Biology subjects

Liu, J.

Publications and source records attributed to Liu, J..

At least 235 records · Page 13Linked to original sources

bioRxiv2026

Ramping-up hippocampal ripples and their neocortical coupling support human visual short-term memory

Emerging evidence suggests that the hippocampus contributes to visual short-term memory (VSTM). However, the neural mechanisms through which hippocampal activity supports the maintenance of VSTM representations remain largely unknown. Here, using intracranial EEG recordings from human participants performing a delayed match-to-sample task for naturalistic objects, we investigated the role of hippocampal ripple activity--brief high-frequency oscillations associated with memory replay--in VSTM maintenance and hippocampal-neocortical communication. We found that hippocampal ripple rates progressively ramped up during the maintenance period and supported successful VSTM. More critically, hippocampal ripples were temporally coupled with the ripples in the lateral temporal lobe (LTL), and these coupled ripples were associated with memory reactivation in the LTL. These findings provide direct evidence that hippocampal-neocortical interaction via coupled ripples supports VSTM, extending the role of hippocampal ripples from long-term consolidation to short-term mnemonic processes and offering new insights into the dynamic coding mechanisms of working memory. Impact StatementHippocampal ripple ramping-up and neocortical coupling support a dynamic coding mechanism for visual short-term memory maintenance

neuroscience↗

bioRxiv2026

A MinD-like ATPase couples flagellation and cell division in spirochetes

Spirochetes are evolutionarily distinct bacteria defined by their spiral morphology, unique means of motility, and periplasmic flagella (PFs). Because these filaments reside within the periplasm and are mechanically integrated with the cell body, their assembly must be precisely coordinated with cell growth and cytokinesis. However, the mechanism that couples flagellar biogenesis to cell division in spirochetes remains unclear. Using the Lyme disease spirochete Borrelia burgdorferi as a model, we identify FlhG (BB0269), a MinD-like ATPase, as a spatial regulator that links cell division to flagellar patterning. In wild-type cells, 7-11 long helical PFs originate from cell poles and assemble into ribbon-like bundles that wrap around the cell cylinder to drive motility. Deletion of flhG disrupts this ordered architecture, causing marked heterogeneity in flagellar number, defective ribbon assembly, aberrant septation, and severe motility impairment. Mechanistically, FlhG dynamically localizes to the poles and midcell during division, where it directs the positioning of FlhF, a signal recognition particle (SRP) -type GTPase controlling flagellar number and placement, and FliF, the MS-ring protein that nucleates flagellar assembly. Through this spatial regulation, FlhG coordinates flagellar assembly with cytokinetic progression. Together, these findings reveal a spatial regulatory mechanism coupling cell division to flagellation, providing insight into understanding how spirochetes coordinate their distinctive morphogenesis, flagellation and motility. SignificanceSpirochetes such as Borrelia burgdorferi, the causative agent of Lyme disease, rely on periplasmic flagella for motility and cell shape, yet how these structures are coordinated with cell division has remained unclear. We identify a MinD-like ATPase, FlhG, as a spatial regulator that couples flagellar assembly to cytokinesis. In contrast to its homologs in other bacteria, FlhG does not regulate flagellar protein levels but instead directs subcellular positioning of key assembly factors. By dynamically redistributing between the cell poles and division site, FlhG synchronizes flagellar patterning with septum formation. These findings uncover a previously unrecognized mechanism linking cell morphogenesis to the cell cycle and reveal how conserved ATPases can be repurposed to organize complex bacterial architectures.

microbiology↗

bioRxiv2026

Therapeutic Stress-induced Activation of PGCC Life Cycle Drives the Resistance Acquisition and Structured Tissue Differentiation

