Support Memory Formation Research Articles

Theta phase precession supports memory formation and retrieval of naturalistic experience in humans.

Associating different aspects of experience with discrete events is critical for human memory. A potential mechanism for linking memory components is phase precession, during which neurons fire progressively earlier in time relative to theta oscillations. However, no direct link between phase precession and memory has been established. Here we recorded single-neuron activity and local field potentials in the human medial temporal lobe while participants (n = 22) encoded and retrieved memories of movie clips. Bouts of theta and phase precession occurred following cognitive boundaries during movie watching and following stimulus onsets during memory retrieval. Phase precession was dynamic, with different neurons exhibiting precession in different task periods. Phase precession strength provided information about memory encoding and retrieval success that was complementary with firing rates. These data provide direct neural evidence for a functional role of phase precession in human episodic memory.

Differential online and offline effects of theta-tACS on memory encoding and retrieval

Theta oscillations support memory formation, but their exact contribution to the communication between prefrontal cortex (PFC) and the hippocampus is unknown. We tested the functional relevance of theta oscillations as a communication link between both areas for memory formation using transcranial alternating current stimulation (tACS). Healthy, young participants learned two lists of Dutch-German word pairs and retrieved them immediately and with a 30-min delay. In the encoding group (N = 30), tACS was applied during the encoding of list 1. List 2 was used to test stimulation aftereffects. In the retrieval group (N = 23), we stimulated during the delayed recall. In both groups, we applied tACS bilaterally at prefrontal and tempo-parietal sites, using either individualized theta frequency or 15 Hz (as control), according to a within-subject design. Stimulation with theta-tACS did not alter overall learning performance. An exploratory analysis revealed that immediate recall improved when word-pairs were learned after theta-tACS (list 2). Applying theta-tACS during retrieval had detrimental effects on memory. No changes in the power of the respective frequency bands were observed. Our results do not support the notion that impacting the communication between PFC and the hippocampus during a task by bilateral tACS improves memory. However, we do find evidence that direct stimulation had a trend for negatively interfering effects during immediate and delayed recall. Hints for beneficial effects on memory only occurred with aftereffects of the stimulation. Future studies need to further examine the effects during and after stimulation on memory formation.

Rescuing impaired hippocampal-cortical interactions and spatial reorientation learning and memory during sleep in a mouse model of Alzheimer's disease using hippocampal 40 Hz stimulation.

One of the earliest symptoms of Alzheimer's disease (AD) is getting lost in space or experiencing deficits in spatial navigation, which involve navigation computations as well as learning and memory. We investigated cross brain region interactions supporting memory formation as a potential causative factor of impaired spatial learning and memory in AD. To assess this relationship between AD pathophysiology, brain changes, and behavioral alterations, we used a targeted approach for clearing amyloid beta and tau to rescue functional interactions in the brain. This research strongly connects brain activity patterns during sleep to tau and amyloid accumulation, and will aid in understanding the mechanisms underlying cognitive dysfunction in AD. Furthermore, the results offer insight for improving early identification and treatment strategies.

What the Acute Stress Response Suggests about Memory.

Research suggests that stress has immediate and long-term effects on attention and memory. Rather than disrupting memory formation and consolidation, acute stress has been shown to shift attention processes resulting in a tradeoff between prioritized and nonprioritized information. Both arousal and stress result in cognitive and neurobiological shifts that often support memory formation. When an acute stressor occurs, it can distort immediate attentional focus, increasing processing for high-priority features while reducing processing for extraneous features. The downstream cognitive consequences for this shift in attention are better memory for some features and poorer memory for others when compared to conditions of low stress. However, individual differences (e.g., sex, age, basal stress response, and stress reactivity) all impact the relationship between the acute stress response and memory. Although acute stress generally benefits memory formation, we suggest that forgetting and later recovery of stressful memories can better be understood by examining factors that influence the subjective experience of stress and stress reactivity.

CD4 Effector TCR Avidity for Peptide on APC Determines the Level of Memory Generated.

