Biology subjects

Shi, W.

Publications and source records attributed to Shi, W..

At least 73 records · Page 4Linked to original sources

bioRxiv2024

Up sampled PSF enables high accuracy 3D super-resolution imaging with sparse sampling rate

Single-molecule localization microscopy (SMLM) provides nanoscale imaging, but pixel integration of acquired SMLM images limited the choice of sample rate which restricts the information content conveyed within each image. We propose an up-sampled point spread function (PSF) inverse modeling method for large-pixel single molecule localization, enabling precise 3D super-resolution imaging with sparse sampling rate. Our approach could reduce data volume or expand the field of view by nearly an order of magnitude, while maintaining high localization accuracy, greatly improving the imaging throughput with limited pixels offered by the existing cameras.

biophysics↗

bioRxiv2024

The Whole Proteome, Phosphoproteome, and Glycoproteome Landscape of Pan-Cancer Cell Lines Profiled by Mass Spectrometry and Reverse Phase Protein Array

Mammalian cancer cell lines are essential model systems in biomedical research. We conducted multi-level proteomics analyses on 54 widely used cancer cell lines derived from various tissue-of-origins using two prominent proteomics technologies: mass spectrometry (MS) and reverse-phase protein array (RPPA). Our analysis identified 10,088 proteins, 33,609 phosphorylation sites across 7,289 phosphoproteins, and 56,350 site-specific glycans on 16,296 glycosylation sites from 5,966 glycoproteins, along with 305 drug-relevant protein and phosphoprotein targets. Our results reveal both consistent and distinct patterns in protein expression and modification between MS and RPPA, underscoring their complementary strengths as discovery tools. Additionally, we identified protein features that distinguish tissue origins across different cell line lineages. This dataset supports model system selection for drug target-related studies in vitro and provides valuable insights into key signaling pathways. Overall, this comprehensive resource enables new opportunities for exploration in cancer biology and offers significant value to research communities focused on biomarker profiling, drug target discovery, and understanding mechanisms across diverse cancer types.

cancer biology↗

bioRxiv2024

pr-independent biogenesis of infectious mature Zika virus particles

Flavivirus assembly at the endoplasmic reticulum is driven by the structural proteins envelope (E) and premembrane (prM). Here, contrary to the established paradigm for flavivirus assembly, we demonstrate that the biogenesis of flavivirus particles does not require an intact prM nor proteolytic activation. The expression of E preceded by a truncated version of prM (M-E) was sufficient for the formation of non-infectious Zika virus subviral particles and pseudo-infectious reporter virions. Subviral particles encoded by a ZIKV M-E DNA vaccine elicited a neutralizing antibody response that was insensitive to the virion maturation state, a feature of flavivirus humoral immunity shown to correlate with protection. M-E vaccines that uniformly present structural features shared with mature virions offer a higher quality and broadly applicable approach to flavivirus vaccination.

microbiology↗

bioRxiv2024

AAB-seq: An antigen-specific and affinity-readable high-throughput BCR sequencing method

B-cell receptor (BCR) sequencing is a powerful antibody discovery tool but current methodology is often inefficient, and lead generation often requires the production and testing of numerous antibody candidates, and it is difficult to provide affinity information for their antibodies at the same time. Here, we introduce AAB-seq (antigen affinity-readable High-throughput BCR sequencing), an efficient antibody screening tool to identify antigen binding affinity of thousands of paired BCRs. It employs fluorophore and DNA barcode-labeled antigen and secondary antibody targeting Ig light chain to label B cells and uses high throughput single cell BCR sequencing and surface protein profiling to obtain the ratio of surface bound antigen to surface BCR in thousands of B-cells. Using AAB-seq, we accurately identified valuable candidate antibodies 1743-3 and 1743-13 from SARS-CoV-2 RBD immunized mouse, providing a basis for further development of SARS-CoV-2 antibody drugs. Thus, AAB-seq allows high throughput identification of antibody sequences paired with antigen affinity, which improves the screening efficiency of functional antibodies and provides an effective solution for the rapid discovery and development of new therapeutic monoclonal antibodies.

