Episodic Memory Formation Research Articles

Understanding the roles of central and autonomic activity during sleep in the improvement of working memory and episodic memory

The last decade has seen significant progress in identifying sleep mechanisms that support cognition. Most of these studies focus on the link between electrophysiological events of the central nervous system during sleep and improvements in different cognitive domains, while the dynamic shifts of the autonomic nervous system across sleep have been largely overlooked. Recent studies, however, have identified significant contributions of autonomic inputs during sleep to cognition. Yet, there remain considerable gaps in understanding how central and autonomic systems work together during sleep to facilitate cognitive improvement. In this article we examine the evidence for the independent and interactive roles of central and autonomic activities during sleep and wake in cognitive processing. We specifically focus on the prefrontal–subcortical structures supporting working memory and mechanisms underlying the formation of hippocampal-dependent episodic memory. Our Slow Oscillation Switch Model identifies separate and competing underlying mechanisms supporting the two memory domains at the synaptic, systems, and behavioral levels. We propose that sleep is a competitive arena in which both memory domains vie for limited resources, experimentally demonstrated when boosting one system leads to a functional trade-off in electrophysiological and behavioral outcomes. As these findings inevitably lead to further questions, we suggest areas of future research to better understand how the brain and body interact to support a wide range of cognitive domains during a single sleep episode.

Independent effects of emotional arousal and reward anticipation on episodic memory formation.

Events that elicit emotional arousal or are associated with reward are more likely remembered. Emotional arousal activates the amygdala and the central noradrenergic system, whereas reward anticipation results in an activity in the mesocorticolimbic dopaminergic system. The activation of both pathways enhances memory formation in the hippocampus where their effects are based on similar neural substrates, e.g. tagging of active hippocampal synapses. Moreover, emotional arousal and reward anticipation both enhance attention, which can also affect memory formation. In addition, both neuromodulators interact on the cellular level. Therefore, we tested in the current functional magnetic resonance imaging study whether simultaneously occurring emotional arousal and reward anticipation might have interacting effects on memory formation. We did not find evidence for such an interaction, neither on the behavioral nor on the neural level. Our results further suggest that reward anticipation enhances memory formation rather by an increase in anticipation-related arousal-reflected in activity in the dorsal anterior cingulate cortex-and not dopaminergic midbrain activity. Accompanying behavioral experiments indicated that the effect of reward anticipation on memory is (i) caused at least to some extent by anticipating the speeded response to obtain the reward and not by the valance of the outcome and (ii) can be observed already immediately after encoding, i.e. before consolidation.

Differential role of neuronal glucose and PFKFB3 in memory formation during development.

The consumption of glucose in the brain peaks during late childhood; yet, whether and how glucose metabolism is differentially regulated in the brain during childhood compared to adulthood remains to be understood. In particular, it remains to be determined how glucose metabolism is involved in behavioral activations such as learning. Here we show that, compared to adult, the juvenile rat hippocampus has significantly higher mRNA levels of several glucose metabolism enzymes belonging to all glucose metabolism pathways, as well as higher levels of the monocarboxylate transporters MCT1 and MCT4 and the glucose transporters endothelial-GLUT1 and GLUT3 proteins. Furthermore, relative to adults, long-term episodic memory formation in juvenile animals requires significantly higher rates of aerobic glycolysis and astrocytic-neuronal lactate coupling in the hippocampus. Only juvenile but not adult long-term memory formation recruits GLUT3, neuronal 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and more efficiently engages glucose in the hippocampus. Hence, compared to adult, the juvenile hippocampus distinctively regulates glucose metabolism pathways, and formation of long-term memory in juveniles involves differential neuronal glucose metabolism mechanisms.

