneal (i.p.) injections of saline (control) or 5mg/kg MK801, to trigger selective degeneration of pyramidal neurons in layers IV-Va of A29 (A29MK801 neurons). These treatments were applied 3days before or two days after contextual fear conditioning, and contextual fear memory was evaluated by scoring freezing in the conditioned context five days after training. Afterwards, brains were fixed and c-Fos and Egr-1 expression were assessed as surrogates of neuronal activity elicited by the recall in A29, A30 and in limbic areas. We found that eliminating A29MK801 neurons after training reduces conditioned freezing to 43.1±9.9% respect to control rats. This was associated with a significant reduction of c-Fos and Egr-1 expression in A30, but not in other limbic areas. On the other hand, eliminating A29MK801 neurons before training caused a mild but significant reduction of conditioned freezing to 79.7±6.8%, which was associated to enhanced expression of c-Fos in A29, A30 and CA1 field of hippocampus, while Egr-1 expression in caudomedial (CEnt) entorhinal cortex was not depressed as in control animals. These observations show that severeness of amnesia differs according to whether A29MK801 neurons were eliminated before or after conditioning, likely because loss of A29MK801 neurons after conditioning disrupt memory engram while their elimination before training allow recruitment of other neurons in A29 for partial compensation of contextual fear learning and memory. These observations add further support for the critical role of A29MK801 neurons in contextual fear learning and memory by connecting limbic structures with A30.

A Sparse, Spatially Biased Subtype of Mature Granule Cell Dominates Recruitment in Hippocampal-Associated Behaviors

Animals can store information about experiences by activating specific neuronal populations, and subsequent reactivation of these neural ensembles can lead to recall of salient experiences. In the hippocampus, granule cells of the dentate gyrus participate in such memory engrams; however, whether there is an underlying logic to granule cell participation has not been examined. Here, we find that a range of novel experiences preferentially activates granule cells of the suprapyramidal blade relative to the infrapyramidal blade. Motivated by this, we identify a suprapyramidal-blade-enriched population of granule cells with distinct spatial, morphological, physiological, and developmental properties. Via transcriptomics, we map these traits onto a sparse and discrete granule cell subtype that is recruited at a 10-fold greater frequency than expected by subtype prevalence, constituting the majority of all recruited granule cells. Thus, in behaviors known to involve hippocampal-dependent memory formation, a rare and spatially localized subtype dominates overall granule cell recruitment.

Functionally Distinct Neuronal Ensembles within the Memory Engram

Memories are believed to be encoded by sparse ensembles of neurons in the brain. However, it remains unclear whether there is functional heterogeneity within individual memory engrams, i.e., if separate neuronal subpopulations encode distinct aspects of the memory and drive memory expression differently. Here, we show that contextual fear memory engrams in the mouse dentate gyrus contain functionally distinct neuronal ensembles, genetically defined by the Fos- or Npas4-dependent transcriptional pathways. The Fos-dependent ensemble promotes memory generalization and receives enhanced excitatory synaptic inputs from the medial entorhinal cortex, which we find itself also mediates generalization. The Npas4-dependent ensemble promotes memory discrimination and receives enhanced inhibitory drive from local cholecystokinin-expressing interneurons, the activity of which is required for discrimination. Our study provides causal evidence for functional heterogeneity within the memory engram and reveals synaptic and circuit mechanisms used by each ensemble to regulate the memory discrimination-generalization balance.

Concurrent Thalamostriatal and Corticostriatal Spike-Timing-Dependent Plasticity and Heterosynaptic Interactions Shape Striatal Plasticity Map.

