Distinct Memory Research Articles

DOP071 Distinctive pathogenic memory T cell and neutrophil responses at diagnosis identify CD patients who develop severe therapy resistant disease

Abstract Background CD4+ memory T cells (Tm) drive chronicity of inflammation in Crohn’s disease (CD). Variability in response to treatments specifically targeting Tmem hamper disease management. Recently, we have established that a subgroup of pediatric CD patients with high frequencies of circulating gut-homing IFN-g-secreting ex-Th17/Th1* TIGITneg Tmem at time of diagnosis develop a severe disease course. Specifically, they fail to reach remission within 6 months or lose remission within 1 year, despite anti-TNF treatment. As neutrophils are key targets of Tmem function, we hypothesized that pathogenic gut-homing IFN-g-secreting ex-Th17/Th1* TIGITneg Tmem alter intrinsic neutrophil transcriptional programming at an early stage, before the cells enter the tissue, associating with therapy resistant intestinal disease. Methods We analyzed clinically well-characterized therapy-naive pediatric CD patients (n=33) and IBD-negative controls (IBDneg;n=15) from the PIBD-SETQ cohort at time of diagnosis; performed bulk RNA-seq of purified circulating neutrophils, bulk RNAseq of intestinal biopsies, multiparameter flow cytometry of circulating immune cells and plasma proteomics using Proximity Extension Assay technology. Results At diagnosis, CD neutrophils differentially expressed 263 genes (DEGs) compared to IBDneg neutrophils. CD neutrophil transcriptomes were enriched for pathways related to neutrophil activation, granule biology, and IFN signaling. Hierarchical clustering of CD patients on the basis of the 263 DEGs identified two patient clusters: cluster_1 with a neutrophil transcriptional pattern similar to IBDneg, and cluster_2 with a pronounced enrichment in IFN and TNF signaling and complement genes. In line with our hypothesis, neutrophil cluster_2 patients had higher frequencies of circulating gut-homing IFN-g-secreting ex-Th17/Th1* TIGITneg Tm, reduced frequencies of inhibitory Tm and higher plasma concentrations IFN-g pathway-associated proteins including IFN-γ, CDCP1, and CXCL9 compared to cluster_1 patients. Crucially, lesional colonic biopsies of neutrophil cluster_2 patients were transcriptionally distinct from cluster_1 with a signature of increased IFN-g signaling, extracellular matrix re-organization and Fc-receptor expression but did not differ in the number of infiltrating neutrophils/mm2 or histological disease activity. In line with this distinctive immunotype, cluster_2 patients had higher clinical disease scores, higher endoscopic scores and lower rates of normal FCP remission at 1 year after diagnosis despite similar anti-TNF use compared to cluster_1 patients. Conclusion We define a subgroup of pediatric CD patients who have a distinctive pathogenic Tm-neutrophil immunotype at diagnosis and develop severe therapy resistant disease.

The role of spatial processing in verbal serial order working memory.

In a sequence, at least two aspects of information-the identity of items and their serial order-are maintained and supported by distinct working memory (WM) capacities. Verbal serial order WM is modulated by spatial processing, reflected in the Spatial Position Association of Response Codes (SPoARC) effect-the left-beginning, right-end positional association between space and serial position of verbal WM memoranda. We investigated the individual differences in this modulation with both behavioral and neurobiological approaches. We administered a battery of seven behavioral tasks with 160 healthy adults and collected resting-state fMRI data from a subset of 25 participants. With a multilevel mixed-effects modeling approach, we found that the SPoARC effect's magnitude predicts individual differences in verbal serial order WM capacity and is related to spatial item WM capacity. With a graph-theory-based analytic approach, this interaction between verbal serial order WM and spatial WM was corroborated in that the level of interaction between corresponding cortical regions (indexed by modularity) was predictive of the magnitude of the SPoARC effect. Additionally, the modularity of cortical regions associated with verbal serial order WM and spatial attention predicted the SPoARC effect's magnitude, indicating the involvement of spatial attention in this modulation. Together, our findings highlight multiple sources of the interplay between verbal serial order WM and spatial processing.