A synaptic signal for novelty processing in the hippocampus

Episodic memory formation and recall are complementary processes that rely on opposing neuronal computations in the hippocampus. How this conflict is resolved in hippocampal circuits is unclear. To address this question, we obtained in vivo whole-cell patch-clamp recordings from dentate gyrus granule cells in head-fixed mice trained to explore and distinguish between familiar and novel virtual environments. We find that granule cells consistently show a small transient depolarisation upon transition to a novel environment. This synaptic novelty signal is sensitive to local application of atropine, indicating that it depends on metabotropic acetylcholine receptors. A computational model suggests that the synaptic response to novelty may bias granule cell population activity, which can drive downstream attractor networks to a new state, favouring the switch from recall to new memory formation when faced with novelty. Such a novelty-driven switch may enable flexible encoding of new memories while preserving stable retrieval of familiar ones.

Effects of Information Load on Schema and Episodic Memory Formation.

The formation of semantic memories is assumed to result from the abstraction of general, schema-like knowledge across multiple experiences, while at the same time, episodic details from individual experiences are forgotten. Against this backdrop, our study examined the effects of information load (high vs. low) during encoding on the formation of episodic and schema memory using an elaborated version of an object-place recognition (OPR) task in rats. The task allowed for the abstraction of a spatial rule across four (low information load) or eight (high information load) encoding episodes (spaced apart by a 20 min interval) in which the rats could freely explore two objects in an open field arena. After this encoding phase, animals were left undisturbed for 24 h and then tested either for the expression of schema memory, i.e., for the spatial rule, or memory for an individual encoding episode. Rats in the high information load condition exhibited a more robust schema memory for the spatial rule than in the low information load condition. In contrast, rats in the low load condition showed more robust memory for individual learning episodes than in the high information load condition. Our findings of opposing effects might point to an information-load-dependent competitive relationship between processes of schema and episodic memory formation, although other explanations are possible.

A Predictive Processing Model of Episodic Memory and Time Perception

Human perception and experience of time are strongly influenced by ongoing stimulation, memory of past experiences, and required task context. When paying attention to time, time experience seems to expand; when distracted, it seems to contract. When considering time based on memory, the experience may be different than what is in the moment, exemplified by sayings like "time flies when you're having fun." Experience of time also depends on the content of perceptual experience-rapidly changing or complex perceptual scenes seem longer in duration than less dynamic ones. The complexity of interactions among attention, memory, and perceptual stimulation is a likely reason that an overarching theory of time perception has been difficult to achieve. Here, we introduce a model of perceptual processing and episodic memory that makes use of hierarchical predictive coding, short-term plasticity, spatiotemporal attention, and episodic memory formation and recall, and apply this model to the problem of human time perception. In an experiment with approximately 13,000 human participants, we investigated the effects of memory, cognitive load, and stimulus content on duration reports of dynamic natural scenes up to about 1 minute long. Using our model to generate duration estimates, we compared human and model performance. Model-based estimates replicated key qualitative biases, including differences by cognitive load (attention), scene type (stimulation), and whether the judgment was made based on current or remembered experience (memory). Our work provides a comprehensive model of human time perception and a foundation for exploring the computational basis of episodic memory within a hierarchical predictive coding framework.

Basal Forebrain Impairment: Understanding the Mnemonic Function of the Septal Region Translates in Therapeutic Advances.

The basal forebrain is one of the three major brain circuits involved in episodic memory formation together with the hippocampus and the diencephalon. The dysfunction of each of these regions is known to cause anterograde amnesia. While the hippocampal pyramidal neurons are known to encode episodic information and the diencephalic structures are known to provide idiothetic information, the contribution of the basal forebrain to memory formation has been exclusively associated with septo-hippocampal cholinergic signaling. Research data from the last decade broadened our understanding about the role of septal region in memory formation. Animal studies revealed that septal neurons process locomotor, rewarding and attentional stimuli. The integration of these signals results in a systems model for the mnemonic function of the medial septum that could guide new therapeutic strategies for basal forebrain impairment (BFI). BFI includes the disorders characterized with basal forebrain amnesia and neurodegenerative disorders that affect the basal forebrain. Here, we demonstrate how the updated model of septal mnemonic function can lead to innovative translational treatment approaches that include pharmacological, instrumental and behavioral techniques.

Episodic boundary cells in human medial temporal lobe during the free recall task.