immunology↗

bioRxiv2024

Transcriptomic alterations including p53 pathway dysregulation prime DNMT3A mutant cells for transformation

DNMT3A mutations are prevalent in haematologic malignancies. Our mouse model introduced the murine homologue (R878H) of the human hotspot R882H mutation into the mouse Dnmt3a locus, resulting in globally reduced DNA methylation in all tissues. Mice with heterozygous R878H mutations developed {gamma}-radiation induced thymic lymphoma more rapidly than control mice, suggesting a vulnerability to stress stimuli in Dnmt3aR878H/+ cells. In competitive transplantations, Dnmt3aR878H/+ Lin-Sca-1+Kit+ (LSK) cells had a competitive advantage over wt cells, indicating a self-renewal phenotype at the expense of differentiation. RNA-sequencing of Dnmt3aR878H/+ LSKs exposed to low dose {gamma}-radiation showed downregulation of the p53 pathway. Accordingly, reduced PUMA expression was observed by flow cytometry in the bone marrow of {gamma}-irradiated Dnmt3aR878H/+ mice due to altered p53 signalling. These findings provide new insights as to how DNMT3A mutations cause subtle changes in the transcriptome of LSK cells which contribute to their increased self-renewal and propensity for malignant transformation. SIGNIFICANCEHotspot DNMT3A R882H mutations are overrepresented in leukaemia suggesting that they confer a susceptibility to disease if further mutations are acquired. To advance therapies for DNMT3A mutant disease, it is essential to understand the mechanisms by which this mutation primes cells for malignant transformation.

cancer biology↗

bioRxiv2024

PCL-seq: enhanced high-resolution transcriptomic profiling of region of interest in fresh frozen and FFPE tissues

The spatial heterogeneity of gene expression has propelled the development of multiple spatial transcriptomics technologies. Here, we present photocleavage and ligation sequencing (PCL-seq), an method for spatial indexing using a light-controlled DNA labeling strategy on tissue section. PCL-seq uses photocleavable oligonucleotides and ligation adapters to construct transcription profiles of region of interest (ROI), selected by microscopically controlled photo illumination apparatus in tissue sections. Applied to mouse embryos, PCL-seq obtains gene expression matrices that align with spatial locations and competitive data quality, featuring around 1.7x105 UMIs and 8,600 genes (irradiation diameter=100{micro}m). PCL-seq can also apply to formalin fixation and paraffin embedding (FFPE) mouse embryo sections, whereas obtained competitive data output and recovered thousands of differentially enriched transcripts from limb and skeleton. Additionally, PCL-seq can achieve subcellular resolution, which was demonstrated for differential expression between nuclear and cytoplasmic. Thus, PCL-seq provides an accessible workflow for spatial transcriptomic analysis in frozen and FFPE tissue at subcellular resolution.

genomics↗

bioRxiv2024

Proteomics Landscape of Triple-Negative Apocrine Breast Carcinoma Reveals Molecular Mechanisms of Tumorigenesis and Characteristics of Chemo-insensitivity

Triple-negative apocrine carcinoma (TNAC) is an exceptionally rare, chemotherapy-insensitive subtype of triple-negative breast cancer (TNBC) characterized by androgen receptor (AR) positivity and low proliferative activity. Despite poor chemotherapy response, TNAC exhibits favorable long-term survival, suggesting distinct resistance mechanisms. Here, we integrate mass spectrometry-based proteomics and whole-exome sequencing (WES) to characterize TNACs molecular features. We identify progressive overexpression of PI3K/AKT and AR signaling proteins, along with ECM remodeling and upregulation of GTPase-related proteins, highlighting TNACs invasive potential. WES reveals somatic mutations in ECM-related genes (COL18A1) and immune-associated genes (C3, NRDC), implicating the tumor microenvironment. Unlike TNBC, post-chemotherapy TNAC proteomics shows mixed ribosomal regulation and heightened inflammation, rather than reliance on proliferation, suggesting a need for targeted metabolic and immune therapies. Our findings support PI3K/AKT inhibitors and AR antagonists, potentially alongside GTPase inhibitors, metabolic disruptors, and immune therapy, as alternative strategies to standard chemotherapy in TNAC.