To elucidate how cancer cells generate resistance and defined forms of tissue structure in response to therapeutic stress, we tracked the temporal dynamics of life cycle of polyploid giant cancer cells (PGCCs) induced by the mitotic destabilizer vincristine (VCR). Live-cell fluorescence imaging revealed that VCR activated a distinct endoreplication-based life cycle, which replaced canonical mitosis. PGCCs exhibited reduced proliferative activity, enhanced epithelial-mesenchymal transition (EMT), progressive acquisition of blastomere-like features, and broad multilineage differentiation potential. Both PGCC populations and single PGCC-derived progeny displayed time- and dose-dependent acquisition of malignant traits in vitro and tumorigenic capacity in vivo. PGCC-derived spheroids exhibited ability to differentiate into the cells of origin from three germ layers. Importantly, pre-budding PGCCs induced by higher VCR concentrations exhibited enhanced ability for glandular structure formation and tissue differentiation. Morphologically, the nuclei of PGCC-derived spheroids underwent growth in size, formation of luminal structure, and followed by maturation of lumen. Mechanistically, PGCCs entered a senescent state characterized by elevated senescence-associated secretory phenotype (SASP)-manifested by rich proinflammatory cytokines. Notably, silencing IL1{beta}, IL6, or IL8, or pharmacological inhibition of their receptors, suppressed PGCC formation, budding, EMT, and blastomere-like reprogramming into structured tissue. Our studies provide novel mechanistic insights into early embryogenesis and tumorigenesis at the tissue structural developmental level.

cancer biology↗

bioRxiv2026

Biohybrid Robots with Embedded Conductive Fibers for Actuation, Sensing, and Closed-loop Control

Living organisms achieve adaptive actuation through the seamless integration of neural motor control circuitry and proprioceptive feedback. While biohybrid robotics aims to replicate these capabilities by merging engineered muscle with synthetic scaffolds, the field remains limited by interfaces that lack the efficiency and closed-loop regulation of natural neuromuscular systems. Here, we introduce a biohybrid muscle actuator system featuring a bioelectronic interface based on soft poly(3,4-ethylenedioxythiophene) (PEDOT) fibers for stimulation and sensing. These fibers conformally couple to muscle tissues, eliciting robust contractions at voltages as low as 1 V--requiring ultra-low power (0.376 {+/-} 0.034 mW) and preserving long-term tissue viability. By leveraging the independent addressability of these fibers, we demonstrate selective actuation of individual muscle units to achieve precise spatiotemporal control of a two-muscle-powered walking biohybrid robot, reaching a locomotion speed of 5.43 {+/-} 0.79 mm/min. When configured as strain sensors, the fibers exhibit a high gauge factor of 155.45 {+/-} 6.59 and resolve contractile displacements within tens of micrometers. We demonstrate that this sensing modality can be integrated into a closed-loop controller to autonomously modulate stimulation based on real-time feedback, significantly mitigating muscle fatigue (p = 0.038) during continuous operation. This work establishes a versatile platform for efficient actuation and intrinsic feedback sensing, providing a blueprint for efficient, autonomous, and adaptive biohybrid machines. SummarySoft conductive fibers enable a bioelectronic interface for low-power actuation and closed-loop control in biohybrid robots.

bioengineering↗

bioRxiv2026

A rugged binding landscape unifies static and dynamic paradigms in protein-protein interactions

Predicting protein-protein interaction (PPI) affinities from structural data remains a challenge. Although binding funnel theory describes the formation of native complexes, the topography of the funnel bottom and its influence on affinity are often overlooked. Using two well-controlled nanobody-antigen datasets as model systems, we demonstrate that PPI can exist in both static and dynamic binding paradigms. These two nanobody series adopt nearly identical binding poses toward their respective antigens yet exhibit diverse affinities, each representing a distinct paradigm: a static paradigm in which affinity can be ranked by Rosetta scoring of co-crystal structures alone, and a dynamic paradigm in which affinity can only be ranked using molecular dynamics-sampled ensembles. The two paradigms differ in interfacial dynamics. In the dynamic series, the relative motion between binding partners ({Delta}RMSF) is temperature-sensitive, with optimal affinity correlation at 298 K. In the static series, {Delta}RMSF is minimal and insensitive to temperature. Local frustration analysis establishes a mechanistic bridge between interfacial dynamics and landscape topology. Dynamic interfaces exhibit increased frustration upon thermal sampling, facilitating sampling of functionally relevant microstates, whereas static interfaces show minimal frustration changes across temperatures. The temperature-dependent frustration difference mirrors {Delta}RMSF sensitivity, confirming local frustration as a determinant of interfacial dynamics. Furthermore, static interfaces are characterized by a higher density of canonical hotspot residues, while dynamic interfaces utilize interfacial ruggedness to modulate affinity. Together, these results demonstrate that conserved binding modes can encode different energy landscapes and provide a practical framework for determining when ensemble-based sampling is required for accurate affinity prediction.