A necessary condition for forming episodic memories is the construction of specific episodes demarcated from other episodes in space and time. Evidence from studies of episodic memory formation using rodent models suggest that the medial temporal lobe (MTL) supports the representation of boundary information. Building on recent work using human microelectrode recordings as well, we hypothesized of human MTL neurons with firing rates sensitive to episodic boundary information. We identified 27 episodic boundary neurons out of 736 single neurons recorded across 27 subjects. Firing of these neurons increased at the beginning and end of mnemonically relevant episodes in the free recall task. We distinguish episodic boundary neurons from a population of ramping neurons (n=58), which are time-sensitive neurons whose activity provides complementary information during episodic representation. Episodic boundary neurons exhibited a U-shaped activity pattern demonstrating increased activity after both beginning and end boundaries of encoding and retrieval epochs. We also describe evidence that the firing of boundary neurons within episodic boundaries is organized by hippocampal theta oscillations, using spike-field coherence metrics.

Altered neural correlates of episodic memory for food and non-food cues in females with overweight/obesity

Episodic memory formation is fundamental to cognition and plays a key role in eating behaviors, indirectly promoting the maintenance and acceleration of weight gain. Impaired episodic memory function is a hallmark of people with overweight/obesity, nevertheless, little research has been conducted to explore the effects of overweight/obesity on neural networks associated with episodic memory. The current study aimed to unravel the behavioral responses and neurocognitive mechanisms underlying the episodic memory for food and non-food cues in females with overweight/obesity. To explore this issue, a group of females with overweight/obesity (n = 26) and a group of age-matched females with healthy weight (n = 28) participated in a functional magnetic resonance imaging (fMRI) event-related episodic memory paradigm, during which pictures of palatable food and pictures of neutral daily necessities were presented. Whole-brain analyses revealed differential engagement in several neural regions between the groups during an episodic memory task. Specifically, compared to the healthy weight controls, females with overweight/obesity exhibited reduced brain activity in the temporal, parietal, and frontal regions during episodic memory encoding and successful retrieval of both food and non-food cues. Additionally, activation patterns in the left hippocampus and right olfactory cortex of females with and without overweight/obesity suggested that item memory changed according to the type of stimuli presented during item memory. Specifically, females with overweight/obesity showed greater engagement of the left hippocampus and right olfactory cortex when processing food cues, but less activation of the left hippocampus and right olfactory cortex when presented with non-food cues. Consistent with the obesity and suboptimal food-related decision theoretical model, these findings provide evidence of dissociation of the neural underpinnings of episodic memory in females with overweight/obesity and underline important effects of overweight/obesity on brain functions related to episodic memory.

The anterior thalamic nuclei: core components of a tripartite episodic memory system.

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.

Presubiculum principal cells are preserved from degeneration in knock-in APP/TAU mouse models of Alzheimer’s disease

The presubiculum (PRS) is an integral component of the perforant pathway that has recently been recognised as a relatively unscathed region in clinical Alzheimer’s disease (AD), despite neighbouring components of the perforant pathway, CA1 and the entorhinal cortex, responsible for formation of episodic memory and storage, showing severe hallmarks of AD including, amyloid-beta (Aβ) plaques, tau tangles and marked gliosis. However, the question remains whether this anatomical resilience translates into functional resilience of the PRS neurons. Using neuroanatomy combined with whole-cell electrophysiological recordings, we investigated whether the unique spatial profile of the PRS was replicable in two knock-in mouse models of AD, APPNL-F/NL-F, and APPNL-F/MAPTHTAU and whether the intrinsic properties and morphological integrity of the PRS principal neurons was maintained compared to the lateral entorhinal cortex (LEC) and hippocampal CA1 principal cells. Our data revealed an age-dependent Aβ and tau pathology with neuroinflammation in the LEC and CA1, but a presence of fleece-like Aβ deposits with an absence of tau tangles and cellular markers of gliosis in the PRS of the mouse models at 11–16 and 18–22 months. These observations were consistent in human post-mortem AD tissue. This spatial profile also correlated with functional resilience of strong burst firing PRS pyramidal cells that showed unaltered sub- and suprathreshold intrinsic biophysical membrane properties and gross morphology in the AD models that were similar to the properties of pyramidal cells recorded in age-matched wild-type mice (11–14 months). This was in contrast to the LEC and CA1 principal cells which showed altered subthreshold intrinsic properties such as a higher input resistance, longer membrane time constants and hyperexcitability in response to suprathreshold stimulation that correlated with atrophied dendrites in both AD models. In conclusion, our data show for the first time that the unique anatomical profile of the PRS constitutes a diffuse AD pathology that is correlated with the preservation of principal pyramidal cell intrinsic biophysical and morphological properties despite alteration of LEC and CA1 pyramidal cells in two distinct genetic models of AD. Understanding the underlying mechanisms of this resilience could be beneficial in preventing the spread of disease pathology before cognitive deficits are precipitated in AD.