Coordinated representations for naturalistic memory encoding and retrieval in hippocampal neural subspaces

Our naturalistic experiences are organized into memories through multiple processes, including novelty encoding, memory formation, and retrieval. However, the neural mechanisms coordinating these processes remain elusive. Using fMRI data acquired during movie viewing and subsequent narrative recall, we examine hippocampal neural subspaces associated with distinct memory processes and characterized their relationships. We quantify novelty in character co-occurrences and the valence of relationships and estimate event memorability. Within the hippocampus, the novelty subspaces encoding each type exhibit partial overlap, and these overlapping novelty subspaces align with the subspace involved in memorability. Notably, following event boundaries, hippocampal states within these subspaces align inversely along a shared coding axis, predicting subsequent recall performance. This novelty-memorability alignment is selectively observed during encoding but not during retrieval. Finally, the identified functional subspaces reflect the intrinsic functional organization of the hippocampus. Our findings offer insights into how the hippocampus dynamically coordinates representations underlying memory encoding and retrieval at the population level to transform ongoing experiences into enduring memories.

Language enables the acquisition of distinct sensorimotor memories for speech.

Interactions between the context in which a sensorimotor skill is learned and the recall of that memory have been primarily studied in limb movements, but speech production requires movement, and many aspects of speech processing are influenced by task-relevant contextual information. Here, in ecologically valid speech (read sentences), we test whether English-French bilinguals can use the language of production to acquire and recall distinct motor plans for similar speech sounds spanning the production workspace. Participants experienced real-time alterations of auditory feedback while producing interleaved English and French sentences. The alterations were equal in magnitude but opposite in direction between languages. Over three experiments (n=15 in each), we observed language-specific sensorimotor learning in speech that countered the alterations and persisted after the alterations were removed. The effects were not observed in a fourth experiment (n=15) when the feedback alterations were tied to a non-linguistic cue. In a fifth experiment (n=15), we provide further confirmation that the observed language-specific changes in speech production were confined to sentence production, the linguistic level at which they were learned. The results contrast with recent work and theories of second language learning that predict broad interference between L1 and L2 phonetic representations. When faced with contrasting sensorimotor demands between languages, bilinguals readily acquire and recall highly specific motor representations for speech.

What is shared and what is not: How the Cold War era in northeastern Thailand is remembered on social media

This article investigates memories of the Cold War era in Thailand, through online practices on Facebook pages administered by residents of a borderland province in the Northeast that was a key front line during the conflict. The possibilities for greater access to, and dissemination of, information afforded by digital media technologies have created a new environment for the production of shared knowledge about the past. However, on these pages, instead of converging plural memories, participatory online culture and the use of the language of memory have enabled the creation of distinct and separated memory spaces. This article calls attention in particular to what is silenced and absent in what people are sharing online. It argues that the deep-seated ethnic politics of the Cold War have an afterlife in Thai society—especially in the country's ‘margins’ where the conflict was most violent—that is reflected as much by what is not said as by what is said online.

PP4.13 – 00012 Distinct CD4 tissue-resident memory (TRM) depletion and CD8 TRM function between the small and large intestine indicate regionspecific mechanisms for gut pathology in people with HIV (PWH)

PP4.13 – 00012 Distinct CD4 tissue-resident memory (TRM) depletion and CD8 TRM function between the small and large intestine indicate regionspecific mechanisms for gut pathology in people with HIV (PWH)

011 Distinct tissue-resident memory T cells persist in the epidermis of allergic contact dermatitis

011 Distinct tissue-resident memory T cells persist in the epidermis of allergic contact dermatitis

Precise Localization for Anatomo-Physiological Hallmarks of the Cervical Spine by Using Neural Memory Ordinary Differential Equation.