biophysics↗

bioRxiv2026

A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

cancer biology↗

bioRxiv2026

Rab12 is a regulator of mitophagy and mitochondrial homeostasis

Rab GTPases orchestrate vesicular trafficking, but their contributions to mitochondrial quality control are not fully defined, despite links to multiple mitochondria-related human diseases. We conducted a family-wide siRNA-based screen using mt-mKeima/YFP-Parkin HeLa cells to identify regulators of depolarization-induced mitophagy. The screen identified several candidate Rabs, and follow-up studies validated Rab12 as a negative regulator of mitophagy. Rab12 knockdown or knockout augments clearance of damaged mitochondria basally and/or after FCCP-induced depolarization, with findings reproduced across distinct cell types. Rab12 depletion increased mitochondrial content, lowered mitochondrial membrane potential, and reduced mitochondrial DNA damage, without detectable changes in overall cellular bioenergetic capacity. Together, these results indicate that Rab12 restrains mitophagic engagement and its loss permits accumulation of lower-functioning mitochondria that are hypersensitive to mitophagy-inducing stress. Rab12 thus emerges as a novel effector linking vesicular trafficking machinery and mitochondrial homeostasis, with potential implications for neurodegenerative disorders and other Rab-associated diseases.

cell biology↗

bioRxiv2026

Polyclonal-Monoclonal Transition in Lung Squamous Cell Carcinoma Evolution

The evolutionary trajectory of lung squamous cell carcinoma (LUSC) remains poorly defined, hindering the development of effective therapies. By integrating genomic and transcriptomic sequencing from human LUSC specimens, we delineated a polyclonal-to-monoclonal evolutionary trajectory during LUSC progression. This evolutionary pattern was corroborated by single-cell RNA sequencing, which revealed consistent tumor cell heterogeneity. Specifically, the SBS5 mutational signature was enriched and correlated with poor prognosis independent of tumor stage. By further utilizing the spontaneous LUSC mouse model to identify key genomic and genetic events in LUSC progression, we observed that the JNK pathway was inhibited and that cytoskeleton-related pathways were dysregulated during LUSC development, and identified the mutations in the JNK pathway (e.g., DACT1) and cytoskeletal regulators (e.g., KIF26A). Collectively, these findings established a polyclonal-monoclonal evolution paradigm for LUSC, potentially regulated by JNK pathways, which could benefit LUSC precision therapeutics.

genomics↗

bioRxiv2026

Single-cell lung eQTL dataset of Asian never-smokers highlights the roles of alveolar cells in lung cancer etiology

Single-cell expression quantitative trait loci (sc-eQTL) analyses are powerful in identifying context-specific susceptibility genes from genome-wide association studies (GWAS) loci. However, few studies have comprehensively investigated cells of lung cancer origin in non-European populations. Here, we built a lung sc-eQTL dataset from 129 Korean women never-smokers with epithelial cell enrichment. eQTL mapping identified 2,229 genes with an eQTL in 33 cell types, including East Asian-specific findings when compared to predominantly European datasets. Integration with single-cell chromatin accessibility data demonstrated an enrichment of cell-type specific eQTLs in cell-type matched candidate enhancers, while shared eQTLs were more frequently found near promoters. Colocalization and transcriptome-wide association study unveiled 36 susceptibility genes from 22 cell types in 22 lung cancer loci, including 10 loci not achieving genome-wide significance in prior GWAS. Around 47% of these genes were from cells of the alveoli, underscoring their importance, especially in lung adenocarcinoma (LUAD) susceptibility. Focusing on the trajectory of alveolar epithelial cell regeneration, we detected 785 cell-state-interacting QTLs, which overlapped with 28% (10) of the identified susceptibility genes. Finally, we experimentally validated East Asian-and alveolar type 2 cell-specific eQTL of TCF7L2 underlying East Asian LUAD locus, 10q25.2. Consistent with its role as a Wnt/{beta}-catenin effector, TCF7L2 displayed significant effect on lung adenocarcinoma cell growth. Our data highlighted context-specific susceptibility genes, especially from alveolar cells of lung, contributing to lung cancer etiology.

genetics↗

bioRxiv2026

Apical Localization of RNA Polymerases Modulate Transcription Dynamics and Supercoiling Domains Revealed by Cryo-ET

