Biology subjects

Cho, J.

Publications and source records attributed to Cho, J..

At least 19 recordsLinked to original sources

bioRxiv2026

Folic acid polyglutamylation triggers MAP2K5 signaling to induce adipocyte lipid catabolism

Adipocyte signaling adaptively responds to macronutrients, but how essential micronutrients impact lipid homeostasis remains poorly understood. Here, we demonstrate that folate polyglutamylation, the sequential conjugation of glutamate residues to folate, serves as a dynamic biochemical process regulating metabolic signaling. Using our folate metabolomics platform, we show that polyglutamylated folic acid accumulates in healthy adipose tissue, but is depleted in obesity across mice and humans, independent of circulating folate levels. Genetic ablation of the polyglutamylation enzyme folylpolyglutamate synthase (Fpgs) in adipocytes suppresses lipid catabolism to induce cell-autonomous lipid accumulation, operating independently of canonical adipogenesis or downstream one-carbon flux. Target-engagement proteomics identifies monoglutamylated folic acid as a Map2k5-interacting molecule that inhibits Map2k5 activity, whereas Fpgs-mediated folic acid polyglutamylation acts as a chemical switch that disrupts this interaction to promote lipolysis. In vivo, whole-body inhibition of Map2k5 or adipose-targeted genetic depletion of Fpgs increases body fat mass in the absence of dietary obesogenic triggers. Furthermore, single-cell and single-nuclear transcriptomic analyses establish the Fpgs-Map2k5 pathway as a core transcriptional signature of mouse and human adipose tissues. These findings uncover a non-canonical signaling role for folate that regulates adipocyte lipid homeostasis.

biochemistry↗

bioRxiv2026

Neurotropic strains of Listeria monocytogenes preferentially invade enteric glial cells

Certain strains of the facultative intracellular bacterial pathogen Listeria monocytogenes are thought to invade cranial nerves in the gut and disseminate directly to the brainstem to cause rhombencephalitis in both humans and ruminants. Bacteria with actin tails were previously observed within neurons of naturally infected sheep, but the mechanism for how these neurotropic strains access the nervous system has not been well characterized. Using a foodborne mouse model of listeriosis, we show here that bypassing the gut phase of infection prevents colonization of the brain, confirming that invasion of the nervous system happens in the intestinal tract. L. monocytogenes did not efficiently invade neuronal cell lines, although they could replicate exponentially in the cytosol and form actin tails. Instead, the neurotropic strains displayed a preferential ability to invade enteric glial cells, a specialized subset of glia that support neurons and are critical for intestinal homeostasis. Using an in vitro co-culture system, we demonstrated that neurotropic L. monocytogenes could readily invade enteric glial cells and use ActA-mediated actin-based motility to spread to adjacent neurons. These results suggest that invasion of enteric glial cells is a novel virulence strategy that can promote brainstem infection following foodborne transmission of L. monocytogenes. IMPORTANCEThis study provides further evidence for dissemination of neurotropic strains of L. monocytogenes from the gut directly to the brain via axonal migration using foodborne mouse model of listeriosis. It is the first report showing that enteric glial cells, a specialized subset of cells in the gut that support intestinal neurons, are susceptible to pathogenic bacterial infection.

microbiology↗

bioRxiv2026

Gut microbiome derived folate metabolite suppresses colorectal cancer progression

The gut microbiota influences colorectal cancer (CRC) progression, primarily through the secretion of small molecule metabolites. While numerous microbial products are known to drive CRC, endogenous protective mechanisms remain largely uncharacterized. Utilizing a folate metabolomics platform, we demonstrate that the healthy gut microbiota produces folinic acid (FA), a known chemotherapeutic adjuvant also known as leucovorin. This microbially derived folinic acid is progressively depleted in mouse models of colitis-associated CRC and in human clinical metagenomic cohorts with advancing disease severity. Mechanistically, folinic acid acts as a signaling molecule that directly binds and inhibits the intracellular protease calpain-2. This interaction stabilizes epithelial E-cadherin protein expression and suppresses CRC epithelial-to-mesenchymal transition driving metastasis. Genetically manipulating gut microbial production of FA is sufficient to modulate CRC in vivo, even in the presence of chronic inflammation. This study reframes folinic acid from a chemotherapeutic enhancer to an endogenous microbial metabolite that actively suppresses CRC progression.