Effect of disrupted episodic memory on food consumption: no impact of neuronal loss of endophilin A1 on food intake and energy balance

Food intake is generally assumed to reflect a regulatory tension between homeostatic and hedonic drivers. Information from individuals with memory dysfunction suggests that episodic memory may also play a significant role. We reasoned that if memory influences food intake, then disrupting a genetic factor that is important in episodic memory formation should affect food intake and energy balance. We performed spatial learning tests on neuronal specific endophilin A1 (EENA1) KO mice using the four-arm baited version of the radial arms maze (RAM). Energy regulation has also been evaluated. As anticipated neuronal EENA1 KO mice had impaired spatial memory. However, loss of endophilin A1 did not result in greater food intake, or altered energy absorption efficiency, relative to wild-type (WT) mice, when fed either low or high fat diets. Moreover, loss of EENA1 did not significantly affect other features of energy balance—physical activity and energy expenditure. No statistically significant changes were observed in the expression of hypothalamic neuropeptides related to food intake regulation, or circulating levels of leptin. We conclude that food intake and energy balance are largely governed by homeostatic and hedonic processes, and when these processes are intact memory probably plays a relatively minor role in food intake regulation.

Electrophysiological foundations of the human default-mode network revealed by intracranial-EEG recordings during resting-state and cognition

Investigations using noninvasive functional magnetic resonance imaging (fMRI) have provided significant insights into the unique functional organization and profound importance of the human default mode network (DMN), yet these methods are limited in their ability to resolve network dynamics across multiple timescales. Electrophysiological techniques are critical to address these challenges, yet few studies have explored the neurophysiological underpinnings of the DMN. Here we investigate the electrophysiological organization of the DMN in a common large-scale network framework consistent with prior fMRI studies. We used intracranial EEG (iEEG) recordings, and evaluated intra- and cross-network interactions during resting-state and its modulation during a cognitive task involving episodic memory formation. Our analysis revealed significantly greater intra-DMN phase iEEG synchronization in the slow-wave (< 4 Hz), while DMN interactions with other brain networks was higher in the beta (12–30 Hz) and gamma (30–80 Hz) bands. Crucially, slow-wave intra-DMN synchronization was observed in the task-free resting-state and during both verbal memory encoding and recall. Compared to resting-state, slow-wave intra-DMN phase synchronization was significantly higher during both memory encoding and recall. Slow-wave intra-DMN phase synchronization increased during successful memory retrieval, highlighting its behavioral relevance. Finally, analysis of nonlinear dynamic causal interactions revealed that the DMN is a causal outflow network during both memory encoding and recall. Our findings identify frequency specific neurophysiological signatures of the DMN which allow it to maintain stability and flexibility, intrinsically and during task-based cognition, provide novel insights into the electrophysiological foundations of the human DMN, and elucidate network mechanisms by which it supports cognition.