Protein interactions with canonical B-form DNA are well-characterized, yet the effect on these interactions of torsionally constrained DNA--ubiquitous in cells--remains underexplored. Using cryo-electron tomography (cryo-ET), we 3D-reconstructed entire negatively supercoiled DNA substrates bound to active RNA polymerase (RNAP), revealing diverse DNA supercoiling conformations and their interplay with transcription. RNAP preferentially localizes at plectoneme apices in a swiveled, pause-prone state. RNAP, along with other DNA-melting proteins like dCas9, can act as torsional roadblocks that segregate "twin-supercoiling domains" during active transcription, independent of external DNA/RNAP tethering. Co-transcribing RNAPs further intensify this domain separation: tandem oriented RNAPs relieve negative supercoiling more effectively than opposing ones, promote greater RNAP accumulation and enhanced elongation, both in vitro and in vivo. Topoisomerase I relieves torsional stress and facilitates RNAP escape from apical stalls, thereby supporting apical transcription regulation. Together, these findings support a load-and-release mechanism at plectoneme apices that may underlie supercoiling-dependent transcriptional bursting.

biophysics↗

bioRxiv2026

Degradation of mucin O-glycans by a human gut symbiont requires a complex enzyme repertoire and promotes colonization

Secreted mucins are the major component of the mucus layer that protects intestinal epithelial surfaces by blocking excessive interactions with the microbiota. Mucins are complex glycoproteins decorated with over 100 different O-glycans. Some bacteria can utilize mucins and excessive degradation has been associated with disruption of the mucus barrier and inflammation. Despite the importance of mucins, a detailed enzymatic pathway by which gut bacteria degrade colonic mucin O-glycans and the impact of this process on gut colonization are unknown. Here, we identified >100 genes that are expressed by the symbiont Bacteroides thetaiotaomicron during growth on different O-glycan substrates, revealing effects of glycan structure on gene expression. The characterization of 33 glycoside hydrolase enzymes revealed the pathway for colonic O-glycan degradation by this bacterium. In vivo competition experiments show that multiple exo-acting enzymes targeting mucin capping structures are central to gut colonization and may provide targets to inhibit bacterial mucin degradation.

microbiology↗

bioRxiv2026

Low-Dimensional Frontal Feedback Resolves High-Dimensional Visual Ambiguity in Human Visual Cortex

One major distinction between artificial neural networks and biological brains is the prevalence of extensive, long-range feedback connections in biological systems. Here we investigate unique contributions of these hierarchical feedback signals beyond feedforward processing and local recurrence by exploring their mechanistic role in resolving visual ambiguity caused by occlusion. Both empirical fMRI and EEG experiments and computational modeling show that when sensory evidence for faces became insufficient, the ventrolateral prefrontal cortex (vlPFC) sustained a low-dimensional belief state (e.g., animate vs. inanimate objects) and transmitted this abstract information back to the animacy map in the ventral temporal cortex (VTC) encompassing face-selective representations. Critically, in the hierarchical vision model inspired by this finding, this frontal feedback did not reshape the attractor geometry of the VTC; instead, it provided guidance to reroute ongoing neural dynamics away from ambiguous pseudo-states toward face attractor basins in the energy representational landscape. This control-based mechanism of feedback signals thus enabled perceptual completion by reconstructing missing facial features with temporal costs verified through EEG. Together, this multimodal study bridges analysis-by-synthesis theories of vision and dynamical-systems perspectives on long-range feedback as state-space control, and offers inspiration for the design of hierarchical AI architectures incorporating feedforward, recurrent, and feedback connections.

neuroscience↗

bioRxiv2026

Effect of dietary Chitosan supplementation on Intestinal Barrier Function and Growth Performance in weaned piglets challenged by Enterohemorrhagic haemolytic Escherichia coli

Enterohemorrhagic Escherichia coli O157:H7 (EHEC) is an important zoonotic pathogen that disrupts intestinal epithelial barrier integrity and induces excessive inflammatory responses, thereby leading to impaired growth performance and intestinal injury. EHEC is also an important cause Hemolytic Uremic Syndrome (HUS) in children and older adults. In pig production, chitosan is considered a promising alternative to antibiotics due to its bioadhesive and antimicrobial properties, but the effects and underlying mechanisms of chitosan (COS) under pathogenic challenge remain to be elucidated. One hundred and eight pigs were randomly divided into three treatments: an unchallenged control group (CON), an EHEC-challenged control group (ECON), and an EHEC-challenged group supplemented with 100 mg/kg COS (ECOS). Results show that EHEC challenge increased the feed conversion ratio (FCR), increased inflammatory cytokine levels, disrupted intestinal morphology, and downregulated tight junction and nutrient transporter gene expression (P<0.05). Dietary COS supplementation significantly improved average daily gain (ADG) and FCR during day 6-14 (P<0.05). Moreover, COS reduced fecal shedding of total E. coli (P = 0.085) and EHEC, attenuated systemic inflammation by decreasing serum TNF- and IL-6 levels, and enhanced humoral immunity as indicated by increased IgA and IgM concentrations (P<0.05). Importantly, COS alleviated EHEC-induced intestinal injury by restoring villus height and villus-to-crypt ratio, with enhanced mucosal digestive enzyme activities, and upregulated expression of tight junction proteins (ZO-1 and occludin) and nutrient transporters (SGLT-1 and PEPT1) (P<0.05). In conclusion, these findings indicate that dietary COS improves growth performance in EHEC-challenged weaned pigs, with enhanced intestinal barrier integrity and nutrient transport capacity.