cancer biology↗

bioRxiv2026

Single-nucleus multiome sequencing identifies candidate regulators of mouse gastric epithelial homeostasis

Background & AimsGastric epithelial cells maintain homeostasis through dynamic self-renewal mechanisms involving stem and progenitor cells; however, identifying them has been challenging. This study aims to identify stem cells of healthy gastric epithelium and cell type-specific regulators defining gastric epithelial homeostasis via single-nucleus multiome analysis. MethodsTen unique gastric samples were collected from 8-12 week old wildtype mice. Isolated nuclei were subjected to simultaneous profiling of gene expression and chromatin accessibility. After quality control, 31,598 cells were analyzed with Seurat and Signac using weighted-nearest neighbors analysis for joint RNA and ATAC clustering. Furthermore, SCENIC+, MultiVelo, EpiCHAOS and Cell plasticity score were used to uncover gene regulatory networks, cell state dynamics and lineage trajectories. ResultsOur analyses were validated by the identification of known regulators of stem-cell differentiation into mature cell types. More importantly, it revealed previously uncharacterized regulatory networks comprising novel transcription factor combinations that define cell identities, including Ppara, Pparg, Arid5b and Sox5 as candidate regulators of parietal, foveolar, chief and neck cells, respectively. Further, our data support the identity of isthmus cells as stem-like cells of healthy gastric epithelium, as evidenced by epigenetic plasticity that simultaneously contains open chromatin states of all differentiated cell types in the absence of transcriptional reprogramming. ConclusionConsistent with Waddingtons epigenetic landscape hypothesis, gastric epithelial homeostasis is controlled by orchestrated epigenetic and transcriptional programs. Contrary to the prevailing hypothesis, stem cells can be defined not by a separate epigenetic state but by epigenetic superposition of differentiated cell states. Future work is needed to define the universality of these results.

genomics↗

bioRxiv2026

A circuit-to-muscle signaling axis controls locomotor gait transitions in C. elegans

Animals switch between locomotor gaits to adapt to changing environments, yet how defined neural circuits and genes coordinate gait transitions remains poorly understood. Here, we show that the head motor neuron SMB acts as a critical gating node that enables the transition from crawling to swimming in Caenorhabditis elegans. SMB ablation disrupts head-body synchronization, prolongs muscle activation, and impairs curvature switching during swimming, indicating that the SMB neurons function to constrain motor output to stabilize swimming-specific oscillations. Through an unbiased forward genetic screen, we identify the NALCN channel complex component UNC-79 and the muscle nicotinic acetylcholine receptor subunit UNC-29 as key molecular determinants of gait transition. UNC-79 functions across multiple head interneuron modules to stabilize circuit-wide excitability required for sustained swimming, whereas UNC-29 acts cell-autonomously in body wall muscles to refine calcium amplitude and propagation dynamics. Genetic epistasis analyses position the SMB neurons upstream of UNC-29-mediated muscle activation, establishing a circuit-to-muscle signaling axis that links defined head motor neurons to downstream molecular effectors. Together, our findings show that gait transition emerges from coordinated modulation of neuronal excitability and muscle calcium dynamics, providing a mechanistic framework for how neural circuits reconfigure motor states to adapt locomotor behavior. HIGHLIGHTSO_LIThe SMB head motor neurons govern the crawl-to-swim transition C_LIO_LIUNC-79/NALCN stabilizes circuit excitability for sustained swimming C_LIO_LIMuscle nAChR subunit UNC-29 tunes calcium gain during gait transition C_LIO_LIA circuit-to-muscle pathway coordinates locomotor state transition C_LI IN BRIEFGait transitions require coordinated changes in neural circuit activity and muscle output. Moon et al. show that the SMB head motor neurons regulate the switch from crawling to swimming in C. elegans by coupling distributed circuit excitability to muscle calcium gain control, defining a circuit-to-muscle pathway that stabilizes locomotor state transitions.

neuroscience↗

bioRxiv2026

Microbial metabolism of methotrexate produces a STAT3 signaling molecule that alleviates gut inflammation