A hippocampus dependent neural circuit loop underlying the generation of auditory mismatch negativity

Extracting relevant information and transforming it into appropriate behavior, is a fundamental brain function, and requires the coordination between the sensory and cognitive systems, however, the underlying mechanisms of interplay between sensory and cognition systems remain largely unknown. Here, we developed a mouse model for mimicking human auditory mismatch negativity (MMN), a well-characterized translational biomarker for schizophrenia, and an index of early auditory information processing. We found that a subanesthetic dose of ketamine decreased the amplitude of MMN in adult mice. Using pharmacological and chemogenetic approaches, we identified an auditory cortex–entorhinal cortex–hippocampus neural circuit loop that is required for the generation of MMN. In addition, we found that inhibition of dCA1→MEC circuit impaired the auditory related fear discrimination. Moreover, we found that ketamine induced MMN deficiency by inhibition of long-range GABAergic projection from the CA1 region of the dorsal hippocampus to the medial entorhinal cortex. These results provided circuit insights for ketamine effects and early auditory information processing. As the entorhinal cortex is the interface between the neocortex and hippocampus, and the hippocampus is critical for the formation, consolidation, and retrieval of episodic memories and other cognition, our results provide a neural mechanism for the interplay between the sensory and cognition systems.

Impairment of aversive episodic memories during Covid-19 pandemic: The impact of emotional context on memory processes

The threatening context of the COVID-19 pandemic provided a unique setting to study the effects of negative psychological symptoms on memory processes. Episodic memory is an essential function of the human being related to the ability to store and remember experiences and anticipate possible events in the future. Studying this function in this context is crucial to understand what effects the pandemic will have on the formation of episodic memories. To study this, the formation of episodic memories was evaluated by free recall, recognition, and episode order tasks for an aversive and neutral content. The results indicated that aversive episodic memory is impaired both in the free recall task and in the recognition task. Even the beneficial effect that emotional memory usually has for the episodic order was undermined as there were no differences between the neutral and aversive condition. The present work adds to the evidence that indicates that the level of activation does not modify memory processes in a linear way, which also depends on the type of recall and the characteristics of the content to be encoded.

Prediction Errors for Aversive Events Shape Long-Term Memory Formation through a Distinct Neural Mechanism.

Prediction errors (PEs) have been known for decades to guide associative learning, but their role in episodic memory formation has been discovered only recently. To identify the neural mechanisms underlying the impact of aversive PEs on long-term memory formation, we used functional magnetic resonance imaging, while participants saw a series of unique stimuli and estimated the probability that an aversive shock would follow. Our behavioral data showed that negative PEs (i.e., omission of an expected outcome) were associated with superior recognition of the predictive stimuli, whereas positive PEs (i.e., presentation of an unexpected outcome) impaired subsequent memory. While medial temporal lobe (MTL) activity during stimulus encoding was overall associated with enhanced memory, memory-enhancing effects of negative PEs were linked to even decreased MTL activation. Additional large-scale network analyses showed PE-related increases in crosstalk between the "salience network" and a frontoparietal network commonly implicated in memory formation for expectancy-congruent events. These effects could not be explained by mere changes in physiological arousal or the prediction itself. Our results suggest that the superior memory for events associated with negative aversive PEs is driven by a potentially distinct neural mechanism that might serve to set these memories apart from those with expected outcomes.

Metabolomic profiling reveals a differential role for hippocampal glutathione reductase in infantile memory formation.

The metabolic mechanisms underlying the formation of early-life episodic memories remain poorly characterized. Here, we assessed the metabolomic profile of the rat hippocampus at different developmental ages both at baseline and following episodic learning. We report that the hippocampal metabolome significantly changes over developmental ages and that learning regulates differential arrays of metabolites according to age. The infant hippocampus had the largest number of significant changes following learning, with downregulation of 54 metabolites. Of those, a large proportion was associated with the glutathione-mediated cellular defenses against oxidative stress. Further biochemical, molecular, and behavioral assessments revealed that infantile learning evokes a rapid and persistent increase in the activity of neuronal glutathione reductase, the enzyme that regenerates reduced glutathione from its oxidized form. Inhibition of glutathione reductase selectively impaired long-term memory formation in infant but not in juvenile and adult rats, confirming its age-specific role. Thus, metabolomic profiling revealed that the hippocampal glutathione-mediated antioxidant pathway is differentially required for the formation of infantile memory.