cancer biology↗

bioRxiv2024

What scRNA sequencing taught us about MGMT expression in glioblastoma

IntroductionThe promoter methylation status of O-6-methylguanine-DNA methyltransferase (MGMTp) is an established predictive and prognostic marker in GBM. Previous studies showed that the expression of MGMT based on immunohistochemistry was variable and lacked association with survival. This in part is because non-tumor cells including endothelial cells and macrophages express MGMT. Advanced technologies such as single-cell RNA (scRNA) sequencing have helped to elucidate the cellular composition of cancer and its microenvironment. scRNA sequencing allows to assess gene expression level in tumor cells specifically. MethodsWe used publicly available data from two recent GBM scRNA studies that included MGMTp methylation status data for patients to explore and uncover details about MGMT expression at the single-cell level: CPTAC (13 primary samples) and Neftel (20 primary samples). ResultsIn the CPTAC study, MGMT expression ranged from 0.19%-1.43% in the MGMTp methylated group (median 0.82%), and from 2.17%-28.36% in the MGMTp unmethylated group (median 5.7%). It therefore appears that 2% is a reasonable expression cutoff to predict the MGMTp methylation status based on scRNA data. In the Neftel study, MGMT expression ranged from 0-1.26% in the MGMTp methylated group (median 0.59%), and from 0.3-27.67% in the MGMTp unmethylated group (median 12.44%). Three unmethylated samples (out of 16) did not follow the 2% rule. It remains unclear if this is due to technical inaccuracies as the Neftel paper did not specify the method used to detect MGMTp methylation or even mere typos. Alternatively, could it be that truly MGMTp unmethylated samples can have low MGMT expression? Could this explain why some unmethylated MGMTp GBM patients surpass the expected survival? Interestingly, gene set enrichment analysis shows that MGMT expressing cells are enriched with mesenchymal genes, whereas MGMT negative cells are enriched with proneural genes. ConclusionFewer than 2% of GBM cells express MGMT when MGMTp is methylated.

cancer biology↗

bioRxiv2024

The single-cell make-up of adult diffuse glioma based on the 2021 WHO classification

IntroductionSingle-cell RNA sequencing (scRNA-seq) has helped to elucidate the cellular composition of cancer and its microenvironment. Recent scRNA-seq studies have highlighted the heterogeneity of glioblastoma (GBM). Moreover, single-cell GBM analyses have proposed resemblance of GBM cells to radial glia and outer radial glia supporting the hypothesis that remnants of developmental tissue get reactivated in cancer. A recent study isolated neural progenitor cells (NPCs) from developing fetal human brain (gestational week 17-19) and classified NPCs based on their expression of THY1, CD24 and EGFR. Ventricular radial glia are THY1-CD24-EGFR+ whereas outer radial glia are THY1-CD24-EGFR-. Early neuron precursors are CD24+THY1-EGFR+ and glial progenitor cells (GPCs) are THY1+EGFR+. GPCs give rise to THY1+EGFR+PDGFRA+ pre-oligodendrocyte progenitor cells. The importance of EGFR in NPCs again highlights the resemblance to glioma. MethodsWe aimed to apply the classification above in IDH mutant astrocytoma and oligodendroglioma as well as IDHwt glioblastoma samples. We used three publicly available datasets: Wang (paired 74 IDHwt primary and recurrent samples), Tirosh (6 primary oligodendroglioma samples) and Venteicher (10 primary IDH mutant astrocytoma). ResultsIn IDH mutant astrocytoma, 82.63% of cells express THY1+ (mostly EGFR+PDGFRA+) and 10.76% of cells are THY1-CD24-EGFR+. In oligodendroglioma, 75% of cells are THY1+ (mostly EGFR+PDGFRA+) and 12.07% are THY1-CD24-EGFR+. In IDHwt EGFR amplified primary GBM samples, 87.5% of cells are THY1-CD24-EGFR+. This percentage drops to 70.4% in the recurrent setting. THY1-CD24-EGFR-cells increase from 9.7% to 23.1% at recurrence. In IDHwt EGFRwt primary GBM samples, 48.6% of cells are THY1-CD24-EGFR+ and 44.15% are THY1-CD24-EGFR-. In the recurrent setting, 43.26% of cells are THY1-CD24-EGFR+ and 49.58% are THY1-CD24-EGFR-. ConclusionIDH mutant gliomas and IDHwt glioblastoma express different progenitor cell markers. THY1 is highly expressed in IDH mutant gliomas.