Initial TCR affinity for peptide Ag is known to impact the generation of memory; however, its contributions later, when effectors must again recognize Ag at 5-8 d postinfection to become memory, is unclear. We examined whether the effector TCR affinity for peptide at this "effector checkpoint" dictates the extent of memory and degree of protection against rechallenge. We made an influenza A virus nucleoprotein (NP)-specific TCR transgenic mouse strain, FluNP, and generated NP-peptide variants that are presented by MHC class II to bind to the FluNP TCR over a broad range of avidity. To evaluate the impact of avidity invivo, we primed naive donor FluNP in influenza A virus-infected host mice, purified donor effectors at the checkpoint, and cotransferred them with the range of peptides pulsed on activated APCs into second uninfected hosts. Higher-avidity peptides yielded higher numbers of FluNP memory cells in spleen and most dramatically in lung and draining lymph nodes and induced better protection against lethal influenza infection. Avidity determined memory cell number, not cytokine profile, and already impacted donor cell number within several days of transfer. We previously found that autocrine IL-2 production at the checkpoint prevents default effector apoptosis and supports memory formation. Here, we find that peptide avidity determines the level of IL-2 produced by these effectors and that IL-2Rα expression by the APCs enhances memory formation, suggesting that transpresentation of IL-2 by APCs further amplifies IL-2 availability. Secondary memory generation was also avidity dependent. We propose that this regulatory pathway selects CD4 effectors of highest affinity to progress to memory.

Relational memory function in schizophrenia: Electrophysiological evidence for early perceptual and late associative abnormalities.

We used event-related potentials (ERPs) to examine encoding and retrieval during episodic memory in people with schizophrenia (SZ) and biological relatives of SZ (SZr). To isolate contextual from item-specific aspects of memory, we employed the Relational and Item-Specific Encoding (RISE) task. Twenty two healthy controls (HCs), 22 SZ, and 19 SZr, encoded visual depictions of objects when displayed alone (item-specific) or in pairs (relational encoding), and were later tested on recognition of specific objects and whether pairs of objects had appeared together. An early posterior component (P2) during encoding predicted later recognition and was diminished in SZ. A late negative potential (LNP) over left frontal brain regions during recognition was larger for relationally encoded objects than new and item-specific encoded objects in HCs. This pattern was absent for SZ and SZr. Smaller P2 and LNP components were associated with greater self-reported cognitive-perceptual abnormalities. Early posterior brain responses likely relevant to perceptual functions supporting memory formation were diminished in schizophrenia. Late frontal electrophysiological responses associated with relational aspects of memory appear diminished in SZ and SZr, potentially reflecting the influence of genetic liability for schizophrenia on brain functions supporting episodic memory.

Learning-related changes in cellular activity within mouse dentate gyrus during trace eyeblink conditioning.

Because the dentate gyrus serves as the first site for information processing in the hippocampal trisynaptic circuit, it an important structure for the formation of associative memories. Previous findings in rabbit had recorded populations of cells within dentate gyrus that may bridge the temporal gap between stimuli to support memory formation during trace eyeblink conditioning, an associative learning task. However, this previous work was unable to identify the types of cells demonstrating this type of activity. To explore these changes further, we did in vivo single-neuron recording in conjunction with physiological determination of cell types to investigate the functional role of granule cells, mossy cells, and interneurons in dentate gyrus during learning. Tetrode recordings were performed in young-adult mice during training on trace eyeblink conditioning, a hippocampal-dependent temporal associative memory task. Conditioned mice were able to successfully learn the task, with male mice learning at a faster rate than female mice. In the conditioned group, granule cells tended to show an increase in firing rate during conditioned stimulus presentation while mossy cells showed a decrease in firing rate during the trace interval and the unconditioned stimulus. Interestingly, populations of interneurons demonstrated learning-related increases and decreases in activity that began at onset of the conditioned stimulus and persisted through the trace interval. The current study also found a significant increase in theta power during stimuli presentation in conditioned animals, and this change in theta decreased over time. Ultimately, these data suggest unique involvement of granule cells, mossy cells, and interneurons in dentate gyrus in the formation of a trace associative memory. This work expands our knowledge of dentate gyrus function, helping to discern how aging and disease might disrupt this process.