The striatum integrates inputs from the cortex and thalamus, which display concomitant or sequential activity. The striatum assists in forming memory, with acquisition of the behavioral repertoire being associated with corticostriatal (CS) plasticity. The literature has mainly focused on that CS plasticity, and little remains known about thalamostriatal (TS) plasticity rules or CS and TS plasticity interactions. We undertook here the study of these plasticity rules. We found bidirectional Hebbian and anti-Hebbian spike-timing-dependent plasticity (STDP) at the thalamic and cortical inputs, respectively, which were driving concurrent changes at the striatal synapses. Moreover, TS- and CS-STDP induced heterosynaptic plasticity. We developed a calcium-based mathematical model of the coupled TS and CS plasticity, and simulations predict complex changes in the CS and TS plasticity maps depending on the precise cortex-thalamus-striatum engram. These predictions were experimentally validated using triplet-based STDP stimulations, which revealed the significant remodeling of the CS-STDP map upon TS activity, which is notably the induction of the LTD areas in the CS-STDP for specific timing regimes. TS-STDP exerts a greater influence on CS plasticity than CS-STDP on TS plasticity. These findings highlight the major impact of precise timing in cortical and thalamic activity for the memory engram of striatal synapses.

Microglia modulate memories

Neuroscience Synaptic reorganization and circuit rewiring leads to loss or weakening of connections between neurons and may result in the erasure of previously formed memories. Microglia eliminate excessive synapses in the developing brain and regulate the dynamics of synaptic connections between neurons throughout life. However, it is still unclear whether forgetting is related to microglia activity and how microglia regulate memory erasure in the adult brain. Wang et al. discovered that microglia eliminated synaptic components in the adult hippocampus and that depleting microglia or inhibiting phagocytosis of microglia prevented forgetting. Synapse elimination by microglia may thus lead to degradation of memory engrams and forgetting of previously learned contextual fear memory. Science , this issue p. [688][1] [1]: /lookup/doi/10.1126/science.aaz2288

Microglia mediate forgetting via complement-dependent synaptic elimination.

Synapses between engram cells are believed to be substrates for memory storage, and the weakening or loss of these synapses leads to the forgetting of related memories. We found engulfment of synaptic components by microglia in the hippocampi of healthy adult mice. Depletion of microglia or inhibition of microglial phagocytosis prevented forgetting and the dissociation of engram cells. By introducing CD55 to inhibit complement pathways, specifically in engram cells, we further demonstrated that microglia regulated forgetting in a complement- and activity-dependent manner. Additionally, microglia were involved in both neurogenesis-related and neurogenesis-unrelated memory degradation. Together, our findings revealed complement-dependent synapse elimination by microglia as a mechanism underlying the forgetting of remote memories.

Neuronal ensemble-specific DNA methylation strengthens engram stability

Memories are encoded by memory traces or engrams, represented within subsets of neurons that are synchronously activated during learning. However, the molecular mechanisms that drive engram stabilization during consolidation and consequently ensure its reactivation by memory recall are not fully understood. In this study we manipulate, during memory consolidation, the levels of the de novo DNA methyltransferase 3a2 (Dnmt3a2) selectively within dentate gyrus neurons activated by fear conditioning. We found that Dnmt3a2 upregulation enhances memory performance in mice and improves the fidelity of reconstitution of the original neuronal ensemble upon memory retrieval. Moreover, similar manipulation in a sparse, non-engram subset of neurons does not bias engram allocation or modulate memory strength. We further show that neuronal Dnmt3a2 overexpression changes the DNA methylation profile of synaptic plasticity-related genes. Our data implicates DNA methylation selectively within neuronal ensembles as a mechanism of stabilizing engrams during consolidation that supports successful memory retrieval.

Amygdala Reward Neurons Form and Store Fear Extinction Memory

The ability to extinguish conditioned fear memory is critical for adaptive control of fear response, and its impairment is a hallmark of emotional disorders like post-traumatic stress disorder (PTSD). Fear extinction is thought to take place when animals form a new memory that suppresses the original fear memory. However, little is known about the nature and the site of formation and storage of this new extinction memory. Here we demonstrate that a fear extinction memory engram is formed and stored in a genetically distinct basolateral amygdala (BLA) neuronal population that drives reward behaviors and antagonizes the BLA's original fear neurons. Activation of fear extinction engram neurons and natural reward-responsive neurons overlap significantly in the BLA. Furthermore, these two neuronal subsets are mutually interchangeable in driving reward behaviors and fear extinction behaviors. Thus, fear extinction memory is a newly formed reward memory. VIDEO ABSTRACT.