In the evaluation of cervical spine disorders, precise positioning of anatomo-physiological hallmarks is fundamental for calculating diverse measurement metrics. Despite the fact that deep learning has achieved impressive results in the field of keypoint localization, there are still many limitations when facing medical image. First, these methods often encounter limitations when faced with the inherent variability in cervical spine datasets, arising from imaging factors. Second, predicting keypoints for only 4% of the entire X-ray image surface area poses a significant challenge. To tackle these issues, we propose a deep neural network architecture, NF-DEKR, specifically tailored for predicting keypoints in cervical spine physiological anatomy. Leveraging neural memory ordinary differential equation with its distinctive memory learning separation and convergence to a singular global attractor characteristic, our design effectively mitigates inherent data variability. Simultaneously, we introduce a Multi-Resolution Focus module to preprocess feature maps before entering the disentangled regression branch and the heatmap branch. Employing a differentiated strategy for feature maps of varying scales, this approach yields more accurate predictions of densely localized keypoints. We construct a medical dataset, SCUSpineXray, comprising X-ray images annotated by orthopedic specialists and conduct similar experiments on the publicly available UWSpineCT dataset. Experimental results demonstrate that compared to the baseline DEKR network, our proposed method enhances average precision by 2% to 3%, accompanied by a marginal increase in model parameters and the floating-point operations (FLOPs). The code (https://github.com/Zhxyi/NF-DEKR) is available.

Novel off-context experience constrains hippocampal representational drift.

The hippocampus forms unique neural representations for distinct experiences, supporting the formation of different memories.1,2,3,4,5,6 Hippocampal representations gradually change over time as animals repeatedly visit the same familiar environment ("representational drift").7,8,9,10,11,12 Such drift has also been observed in other brain areas, such as the parietal,13,14 visual,15,16,17 auditory,18,19 and olfactory20 cortices. While the underlying mechanisms of representational drift remain unclear, a leading hypothesis suggests that it results from ongoing learning processes.20,21,22 According to this hypothesis, because the brain uses the same neural substrates to support multiple distinct representations, learning of novel stimuli or environments leads to changes in the neuronal representation of a familiar one. If this is true, we would expect drift in a given environment to increase following new experiences in other, unrelated environments (i.e., off-context experiences). To test this hypothesis, we longitudinally recorded large populations of hippocampal neurons in mice while they repeatedly visited a familiar linear track over weeks. We introduced off-context experiences by placing mice in a novel environment for 1h after each visit to the familiar track. Contrary to our expectations, these novel episodes decreased place cells' representational drift. Our findings are consistent with a model in whichrepresentations of distinct memories occupy different areas within the neuronal activity space,and the drift of each of them within that space is constrained by the area occupied by the others.

Comparative Analysis of LSTM Architectures for Wind Speed Forecasting: A Case Study in Muş, Turkey

This study assesses the effectiveness of five distinct Long Short-Term Memory (LSTM) architectures for forecasting wind speed in Muş, Turkey. The models include Vanilla LSTM, Stacked LSTM, Bidirectional LSTM, Attention LSTM, and Residual LSTM. The data, obtained from the Muş Meteorological Office, underwent preprocessing to handle missing values by averaging the same day and month values between 1969 and 2023. The dataset, containing 20,088 daily wind speed measurements, was split into training and test sets, with 80% allocated for training and 20% for testing. Each model was trained over 100 epochs with a batch size of 32, and performance was assessed using Mean Squared Error (MSE), Mean Absolute Error (MAE), and Mean Absolute Percentage Error (MAPE). The Vanilla LSTM model showed the lowest MSE and MAE values, indicating superior overall performance, while the Attention LSTM model achieved the lowest MAPE, demonstrating better percentage accuracy. These findings indicate that the Vanilla and Attention LSTM models are the most effective for wind speed forecasting, with the choice between them depending on the prioritization of total error versus percentage error.

A contextual fear conditioning paradigm in head-fixed mice exploring virtual reality.