Methotrexate (MTX) therapy in inflammatory bowel disease (IBD) is often limited by inter-individual variability in clinical response and adverse effects. Gut microbiota contribute to MTX therapeutic response and toxicity by metabolizing MTX and altering its bioavailability. However, how inflammation alters microbial MTX metabolism and how its metabolites influence the host remain poorly understood. Here, we identify Clostridium asparagiforme as a potent and efficient metabolizer of methotrexate, producing deoxyaminopteroic acid (DAMPA) in the distal gastrointestinal tract. We demonstrate that DAMPA preserves mitochondrial integrity by promoting mitophagy in intestinal epithelial cells through mitochondrial STAT3 signaling. DAMPA administration attenuates intestinal inflammation in vivo, and improves metabolic dysfunction associated with IBD. Together, these findings reveal an unappreciated role for a gut microbial MTX metabolite in mediating epithelial homeostasis during intestinal inflammation, thus reframing microbial MTX metabolism from passive drug detoxification to active regulation of host mitochondrial and inflammatory homeostasis.

microbiology↗

bioRxiv2026

Snapshots of Internal Protein Crystal Architecture at the Nanoscale

Macromolecular crystallography has historically inferred models of internal crystal architecture from reciprocal-space measurements of Bragg reflections. Nevertheless, direct real-space visualization of crystallographic disorder remains elusive, particularly at the nanoscale. Using a 15-nanometer probe, here we apply both ambient-temperature and cryogenic four-dimensional scanning transmission electron microscopy (4D-STEM) to map the topography of coherently diffracting domains (CDDs) in lysozyme and myoglobin microcrystals at length scales 100x finer than conventional X-ray and electron beams. Virtual dark-field reconstructions from individual Bragg reflections reveal that each peak arises from spatially distinct subvolumes. Subdomain analysis demonstrates that these CDDs behave as orientationally monolithic units analogous to single mosaic blocks. Under sustained irradiation, protein CDDs undergo continuous rearrangements spanning several micrometers of internal movement. Furthermore, pinpoint high-dose "impact crater" experiments reveal delocalized radiolytic damage propagating hundreds of nanometers from primary irradiation sites, behavior similar to small-molecule crystals but amplified in both rate and magnitude. Together, these results establish macromolecular microcrystals as dynamic assemblies whose internal architecture continuously reorganizes during irradiation, laying the foundation for realistic models of mosaicity directly informed by both real-space and reciprocal-space observations.

biophysics↗

bioRxiv2025

10,239 whole genomes with multiomic and clinical health information as the Korean population multiomic reference dataset

We present Korea10K, the largest genomic dataset of the Korean population, comprising 10,239 high-coverage whole genomes (mean depth 30x) with matched multiomic profiles and phenotype data. Korea10K achieves complete and near-complete discovery of very rare and ultra-rare alleles, respectively, at 9,000 Korean genomes. This dataset provides the high-quality population-specific imputation panel, enabling accurate inference of low-frequency variants. Admixture analyses confirm the genetic homogeneity of the Korean population, despite its diverse Y-chromosomal, mitochondrial, and HLA repertoires. This pattern reflects a long and continuous lineage history characterized by persistent internal admixture and genomic homogenization over thousands of years on the Korean peninsula. We also identified 16.8 million genomic variants that directly modify CG sites by creating or abolishing CG dinucleotides, providing the population-scale evidence of coordinated genomic-epigenomic regulatory mechanism in Koreans.

genomics↗

bioRxiv2025

Foxh1 is a locus-specific PRC2 recruiter governing germ layer silencing

Polycomb Repressive Complex 2 (PRC2) establishes H3K27me3 marks to shape spatiotemporal gene expression during embryogenesis. While its dysregulation is linked to developmental disorders, cancer, and aging, the mechanisms guiding PRC2 to specific genomic loci remain a subject of ongoing debate. A prevailing model proposes that PRC2 recruitment occurs via its intrinsic affinity for chromatin rather than through sequence-specific transcription factors. Here, we provide evidence that the maternally deposited pioneer transcription factor Foxh1 plays a critical role in directing PRC2 to specific genomic loci during zygotic genome activation in Xenopus. Foxh1 is a critical transcription factor mediating Nodal signaling, but it also plays an earlier role by pre-binding enhancers prior to signaling activation. This pre-binding is essential for forming enhanceosome complexes that trigger mesendodermal gene expression and drive gastrulation, in cooperation with other maternal transcription factors. Using maternal Foxh1-null embryos, we demonstrate that Foxh1 directly recruits Ezh2, the catalytic subunit of PRC2, to Foxh1-bound loci. Loss of Foxh1 impairs Ezh2 recruitment, leading to a global reduction in H3K27me3. These findings support a dual-function model in which Foxh1 not only activates endodermal gene expression in endoderm, but also recruits PRC2 to silence the same genes in ectoderm. This dual activity of Foxh1 allows the spatially coordinated epigenetic states of the endodermal gene regulatory program during early embryogenesis. HighlightsO_LIFoxh1 recruits Ezh2 to deposit H3K27me3 at specific loci in early embryos C_LIO_LIMaternal Foxh1 loss reduces H3K27me3 and disrupts lineage segregation C_LIO_LIFoxh1 both activates and represses endoderm genes in a context-specific way C_LI