“How learning doesn't work” Children evaluate their cell phone use – An empirical pilot study

In our increasingly digitally organized society, we enjoy great benefits from easier working conditions and the acceleration of developmental processes. Children are expected to be prepared for this and to receive a tablet or cell phone as early as possible. This, however, poses a huge risk because a child’s brain must initially organize itself in an analog fashion. This means that the spatial-modular building of neural networks and the rhythmic timing of brain activities mature very slowly through upbringing and school education to support memory formation and thinking. Once this foundation has been established, a digital workplace will be easily accessible to any young adult. To investigate in more detail the impacts of private cell phone use on the learning abilities of children, we designed a cognitive test that, among other things, measures spatiotemporal abilities and memory performance. A total of 54 third-grade students (aged 8 and 9) were subjected to the testing at an elementary school in the Rhein-Neckar-Kreis/Baden Württemberg region from December 2019 to March 2020. The intensity of private cell phone use was measured with a nonverbal method, the evidence-based water glass method. Prior to testing, we evaluated the children’s ability to evaluate themselves with this nonverbal method and designed a lie item, which allowed us to filter out those children who were unable to evaluate themselves. Due to the high data quality, variance analysis was used to analyze the quantified data statistically. The results showed that prefrontal cortex skills such as spatial perception, concentration, and anticipation were significantly poorer in third-graders with heavy cell phone use compared to those with little or no cell phone use. The heavier the cell phone use, the less well developed was their cognitive memory performance if it included a time delay. Furthermore, we observed a significant impact of the intensity of cell phone use on the motivation to go to school. The frequency of sports activities, playing outdoors, friendships, and homework was not significantly affected by cell phone use. The reason for this could be that modern schoolchildren only have rather limited control over the timing of these activities. Overall, the data suggest that other cognitive and emotional-motivational abilities such as spelling and handwriting are also adversely affected by heavy cell phone use. This could be verified by an investigation with a larger sample size. The findings of this pilot study should be a warning: with the digital transformation, our society could cause severe and also irreversible cognitive damage to the young generation. The discussion shows that brain research findings from the past half century provide comprehensive evidence for this

Contributions of the rodent cingulate-retrosplenial cortical axis to associative learning and memory: A proposed circuit for persistent memory maintenance

While the anterior cingulate (ACC) and retrosplenial (RSC) cortices have been extensively studied for their role in spatial navigation, less is known about how they contribute to associative learning and later memory recall. The limited work that has been conducted on this topic suggests that each of these cortical regions makes distinct, but similar contributions to associative learning and memory. Here, we review evidence from the rodent literature demonstrating that while ACC activity seems to be necessary at remote time points associated with imprecise or generalized memories, the role of the RSC seems to be uniform over time. Together, the lines of evidence reviewed here suggest that the ACC and RSC likely function together to support memory formation and maintenance following associative learning.

Ligand-independent activity of the ghrelin receptor modulates AMPA receptor trafficking and supports memory formation.

The biological signals of hunger, satiety, and memory are interconnected. The role of the hormone ghrelin in regulating feeding and memory makes ghrelin receptors attractive targets for associated disorders. We investigated the effects of the high ligand-independent activity of the ghrelin receptor GHS-R1a on the physiology of excitatory synapses in the hippocampus. Blocking this activity produced a decrease in the synaptic content of AMPA receptors in hippocampal neurons and a reduction in GluA1 phosphorylation at Ser845 Reducing the ligand-independent activity of GHS-R1a increased the surface diffusion of AMPA receptors and impaired AMPA receptor-dependent synaptic delivery induced by chemical long-term potentiation. Accordingly, we found that blocking this GHS-R1a activity impaired spatial and recognition memory in mice. These observations support a role for the ligand-independent activity of GHS-R1a in regulating AMPA receptor trafficking under basal conditions and in the context of synaptic plasticity that underlies learning.

The Quest for the Hippocampal Memory Engram: From Theories to Experimental Evidence.

More than a century after Richard Semon's theoretical proposal of the memory engram, technological advancements have finally enabled experimental access to engram cells and their functional contents. In this review, we summarize theories and their experimental support regarding hippocampal memory engram formation and function. Specifically, we discuss recent advances in the engram field which help to reconcile two main theories for how the hippocampus supports memory formation: The Memory Indexing and Cognitive Map theories. We also highlight the latest evidence for engram allocation mechanisms through which memories can be linked or separately encoded. Finally, we identify unanswered questions for future investigations, through which a more comprehensive understanding of memory formation and retrieval may be achieved.