microbiology↗

bioRxiv2026

FoTO1 orchestrates Taxol biosynthesis through catalytic and non-catalytic mechanisms

Taxol is a blockbuster chemotherapeutic derived from the Pacific Yew tree. Recent work in our group has identified a complete pathway to baccatin III, a key intermediate, that hinges on a novel accessory protein, Facilitator of Taxane Oxidation (FoTO1). This protein dramatically improves yield and alters enzyme product profiles when reconstituting the Taxol pathway in N. benthamiana. FoTO1 has been shown to act early in the biosynthetic pathway improving the yields of product generated by the combination of a plastidial diterpene synthase (taxadiene synthase) and an endoplasmic reticulum (ER) localized cytochrome P450 (T5-alpha-hydroxylase). Here, we show that FoTO1 is an enzyme capable of converting taxadiene-(4),5-epoxide, the likely product of T5H oxidation, into taxadien-5-ol. FoTO1 is also functional in yeast, resolving a key bottleneck for development of a bioproduction route to Taxol in this host. Targeted mutagenesis of key catalytic residues in FoTO1 abrogates function in vitro but not in planta, suggesting non-catalytic contributions of FoTO1 to the taxane pathway. A combination of proximity labelling, bimolecular fluorescence complementation assays, and co-immunoprecipitation studies revealed that FoTO1 interacts with and organizes various P450s in the Taxol pathway. These approaches highlight the importance of both FoTO1s catalytic and non-catalytic functions in improving yields in the early Taxol pathway. Beyond Taxol biosynthesis, FoTO1 boosts yields for diverse diterpene pathways from across phylogeny, suggesting a general role of this protein class in mediating metabolism across the plastid and ER in plants.

biochemistry↗

bioRxiv2026

Context-dependent toxicity of human Tau isoforms in a Drosophila tauopathy model

Tauopathies are characterised by progressive deterioration of brain regions due to abnormal accumulation of the microtubule-associated protein tau (MAPT). Alternative splicing of MAPT pre-mRNA results in six tau isoforms, which are classified into two groups depending on the number of microtubule-binding domain repeats (3R vs 4R). Although many tauopathies are 3R or 4R-specific, the relative contributions of individual isoforms to neurotoxicity remain incompletely understood. To systematically characterise differences in tau isoform toxicity, we created a novel set of Drosophila lines expressing equivalent amounts of the six human tau isoforms (hTau) at levels sufficient to induce visible phenotypes. Using a variety of assays including survival, negative geotaxis and tissue-level or cell-type-specific degeneration, we found that hTau isoform toxicity is not uniform across different biological contexts. Despite generally higher toxicity of 4R isoforms compared to 3R, the effects of individual hTau isoforms varied with the temporal window of expression, tissue type, and neuronal identity. Restricting hTau expression to small homogeneous neuronal populations enabled detailed analysis of isoform-specific degeneration. Neurons previously observed to be vulnerable or resilient to hTau toxicity exhibited differences in the onset and progression of degeneration, suggesting that resilience may be an early and transitory state, with most or all neurons eventually succumbing to tau toxicity over time. Notably, these differences in toxicity were not readily explained by variations in hTau abundance and phosphorylation. Together, our findings demonstrate that tau toxicity is highly context-dependent, clearly isoform-specific, and shaped by interactions between tau and its cellular environment.

neuroscience↗

bioRxiv2026

HMA proteins produce 2',3'-cNMP signaling molecules and activate CNL-mediated immunity in rice