developmental biology↗

bioRxiv2025

Rapid Liquid Chromatography-Mass Spectrometry (rLC-MS) for Deep Metabolomics Analysis of Population Scale Studies

Mass spectrometry (MS)-based metabolomics is a key technology for the interrogation of exogenous and endogenous small molecule mediators that influence human health and disease. To date, however, low throughput of MS systems have largely precluded large-scale metabolomics studies of human populations, limiting power to discover physiological roles of metabolites. Here, we introduce a fully automated rapid liquid chromatography-mass spectrometry (rLC-MS) system coupled to an AI-enabled computational pipeline that enables high-throughput, reproducible, non-targeted metabolite measurements across tens of thousands of samples. This system captures thousands of polar, amphipathic and nonpolar (lipid) metabolites in a human plasma sample in 53 seconds of analytical time, enabling analysis of greater than 1,000 samples per day per instrument. To demonstrate the discovery power of the rLC-MS platform, a subset of samples from Sapients DynamiQ biorepository - comprised of 62,039 total plasma samples collected longitudinally from 11,045 individuals - were selected for deep analysis by rLC-MS to capture a rich, dynamic landscape of chemical variation that reflects both physiological processes and environmental influences. 26,042 plasma samples with matched real-world data (RWD) were chosen for the study, representing 6,935 individuals with diverse demographic backgrounds and disease profiles. Unbiased exploratory analysis revealed human metabotypes that correlate with heterogenous disease phenotypes, including key sub-populations of cardiometabolic and other human diseases. Moreover, a metabolic aging clock machine learning model trained on healthy individuals in this dataset accurately predicted accelerated aging in various chronic diseases, with dynamic reversal of metabolic aging following definitive therapy. These data demonstrate that the rLC-MS platform enables prediction of clinically relevant physiological states from plasma metabolomics at scale in human populations.

biochemistry↗

bioRxiv2025

Impact of exercise intervention on IGF-1 signaling related to muscle regeneration and physical performance in aged mice

Aging encompasses the natural processes of birth, growth, and aging, during which the functional ability of muscles gradually decreases, leading to the loss of muscle size and reduced exercise performance known as sarcopenia. This condition is closely associated with weakness, osteoporosis, and degenerative diseases, increasing the risk of falls, fractures, metabolic diseases, and mortality due to limitations in physical performance among the elderly. This study investigated the effects of exercise intervention on biological markers related to skeletal muscle mass and functions in conjunction with aging. At age of four or twenty, the C57BL/6 mice were assigned to Young control (Y-Con, n = 10) or exercise training (Y--Exe, n = 10), and Aged control (A-Con, n=10) or exercise training (A-Exe, n = 10). Exercise intervention was performed on a rodent motor-driven treadmill with a frequency of 5 days per week for 8 weeks. As a consequence, exercise intervention in mice resulted in positive changes in IGF-1 signaling and muscle phenotype compared to mice that did not undergo exercise intervention, specifically showing prominent effects in the A-Exe group compared to the A-Con group. The mitigating effects of exercise intervention on age-related skeletal muscle dysfunction were accompanied by enhanced exercise performance and muscle function, as assessed by grip strength and the rotarod test. The current findings support previous studies that have reported the positive effect of exercise intervention in alleviating age-related declines in exercise performance and muscle function in older adults.