Novel Multitarget Hydroxamic Acids with a Natural Origin CAP Group against Alzheimer's Disease: Synthesis, Docking and Biological Evaluation.

Hydroxamic acids are one of the most promising and actively studied classes of chemical compounds in medicinal chemistry. In this study, we describe the directed synthesis and effects of HDAC6 inhibitors. Fragments of adamantane and natural terpenes camphane and fenchane, combined with linkers of various nature with an amide group, were used as the CAP groups. Accordingly, 11 original target compounds were developed, synthesized, and exposed to in vitro and in vivo biological evaluations, including in silico methods. In silico studies showed that all synthesized compounds were drug-like and could penetrate through the blood–brain barrier. According to the in vitro testing, hydroxamic acids 15 and 25, which effectively inhibited HDAC6 and exhibited anti-aggregation properties against β-amyloid peptides, were chosen as the most promising substances to study their neuroprotective activities in vivo. All in vivo studies were performed using 5xFAD transgenic mice simulating Alzheimer’s disease. In these animals, the Novel Object Recognition and Morris Water Maze Test showed that the formation of hippocampus-dependent long-term episodic and spatial memory was deteriorated. Hydroxamic acid 15 restored normal memory functions to the level observed in control wild-type animals. Notably, this effect was precisely associated with the ability to restore lost cognitive functions, but not with the effect on motor and exploratory activities or on the level of anxiety in animals. Conclusively, hydroxamic acid 15 containing an adamantane fragment linked by an amide bond to a hydrocarbon linker is a possible potential multitarget agent against Alzheimer’s disease.

The memory trace of a stressful episode

Stress influences episodic memory formation via noradrenaline and glucocorticoid effects on amygdala and hippocampus. A common finding is the improvement of memory for central aspects of a stressful episode. This is putatively related to changes in the neural representations of specific experiences, i.e., their memory traces. Here we show that the memory improvement for objects that were encountered in a stressful episode relates to differences in the neural representations of these objects in the amygdala. Using functional magnetic resonance imaging, we found that stress specifically altered the representations of central objects: compared to control objects, they became more similar to one another and more distinct from objects that were not part of this episode. Furthermore, higher similarity of central objects to the main stressor-the faces of the stress-inducing committee members-predicted better memory. This suggests that the central objects were closely integrated into a stressor-centered memory representation. Our findings provide mechanistic insights into how stress shapes the memory trace and have profound implications for neurocognitive models of stressful and emotional memory.

Stimulation of the left dorsolateral prefrontal cortex with slow rTMS enhances verbal memory formation.

Encoding of episodic memories relies on stimulus-specific information processing and involves the left prefrontal cortex. We here present an incidental finding from a simultaneous EEG-TMS experiment as well as a replication of this unexpected effect. Our results reveal that stimulating the left dorsolateral prefrontal cortex (DLPFC) with slow repetitive transcranial magnetic stimulation (rTMS) leads to enhanced word memory performance. A total of 40 healthy human participants engaged in a list learning paradigm. Half of the participants (N = 20) received 1 Hz rTMS to the left DLPFC, while the other half (N = 20) received 1 Hz rTMS to the vertex and served as a control group. Participants receiving left DLPFC stimulation demonstrated enhanced memory performance compared to the control group. This effect was replicated in a within-subjects experiment where 24 participants received 1 Hz rTMS to the left DLPFC and vertex. In this second experiment, DLPFC stimulation also induced better memory performance compared to vertex stimulation. In addition to these behavioural effects, we found that 1 Hz rTMS to DLPFC induced stronger beta power modulation in posterior areas, a state that is known to be beneficial for memory encoding. Further analysis indicated that beta modulations did not have an oscillatory origin. Instead, the observed beta modulations were a result of a spectral tilt, suggesting inhibition of these parietal regions. These results show that applying 1 Hz rTMS to DLPFC, an area involved in episodic memory formation, improves memory performance via modulating neural activity in parietal regions.