Plants deploy a sensor repertoire, usually NLRs, to perceive pathogen effectors and activate executor NLR-triggered immunity. Here we reveal that rice HMA proteins function as sensors detecting the Magnaporthe oryzae MAX effector AvrPigm to trigger broad-spectrum blast resistance mediated by the CNL PigmR. AvrPigm is conserved with multiple copies in blast genomes and targets HMA proteins, facilitating HMA translocation into the cytoplasm. Cryo-EM structure of the HPP04HMA reveals a filament-like oligomer with ssDNA/RNA bound inside the filament, which display cyclic nucleotide synthase activity to generate 2',3'-cNMP in a CNL-dependent manner. We further discovered that the LRR domains of the executor CNLs perceive 2',3'-cNMP to mount immunity. Our study thus establishes an unrecognized immunity mode with a distinct repertoire of sensor receptors that produce signaling molecules that are perceived by the LRR domains of executor NLRs to mediate immunity, shedding new light on the sensor-executor conception and immune activation in plants. HighlightsO_LIHMA proteins and CNL receptors form a new sensor-executor mode in plant immunity C_LIO_LICryo-EM reveals the filament-like structure of HMA-ssRNA/ssDNA C_LIO_LIHMA proteins are cyclic nucleotide synthetases to generate 2',3'-cNMP C_LIO_LILRR domains of CNLs perceive 2',3'-cNMP to mediate immunity C_LI

plant biology↗

bioRxiv2026

Efficient Reprogramming of the Epiblast Enables the Generation of Cloned Mice

Somatic cell nuclear transfer (SCNT) can generate viable mammals despite pervasive epigenetic abnormalities in cloned embryos, yet the mechanism underlying this paradox remains unclear. Here we show, using single-cell transcriptomics, that efficient reprogramming occurs exclusively in the epiblast (EPI), but the not primitive endoderm (PrE) of late mouse SCNT blastocysts. Integrating this with previous findings of trophectoderm (TE) aberration, we propose the EPI as the sole effectively reprogrammed lineage. By innovatively employing a Lego-like multi-lineage embryonic aggregation approach, where the extra-embryonic lineages were replaced with fertilization-derived counterparts, we demonstrated that SCNT-derived EPI inherently possesses full-term developmental potential nearly identical to that of fertilized EPI (20.5% vs. 21.8% birth rate), functionally confirming its effective reprogramming. Our study uncovers a lineage-specific asymmetric reprogramming mode where the EPI specifically achieves effective reprogramming, thereby constituting the deterministic basis for cloned animal generation. This work also provides a versatile strategy for investigating lineage potency and function.

developmental biology↗

bioRxiv2026

Reactivating conflicting evaluative memories during sleep reduces decision ambivalence

Memory guides everyday evaluations and decision-making. Yet people often encounter inconsistent information about the same target, giving rise to conflicting evaluative memories and decision ambivalence. Decision ambivalence is not only aversive but also reduces confidence, increases hesitation, and leads to maladaptive choices. While sleep consolidates memories, its role in resolving these evaluative conflicts and shaping decision dynamics remains unknown. Here, we investigated how memory reactivation during sleep, a critical period for memory consolidation and transformation, would reconstruct conflicting evaluative memories and thus influence next-day decision ambivalence. In a valence reversal learning procedure, participants first encoded positive or negative cue-outcome associations (A-B) on Day 1, followed by learning A-C associations yet with opposite valences on Day 2 (i.e., Day 1 negative-to-Day 2 positive and Day 1 positive-to-Day 2 negative). During subsequent non-rapid eye movement (NREM) sleep on Day 2 night, half of the cues were re-presented to sleeping participants to reactivate the cue-associated memories. Upon waking up, participants completed post-sleep evaluation and memory tests. Our results showed that cueing reduced decision ambivalence, especially in the negative-to-positive condition, as evidenced by less curved mouse-tracking trajectories. Meanwhile, cueing promoted the integration of conflicting evaluative memories, again in the negative-to-positive condition. Critically, cueing-induced ambivalence reduction was evident only for items that were integrated after sleep. Electrophysiologically, stronger cue-elicited delta power during NREM sleep predicted next-day ambivalence reduction, while higher cue-elicited spindle probabilities were associated with better memory integration. Together, our findings suggest that memory reactivation during post-learning NREM sleep actively reorganizes conflicting memories, providing a mechanistic pathway through which offline memory reprocessing resolves waking decision ambivalence.

neuroscience↗