physiology↗

bioRxiv2025

Growth hormone is required for hippocampal engram cell maturation

Memory is thought to be stored in a sparse population of neurons or synapses 1. These neurons or synapses collectively termed the engram are necessary and sufficient for memory recall 2,3. Learning induces synaptic strengthening in engram cells at both pre- and postsynaptic sites 4,5. However, the critical time window and the molecule related to the induction of such synaptic changes are unknown. Here we show that the initial translation plays a key role in engram maturation by facilitating pre- and postsynaptic strengthening and that growth hormone (GH) is required to induce this process in the Dentate Gyrus. Using anisomycin, a protein synthesis inhibitor, we found that blocking the initial and the subsequent second wave of translation arrests the maturation of engram cells. Revisiting our hippocampal translatome during memory formation 6 proposed GH as a mediator of engram maturation. Overexpression of the dominant negative (G118R) GH blocked the maturation of the hippocampal engram cell 7. Facilitating activity-dependent GH uptake by injecting recombinant human GH (rhGH) into the animal rescued the arrestment caused by anisomycin. Together, our findings propose GH as a key mediator of hippocampal engram cell maturation.

neuroscience↗

bioRxiv2025

Ultra-High Resolution TR-external EPIK with Deep Learning Image Reconstruction for Enhanced Characterisation of Cortical Depth-dependent Neural Activity

The detection of neural signals using functional MRI at the laminar or columnar level enables non-invasive exploration of fundamental brain function processing and the interconnected pathways within intracortical tissues. The growing interest in this research area is driven by advancements in fMRI acquisition techniques that enhance spatial resolution for high-fidelity mapping. However, the submillimetre voxel sizes commonly employed in layer-specific fMRI studies raise concerns about relatively low signal-to-noise ratios and increased image artefacts in reconstructed images, ultimately limiting the precise delineation of cortical depth-dependent functional activities. This work aims to address this issue by incorporating a deep learning technique for enhanced image reconstruction of the submillimetre fMRI data, acquired with echo-planar-imaging with keyhole (EPIK) combined with the repetition-time-external (TR-external) EPI phase correction scheme. Our network was trained in a self-supervised, scan-specific manner using the sampling strategy from zero-shot self-supervised learning (ZS-SSL) method, which has gained attention for high-resolution MR image reconstruction. Healthy volunteers participated in this study, and the performance of the developed method was evaluated in direct comparison to the conventional reconstruction method using datasets acquired at 7T. The deep learning reconstruction produced reconstructed images with significantly higher SNR than the conventional method, which was further quantitatively validated through histogram analysis. This enhancement was consistent across all slice locations, demonstrating the reliability of the scan-specific deep learning technique.

neuroscience↗

bioRxiv2025

Foxi2 and Sox3 are master regulators controlling ectoderm germ layer specification

In vertebrates, germ layer specification represents a critical transition where pluripotent cells acquire lineage-specific identities. We identify the maternal transcription factors Foxi2 and Sox3 to be pivotal master regulators of ectodermal germ layer specification in Xenopus. Ectopic co-expression of Foxi2 and Sox3 in prospective endodermal tissue induces the expression of ectodermal markers while suppressing mesendodermal markers. Transcriptomics analyses reveal that Foxi2 and Sox3 jointly and independently regulate hundreds of ectodermal target genes. During early cleavage stages, Foxi2 and Sox3 pre-bind to key cis-regulatory modules (CRMs), marking sites that later recruit Ep300 and facilitate H3K27ac deposition, thereby shaping the epigenetic landscape of the ectodermal genome. These CRMs are highly enriched within ectoderm-specific super-enhancers (SEs). Our findings highlight the pivotal role of ectodermal SE-associated CRMs in precise and robust ectodermal gene activation, establishing Foxi2 and Sox3 as central architects of ectodermal lineage specification. HighlightsFoxi2 and Sox3 are master regulators for the ectodermal germ layer and sub-lineages Five ectodermal cell states of early gastrulae are regulated by Foxi2 and Sox3 Foxi2 and Sox3 binding sites in the genome are enriched in ectoderm super-enhancers SE-associated genes show high expression levels, low noise, stabilizing ectodermal regulation

developmental biology↗

bioRxiv2024

Refined Myocardium Segmentation from CT Using a Hybrid-Fusion Transformer

1.Accurate segmentation of the left ventricle (LV) in cardiac CT images is crucial for assessing ventricular function and diagnosing cardiovascular diseases. Creating a sufficiently large training set with accurate manual labels of LV can be cumbersome. More efficient semi-automatic segmentation, however, often includes unwanted structures, such as papillary muscles, due to low contrast between the LV wall and surrounding tissues. This study introduces a two-input-channel method within a Hybrid-Fusion Transformer deep-learning framework to produce refined LV labels from a combination of CT images and semi-automatic rough labels, effectively removing papillary muscles. By leveraging the efficiency of semi-automatic LV segmentation, we train an automatic refined segmentation model on a small set of images with both refined manual and rough semi-automatic labels. Evaluated through quantitative cross-validation, our method outperformed models that used only either CT images or rough masks as input.