Locating the engram: Should we look for plastic synapses or information-storing molecules?

Karl Lashley began the search for the engram nearly seventy years ago. In the time since, much has been learned but divisions remain. In the contemporary neurobiology of learning and memory, two profoundly different conceptions contend: the associative/connectionist (A/C) conception and the computational/representational (C/R) conception. Both theories ground themselves in the belief that the mind is emergent from the properties and processes of a material brain. Where these theories differ is in their description of what the neurobiological substrate of memory is and where it resides in the brain. The A/C theory of memory emphasizes the need to distinguish memory cognition from the memory engram and postulates that memory cognition is an emergent property of patterned neural activity routed through engram circuits. In this model, learning re-organizes synapse association strengths to guide future neural activity. Importantly, the version of the A/C theory advocated for here contends that synaptic change is not symbolic and, despite normally being necessary, is not sufficient for memory cognition. Instead, synaptic change provides the capacity and a blueprint for reinstating symbolic patterns of neural activity. Unlike the A/C theory, which posits that memory emerges at the circuit level, the C/R conception suggests that memory manifests at the level of intracellular molecular structures. In C/R theory, these intracellular structures are information-conveying and have properties compatible with the view that brain computation utilizes a read/write memory, functionally similar to that in a computer. New research has energized both sides and highlighted the need for new discussion. Both theories, the key questions each theory has yet to resolve and several potential paths forward are presented here.

Toward nanoscale localization of memory engrams in Drosophila

The Mushroom Body (MB) is the primary location of stored associative memories in the Drosophila brain. We discuss recent advances in understanding the MB’s neuronal circuits made using advanced light microscopic methods and cell-type-specific genetic tools. We also review how the compartmentalized nature of the MB’s organization allows this brain area to form and store memories with widely different dynamics.

Prose miniatures as an experience of self-identification (author's mini-texts in the Vepsian language)

Prose miniatures of Alexander Ulyanov are analyzed not only as a way of self-expression of the author's ego, but also as an experience of self-identification, awareness of their place in the social world order and historical time. The format of the miniature cycle appears as a convenient form of reproducing key moments of a person's life, which corresponds to the mechanism of memories as processing pop-up engrams of episodic memory into a complete self-reflection. At the same time, focusing on a particular idea unfolds in a specific situation in life. The creative principle of the author of miniatures serves the pragmatics of social adaptation in the surrounding stressful world. It is creativity that turns out to be a tool for assembling the personality in its multiple forms and serves as a way of integration into a heterogeneous external environment. The mechanisms of constructing miniatures in the perspective of achieving self-reliance and integration into the surrounding world are considered. Namely, the thematic diversity, the author's initial data representing a «fluid identity» typical for a person of the twentieth century with the help of a cumulative attitude to «collecting stones» are successfully overcome in the choice of a reflective style of description and the absence of hasty subjective conclusions. The core of self-identification of the series of miniatures by A. S. Ulyanov translates to the reader dignity, self-confidence and readiness for any tests.

Recovery of Forgotten Memories: Modulation of Memory Recall by Brain Histamine System

Even after memories fade they may persist latently in the brain. However, there are no clinically applicable methods for reactivating memory traces and promoting memory retrieval. In the brain histamine modulates learning and memory, sleep and wakefulness, feeding, drinking, and neuroendocrine functions. Animal studies demonstrated that histamine H₃ receptor inverse agonists enhance histamine release in the brain and promote learning and memory. In particular, the H₃ receptor inverse agonists induce recall of forgotten memories-possibly by facilitating reactivation of memory engram cells. Therefore, H₃ receptors are a promising targets for treating cognitive dysfunction. While past clinical trials failed to find beneficial effects of H₃ receptor inverse agonists on learning and memory, a recent study showed that inverse agonists enhance memory retrieval in a participant-dependent manner. This review describes the brain's histaminergic system and the modulation of learning and memory by histamine.