Schinus terebinthifolius Essential Oil Attenuates Scopolamine-Induced Memory Deficits via Cholinergic Modulation and Antioxidant Properties in a Zebrafish Model.

Schinus terebinthifolius is a plant well recognized for its therapeutic profile such as anti-inflammatory and antitumor activities, promoting antibacterial activity and antioxidant and antidiabetic properties. This study aimed at examining whether Schinus terebinthifolius memory-enhancing activities are mediated by cholinergic and brain antioxidant systems in a scopolamine zebrafish model. Schinus terebinthifolius essential oil (10, 25, and 50 μL/L) was delivered to zebrafish by immersion in water for 8 days. Memory deficits were induced by scopolamine (100 μM) administration. Zebrafish were divided into seven groups (n = 15/group): vehicle group, scopolamine (100 μM) group, Schinus terebinthifolius essential oil groups (STF; 10, 25, and 50 μL/L), the imipramine group (IMP; 20 mg/L, as the positive control in the NTT test), and the donepezil group (DP; 10 mg/L, as the positive control in the Y-maze test). Memory status was estimated by the novel tank diving test (NTT) and the Y-maze test and finally was validated by comparison with imipramine (20 mg/L) and donepezil (10 mg/L). Gas chromatography-mass spectrometry (GC-MS) was used to detect oil compounds. Brain levels of acetylcholinesterase (AChE) and antioxidant enzymes were measured. After being exposed to Schinus terebinthifolius essential oil, the scopolamine zebrafish exhibited an improvement of memory processes in the NTT and Y-maze tests. The essential oil attenuated the elevated level of AChE and brain oxidative stress. Schinus terebinthifolius essential oil was found to support memory formation through the inhibition of the AChE activity and decreasing oxidative stress in the scopolamine-treated zebrafish brains.

Episodic memory: Neuronal codes for what, where, and when.

Episodic memory is defined as the ability to recall events in a spatiotemporal context. Formation of such memories is critically dependent on the hippocampal formation and its inputs from the entorhinal cortex. To be able to support the formation of episodic memories, entorhinal cortex and hippocampal formation should contain a neuronal code that follows several requirements. First, the code should include information about position of the agent ("where"), sequence of events ("when"), and the content of the experience itself ("what"). Second, the code should arise instantly thereby being able to support memory formation of one-shot experiences. For successful encoding and to avoid interference between memories during recall, variations in location, time, or in content of experience should result in unique ensemble activity. Finally, the code should capture several different resolutions of experience so that the necessary details relevant for future memory-based predictions will be stored. We review how neuronal codes in entorhinal cortex and hippocampus follow these requirements and argue that during formation of episodic memories entorhinal cortex provides hippocampus with instant information about ongoing experience. Such information originates from (a) spatially modulated neurons in medial entorhinal cortex, including grid cells, which provide a stable and universal positional metric of the environment; (b) a continuously varying signal in lateral entorhinal cortex providing a code for the temporal progression of events; and (c) entorhinal neurons coding the content of experiences exemplified by object-coding and odor-selective neurons. During formation of episodic memories, information from these systems are thought to be encoded as unique sequential ensemble activity in hippocampus, thereby encoding associations between the content of an event and its spatial and temporal contexts. Upon exposure to parts of the encoded stimuli, activity in these ensembles can be reinstated, leading to reactivation of the encoded activity pattern and memory recollection.