bioengineering↗

bioRxiv2024

LRRC8 complexes are adenosine nucleotide release channels regulating platelet activation and arterial thrombosis

Platelet shape and volume changes are early mechanical events contributing to platelet activation and thrombosis. Here, we identify single-nucleotide polymorphisms in Leucine-Rich Repeat Containing 8 (LRRC8) protein subunits that form the Volume-Regulated Anion Channel (VRAC) which are independently associated with altered mean platelet volume. LRRC8A is required for functional VRAC in megakaryocytes (MKs) and regulates platelet volume, adhesion, and agonist-stimulated activation, aggregation, ATP secretion and calcium mobilization. MK-specific LRRC8A cKO mice have reduced arteriolar thrombus formation and prolonged arterial thrombosis without affecting bleeding times. Mechanistically, platelet LRRC8A mediates swell-induced ATP/ADP release to amplify agonist-stimulated calcium and PI3K-AKT signaling via P2X1, P2Y1 and P2Y12 receptors. Small-molecule LRRC8 channel inhibitors recapitulate defects observed in LRRC8A-null platelets in vitro and in vivo. These studies identify the mechanoresponsive LRRC8 channel complex as an ATP/ADP release channel in platelets which regulates platelet function and thrombosis, providing a proof-of-concept for a novel anti-thrombotic drug target.

cell biology↗

bioRxiv2024

Distinct Disruptions in CA1 and CA3 Place Cell Function in Alzheimer's Disease Mice

The hippocampus, a critical brain structure for spatial learning and memory, is susceptible to neurodegenerative disorders such as Alzheimers disease (AD). The APPswe/PSEN1dE9 (APP/PS1) transgenic mouse model is widely used to study the pathology of AD. Although previous research has established AD-associated impairments in hippocampal-dependent learning and memory, the neurophysiological mechanisms underlying these cognitive dysfunctions remain less understood. To address this gap, we investigated the activities of place cells in both CA1 and CA3 hippocampal subregions, which have distinct yet complementary computational roles. Behaviorally, APP/PS1 mice demonstrated impaired spatial recognition memory compared to wild-type (WT) mice in the object location test. Physiologically, place cells in APP/PS1 mice showed deterioration in spatial representation compared to WT. Specifically, CA1 place cells exhibited significant reductions in coherence and spatial information, while CA3 place cells displayed a significant reduction in place field size. Both CA1 and CA3 place cells in APP/PS1 mice also showed significant disruptions in their ability to stably encode the same environment. Furthermore, the burst firing properties of these cells were altered to forms correlated with reduced cognition. Additionally, the theta rhythm was significantly attenuated in CA1 place cells of APP/PS1 mice compared to WT. Our results suggest that distinct alteration in the physiological properties of CA1 and CA3 place cells, coupled with disrupted hippocampal theta rhythm in CA1, may collectively contribute to impaired hippocampal-dependent spatial learning and memory in AD.

neuroscience↗

bioRxiv2024

Alzheimer's pathology disrupts flexible place cell coding and hippocampal-prefrontal neural dynamics during risky foraging decisions in mice

This study investigates how amyloid pathology influences hippocampal-prefrontal neural dynamics and decision-making in Alzheimers disease (AD) using 5XFAD mice, a well-established model system characterized by pronounced early amyloid pathology. Utilizing ecologically-relevant "approach food-avoid predator" foraging tasks, we observed that 5XFAD mice exhibited persistent risk-taking behaviors and reduced adaptability to changing threat conditions, indicative of impaired decision-making. Multi-regional neural recordings revealed rigid hippocampal CA1 place-cell fields, decreased sharp-wave ripple (SWR) frequencies, and disrupted medial prefrontal-hippocampal connectivity, all of which corresponded with deficits in behavioral flexibility during spatial risk scenarios. These findings highlight the critical role of SWR dynamics and corticolimbic circuit integrity in adaptive decision-making, with implications for understanding cognitive decline in AD in naturalistic contexts. By identifying specific neural disruptions underlying risky decision-making deficits, this work provides insights into the neural basis of cognitive dysfunction in AD and suggests potential targets for therapeutic intervention.

neuroscience↗