Contextual fear conditioning is a classical laboratory task that tests associative memory formation and recall. Techniques such as multi-photon microscopy and holographic stimulation offer tremendous opportunities to understand the neural underpinnings of these memories. However, these techniques generally require animals to be head-fixed. There are few paradigms that test contextual fear conditioning in head-fixed mice, and none where the behavioral outcome following fear conditioning is freezing, the most common measure of fear in freely moving animals. To address this gap, we developed a contextual fear conditioning paradigm in head-fixed mice using virtual reality (VR) environments. We designed an apparatus to deliver tail shocks (unconditioned stimulus, US) while mice navigated a VR environment (conditioned stimulus, CS). The acquisition of contextual fear was tested when the mice were reintroduced to the shock-paired VR environment the following day. We tested three different variations of this paradigm and, in all of them, observed an increased conditioned fear response characterized by increased freezing behavior. This was especially prominent during the first trial in the shock-paired VR environment, compared to a neutral environment where the mice received no shocks. Our results demonstrate that head-fixed mice can be fear conditioned in VR, discriminate between a feared and neutral VR context, and display freezing as a conditioned response, similar to freely behaving animals. Furthermore, using a two-photon microscope, we imaged from large populations of hippocampal CA1 neurons before, during, and following contextual fear conditioning. Our findings reconfirmed those from the literature on freely moving animals, showing that CA1 place cells undergo remapping and show narrower place fields following fear conditioning. Our approach offers new opportunities to study the neural mechanisms underlying the formation, recall, and extinction of contextual fear memories. As the head-fixed preparation is compatible with multi-photon microscopy and holographic stimulation, it enables long-term tracking and manipulation of cells throughout distinct memory stages and provides subcellular resolution for investigating axonal, dendritic, and synaptic dynamics in real-time.

Genetic variants associated with age-related episodic memory decline implicate distinct memory pathologies.

Approximately 40% of people aged ≥ 65 experience memory loss, particularly in episodic memory. Identifying the genetic basis of episodic memory decline is crucial for uncovering its underlying causes. We investigated common and rare genetic variants associated with episodic memory decline in 742 (632 for rare variants) Ashkenazi Jewish individuals (mean age 75) from the LonGenity study. All-atom molecular dynamics simulations were performed to uncover mechanistic insights underlying rare variants associated with episodic memory decline. In addition to the common polygenic risk of Alzheimer's disease, we identified and replicated rare variant associations in ITSN1 and CRHR2. Structural analyses revealed distinct memory pathologies mediated by interfacial rare coding variants such as impaired receptor activation of corticotropin releasing hormone and dysregulated L-serine synthesis. Our study uncovers novel risk loci for episodic memory decline. The identified underlying mechanisms point toward heterogenous memory pathologies mediated by rare coding variants. We demonstrated the contribution of the common polygenic risk of Alzheimer's disease to episodic memory decline. We discovered and replicated two risk genes associated with episodic memory declineimplicated by rare variants, were discovered and replicated. We demonstrated molecular mechanisms and potential novel memory pathologies underlying interfacial rare coding variants. Molecular dynamics simulations were performed to understand the downstream effects of risk rare coding variants.

Conflict during learning reconfigures the neural representation of positive valence and approach behavior

Punishing and rewarding experiences can change the valence of sensory stimuli and guide animal behavior in opposite directions, resulting in avoidance or approach. Often, however, a stimulus is encountered with both positive and negative experiences. How is such conflicting information represented in the brain and resolved into a behavioral decision? We address this question by dissecting a circuit for sexual conditioning in C.elegans. In this learning paradigm, an odor is conditioned with both a punishment (starvation) and a reward (mates), resulting in odor approach. We find that negative and positive experiences are both encoded by the neuropeptide pigment dispersing factor 1 (PDF-1) being released from, and acting on, different neurons. Each experience creates a distinct memory in the circuit for odor processing. This results in the sensorimotor representation of the odor being different in naive and sexually conditioned animals, despite both displaying approach. Our results reveal that the positive valence of a stimulus is not represented in the activity of any single neuron class but flexibly represented within the circuit according to the experiences and predictions associated with the stimulus.