Grid overlays reduce bias in mental representations of topographic maps

Abstract. Reading spatial information from topographic maps to form mental representations that guide spatial orientation and navigation is a rather complex cognitive process. Perceptual and knowledge-driven processes interact to support the map reader in building these mental representations. The resulting cognitive maps are not one-to-one mappings of the spatial information and known to be distorted systematically. It is assumed that spatial information is hierarchically organized in these mental models. We are interested in how map design based on cognitive principles supports memory formation and leads to less distorted mental representations.Based on the results of empirical studies we are able to show that overlaid grids in these maps address the hierarchical nature of these mental representations of map space. When map users are asked to learn object locations in a map the availability of overlaid grid layers improve object location memory. This effect is independent of the shape of these grid patterns (square grids or hexagonal grids) and, moreover, can be shown to be effective even in situations where the grids are interrupted by other maps layers (i.e. so-called illusory grids).These results seem best explained by the formation of less distorted mental representations based on the availability of superordinate hierarchical information and the application of Gestalt principles by the map user. Thus again, point to the interaction between perceptual and knowledge-driven processes in the formation of these mental representations of map space. This assumption receives further support by eye-tracking data that reveal that grids do not only attract attention towards their own location but also seem to structure the gaze patterns in relation to the relevant object locations that are not necessarily located close to a grid line.

Chemogenetic Suppression of Medial Prefrontal-Dorsal Hippocampal Interactions Prevents Estrogenic Enhancement of Memory Consolidation in Female Mice.

The importance of the dorsal hippocampus (DH) in mediating the memory-enhancing effects of the sex-steroid hormone 17β-estradiol (E2) is well established. However, estrogen receptors (ERs) are highly expressed in other brain regions that support memory formation, including the medial prefrontal cortex (mPFC). The mPFC and DH interact to mediate the formation of several types of memory, and behavioral tasks that recruit the mPFC are enhanced by systemic E2 administration, making this region a prime candidate for investigating circuit-level questions regarding the estrogenic regulation of memory. Further, infusion of E2 directly into the DH increases dendritic spine density in both the DH and mPFC, and this effect depends upon rapid activation of cell-signaling pathways in the DH, demonstrating a previously unexplored interaction between the DH and mPFC that led us to question the role of the mPFC in object memory consolidation and the necessity of DH-mPFC interactions in the memory-enhancing effects of E2. Here, we found that infusion of E2 directly into the mPFC of ovariectomized mice increased mPFC apical spine density and facilitated object recognition and spatial memory consolidation, demonstrating that E2 in the mPFC increases spinogenesis and enhances on memory consolidation. Next, chemogenetic suppression of the mPFC blocked the beneficial effects of DH-infused E2 on memory consolidation, indicating that systems-level DH-mPFC interactions are necessary for the memory-enhancing effects of E2. Together, these studies provide evidence that E2 in the mPFC mediates memory formation, and reveal that the DH and mPFC act in concert to support the memory-enhancing effects of E2 in female mice.

Cortical circuit activity underlying sleep slow oscillations and spindles

Slow oscillations and sleep spindles are hallmarks of the EEG during slow-wave sleep (SWS). Both oscillatory events, especially when co-occurring in the constellation of spindles nesting in the slow oscillation upstate, are considered to support memory formation and underlying synaptic plasticity. The regulatory mechanisms of this function at the circuit level are poorly understood. Here, using two-photon imaging in mice, we relate EEG-recorded slow oscillations and spindles to calcium signals recorded from the soma of cortical putative pyramidal-like (Pyr) cells and neighboring parvalbumin-positive interneurons (PV-Ins) or somatostatin-positive interneurons (SOM-Ins). Pyr calcium activity was increased more than threefold when spindles co-occurred with slow oscillation upstates compared with slow oscillations or spindles occurring in isolation. Independent of whether or not a spindle was nested in the slow oscillation upstate, the slow oscillation downstate was preceded by enhanced calcium signal in SOM-Ins that vanished during the upstate, whereas spindles were associated with strongly increased PV-In calcium activity. Additional wide-field calcium imaging of Pyr cells confirmed the enhanced calcium activity and its widespread topography associated with spindles nested in slow oscillation upstates. In conclusion, when spindles are nested in slow oscillation upstates, maximum Pyr activity appears to concur with strong perisomatic inhibition of Pyr cells via PV-Ins and low dendritic inhibition via SOM-Ins (i.e., conditions that might optimize synaptic plasticity within local cortical circuits).

Aging-associated changes in hippocampal glycogen metabolism in mice. Evidence for and against astrocyte-to-neuron lactate shuttle.

Lactate derived from astrocytic glycogen has been shown to support memory formation in hippocampi of young animals, inhibiting it in old animals. Here we show, using quantitative mass spectrometry‐based proteomics, immunofluorescence, and qPCR that aging is associated with an increase of glycogen metabolism enzymes concentration and shift in their localization from astrocytes to neurons. These changes are accompanied with reorganization of hippocampal energy metabolism which is manifested by elevated capacity of aging neurons to oxidize glucose in glycolysis and mitochondria, and decreased ability for fatty acids utilization. Our observations suggest that astrocyte‐to‐neuron lactate shuttle may operate in young hippocampi, however, during aging neurons become independent on astrocytic lactate and the metabolic crosstalk between the brain's cells is disrupted.

The Sync/deSync Model: How a Synchronized Hippocampus and a Desynchronized Neocortex Code Memories

Neural oscillations are important for memory formation in the brain. The desynchronization of alpha (10 Hz) oscillations in the neocortex has been shown to predict successful memory encoding and retrieval. However, when engaging in learning, it has been found that the hippocampus synchronizes in theta (4 Hz) oscillations, and that learning is dependent on the phase of theta. This inconsistency as to whether synchronization is "good" for memory formation leads to confusion over which oscillations we should expect to see and where during learning paradigm experiments. This paper seeks to respond to this inconsistency by presenting a neural network model of how a well functioning learning system could exhibit both of these phenomena, i.e., desynchronization of alpha and synchronization of theta during successful memory encoding.We present a spiking neural network (the Sync/deSync model) of the neocortical and hippocampal system. The simulated hippocampus learns through an adapted spike-time dependent plasticity rule, in which weight change is modulated by the phase of an extrinsically generated theta oscillation. Additionally, a global passive weight decay is incorporated, which is also modulated by theta phase. In this way, the Sync/deSync model exhibits theta phase-dependent long-term potentiation and long-term depression. We simulated a learning paradigm experiment and compared the oscillatory dynamics of our model with those observed in single-cell and scalp-EEG studies of the medial temporal lobe. Our Sync/deSync model suggests that both the desynchronization of neocortical alpha and the synchronization of hippocampal theta are necessary for successful memory encoding and retrieval.SIGNIFICANCE STATEMENT A fundamental question is the role of rhythmic activation of neurons, i.e., how and why their firing oscillates between high and low rates. A particularly important question is how oscillatory dynamics between the neocortex and hippocampus support memory formation. We present a spiking neural-network model of such memory formation, with the central ideas that (1) in neocortex, neurons need to break out of an alpha oscillation to represent a stimulus (i.e., alpha desynchronizes), whereas (2) in hippocampus, the firing of neurons at theta facilitates formation of memories (i.e., theta synchronizes). Accordingly, successful memory formation is marked by reduced neocortical alpha and increased hippocampal theta. This pattern has been observed experimentally and gives our model its name-the Sync/deSync model.

Oscillations Synchronize Amygdala-to-Prefrontal Primate Circuits during Aversive Learning

The contribution of oscillatory synchrony in the primate amygdala-prefrontal pathway to aversive learning remains largely unknown. We found increased power and phase synchrony in the theta range during aversive conditioning. The synchrony was linked to single-unit spiking and exhibited specific directionality between input and output measures in each region. Although it was correlated with the magnitude of conditioned responses, it declined once the association stabilized. The results suggest that amygdala spikes help to synchronize ACC activity and transfer error signal information to support memory formation.

Prefrontal Cortex Contributions to the Development of Memory Formation.

The development of the brain, particularly the protracted maturation of the prefrontal cortex (PFC), supports the development of episodic memory. Yet how different regions of the PFC functionally mature to support age-related increases in memory performance remains unclear. We investigated the PFC contribution to subsequent memory (SM) of encoded visual scenes in children, adolescents, and young adults (n = 83). We identified distinct patterns of PFC activations supporting SM: regions in the lateral PFC showed positive SM effects, whereas regions in the superior and medial PFC showed negative SM effects. Both positive and negative SM effects increased with age. The magnitude of negative SM effects in the superior PFC partially mediated the age-related increase in memory. Functional connectivity between lateral PFC and regions in the medial temporal lobe (MTL) increased with age during successful memory formation. In contrast, functional connectivity between the superior PFC and regions in the MTL decreased with age, suggesting an age-related increase in the anti-correlation between these regions. These findings highlight the differential involvement of regions within the PFC supporting memory formation.