Working memory gating in obesity is moderated by striatal dopaminergic gene variants.

Everyday life requires an adaptive balance between distraction-resistant maintenance of information and the flexibility to update this information when needed. These opposing mechanisms are proposed to be balanced through a working memory gating mechanism. Prior research indicates that obesity may elevate the risk of working memory deficits, yet the underlying mechanisms remain elusive. Dopaminergic alterations have emerged as a potential mediator. However, current models suggest these alterations should only shift the balance in working memory tasks, not produce overall deficits. The empirical support for this notion is currently lacking, however. To address this gap, we pooled data from three studies (N = 320) where participants performed a working memory gating task. Higher BMI was associated with overall poorer working memory, irrespective of whether there was a need to maintain or update information. However, when participants, in addition to BMI level, were categorized based on certain putative dopamine-signaling characteristics (single-nucleotide polymorphisms [SNPs]; specifically, Taq1A and DARPP-32), distinct working memory gating effects emerged. These SNPs, primarily associated with striatal dopamine transmission, appear to be linked with differences in updating, specifically, among high-BMI individuals. Moreover, blood amino acid ratio, which indicates central dopamine synthesis capacity, combined with BMI shifted the balance between distractor-resistant maintenance and updating. These findings suggest that both dopamine-dependent and dopamine-independent cognitive effects exist in obesity. Understanding these effects is crucial if we aim to modify maladaptive cognitive profiles in individuals with obesity.

Working memory gating in obesity is moderated by striatal dopaminergic gene variants

Everyday life requires an adaptive balance between distraction-resistant maintenance of information and the flexibility to update this information when needed. These opposing mechanisms are proposed to be balanced through a working memory gating mechanism. Prior research indicates that obesity may elevate the risk of working memory deficits, yet the underlying mechanisms remain elusive. Dopaminergic alterations have emerged as a potential mediator. However, current models suggest these alterations should only shift the balance in working memory tasks, not produce overall deficits. The empirical support for this notion is currently lacking, however. To address this gap, we pooled data from three studies (N = 320) where participants performed a working memory gating task. Higher BMI was associated with overall poorer working memory, irrespective of whether there was a need to maintain or update information. However, when participants, in addition to BMI level, were categorized based on certain putative dopamine-signaling characteristics (single-nucleotide polymorphisms [SNPs]; specifically, Taq1A and DARPP-32), distinct working memory gating effects emerged. These SNPs, primarily associated with striatal dopamine transmission, appear to be linked with differences in updating, specifically, among high-BMI individuals. Moreover, blood amino acid ratio, which indicates central dopamine synthesis capacity, combined with BMI shifted the balance between distractor-resistant maintenance and updating. These findings suggest that both dopamine-dependent and dopamine-independent cognitive effects exist in obesity. Understanding these effects is crucial if we aim to modify maladaptive cognitive profiles in individuals with obesity.

Time-dependent neural arbitration between cue associative and episodic fear memories.

After traumatic events, simple cue-threat associative memories strengthen while episodic memories become incoherent. However, how the brain prioritises cue associations over episodic coding of traumatic events remains unclear. Here, we developed an original episodic threat conditioning paradigm in which participants concurrently form two memory representations: cue associations and episodic cue sequence. We discovered that these two distinct memories compete for physiological fear expression, reorganising overnight from an overgeneralised cue-based to a precise sequence-based expression. With multivariate fMRI, we track inter-area communication of the memory representations to reveal that a rebalancing between hippocampal- and prefrontal control of the fear regulatory circuit governs this memory maturation. Critically, this overnight re-organisation is altered with heightened trait anxiety. Together, we show the brain prioritises generalisable associative memories under recent traumatic stress but resorts to selective episodic memories 24 h later. Time-dependent memory competition mayprovide a unifying account for memory dysfunctions in post-traumatic stress disorders.

Analysis of the multi-term fractional Bateman equations in radioactive decay by means of Mikusiński algebraic calculus

Fractional Bateman equations model the concentrations of nuclear species through a radioactive decay chain, by considering non-Markovian behavior. Cruz-López and Espinosa-Paredes (Nuclear Engineering and Technology, 2022) solved the mathematical problem with a single memory coefficient, based on the Laplace-transform technique. Cruz-López, Espinosa-Paredes and François (Computer Physics Communications, 2022) extended the analysis to several fractional orders, with Laplace transforms and series expansions checked by induction. In this paper, we solve such a case of distinct memory effects, via the more general method of Mikusiński operational calculus. We do not distinguish between equal and different decay rates. Multivariate Mittag-Leffler functions appear in the closed-form expression.

Distortion of overlapping memories relates to arousal and anxiety.

Everyday experiences often overlap, challenging our ability to maintain distinct episodic memories. One way to resolve such interference is by exaggerating subtle differences between remembered events, a phenomenon known as memory repulsion. Here, we tested whether repulsion is influenced by emotional arousal, when resolving memory interference is perhaps most needed. We adapted an existing paradigm in which participants repeatedly studied object-face associations. Participants studied two different-colored versions of each object: a to-be-tested "target" and its not-to-be-tested "competitor" pair mate. The level of interference between target and competitor pair mates was manipulated by making the object colors either highly similar or less similar, depending on the participant group. To manipulate arousal, the competitor object-face associations were preceded by either a neutral tone or an aversive and arousing burst of white noise. Memory distortion for the color of the target objects was tested after each study round to examine whether memory distortions emerge after learning. We found that participants with greater sound-induced pupil dilations, an index of physiological arousal, showed greater memory attraction of target colors towards highly similar competitor colors. Greater memory attraction was also correlated with greater memory interference in the last round of learning. Additionally, individuals who self-reported higher trait anxiety showed greater memory attraction when one of the overlapping memories was associated with something aversive. Our findings suggest that memories of similar neutral and arousing events may blur together after repeated exposures, especially in individuals who show higher arousal responses and symptoms of anxiety.

The influence of categorical stimuli on relational memory binding.

Binding of arbitrary information into distinct memory representations that can be used to guide behavior is a hallmark of relational memory. What is and is not bound into a memory representation and how those things influence the organization of that representation remain topics of interest. While some information is intentionally and effortfully bound-often the information that is consistent with task goals or expectations about what information may be required later-other information appears to be bound automatically. The present set of experiments sought to investigate whether spatial memory would be systematically influenced by the presence and absence of distinct categories of stimuli on a spatial reconstruction task. In this task, participants must learn multiple item-location bindings and place each item back in its studied location after a short delay. Across three experiments, participants made significantly more within-category errors (i.e., misassigning one item to the location of a different item from the same category) than between-category errors (i.e., misassigning one item to the location of an item from a different category) when categories were perceptually or semantically distinct. These data reveal that category information contributed to the organization of the memory representation and influenced spatial reconstruction performance. Together, these results suggest that categorical information can influence memory organization, and not always to the benefit of overall task performance.

Artificial olfactory memory system based on conductive metal-organic frameworks

The olfactory system can generate unique sensory memories of various odorous molecules, guiding emotional and cognitive decisions. However, most existing electronic noses remain constrained to momentary concentration, failing to trigger specific memories for different smells. Here, we report an artificial olfactory memory system utilizing conductive metal-organic frameworks (Ce-HHTP) that integrates sensing and memory and exhibits short- and long-term memory responses to alcohols and aldehydes. Experiments and theoretical calculations show that distinct memories are derived from the specific combinations of Ce-HHTP with O atoms in different guest. An unmanned aircraft equipped with this system realized the sensory memories in established areas. Moreover, the fusion of portable detection boxes and wearable flexible electrodes demonstrated the immense potential in off-site pollution monitoring and health management. This work represents an artificial olfactory memory system with two specific sensory memories under simultaneous conditions, laying the foundation for bionic design with qualities of human olfactory memory.