cancer biology↗

bioRxiv2024

Charge distribution and helical content tune the binding of septins amphipathic helix domain to lipid membranes

Septins are a class of cytoskeletal proteins that preferentially bind to domains of micron-scale curvature on the cell membrane. Studies have shown that amphipathic helix (AH) domains in septin oligomers are essential for septin curvature sensing. Yet, the underlying mechanochemical interactions that modulate this curvature sensing remain ambiguous. Here we use all-atom molecular dynamics alongside a metadynamics enhanced sampling approach to bridge the gap between time and length scales required to optimize and validate experimental design of amphipathic helices. Simulations revealed that the local charge on the termini of an 18-amino-acid AH peptide impacts its helical content and positioning within lipid membranes. These computational observations are confirmed with experiments measuring the binding of synthetic AH constructs with variable helical content and charged termini to lipid vesicles. Taken together, these results identify the helical content of amphipathic helices as a regulator of septin binding affinity to lipid membranes. Additionally, we examined an extended AH sequence including 8 amino acids upstream and downstream of the minimal 18-amino-acid-long AH domain to more closely mimic the native protein in simulations and experiments. Simulations and experiments show that the extended peptide sequence adopts a strong alpha-helical conformation when free in solution, giving rise to a higher affinity to lipid membranes than that of the shorter AH sequence. Together, these results provide insight into how the native septin proteins interact with membranes, and establish general design principles that can guide the interaction of future synthetic materials with lipid membranes in a programmable manner. STATEMENT OF SIGNIFICANCEUnderstanding how cells sense and react to their shape is necessary for numerous biological processes. Here we explore the interactions between amphipathic helices, a curvature sensing protein motif, and lipid membranes. Using molecular dynamics simulations, enhanced simulation sampling techniques, and experiments, we find that increasing the helical content of the amphipathic helix or adding charged capping sequences yields higher membrane binding affinity. Understanding these parameters for membrane-binding could enable us to interface and regulate native protein functions, as well as guide the design of synthetic curvature-sensing materials that can interact with and deform lipid membranes.

biophysics↗

bioRxiv2024

Alpine lakes harbor diverse, endemic and structurally unique RNA viruses

Alpine lakes, characterized by isolation, low temperatures, oligotrophic conditions, and intense ultraviolet radiation, remain a poorly explored ecosystem for RNA viruses. Here, we present the first comprehensive metatranscriptomic study of RNA viruses in Lake Nam Co, a high-altitude alkaline saline lake on the Tibetan Plateau. Using a combination of sequence- and structure-based homology searches, we identified 742 RNA virus species, including 383 novel genus-level groups and 84 novel family-level groups exclusively found in Lake Nam Co. These findings significantly expand the known diversity of the Orthornavirae, uncovering evolutionary adaptations such as permutated RNA-dependent RNA polymerase (RdRP) motifs and distinct RNA secondary structures. Notably, 14 previously unknown RNA virus families potentially infecting prokaryotes were predicted, broadening the known host range of RNA viruses and questioning the traditional assumption that RNA viruses predominantly target eukaryotes. The presence of auxiliary metabolic genes (AMGs) in viral genomes suggested that RNA viruses (families f.0102 and Nam-Co_family_51) exploit host energy production mechanisms in energy-limited alpine lakes. Low nucleotide diversity, SNP frequencies, and pN/pS ratios indicate strong purifying selection in Nam Co viral populations. Our findings offer insights into RNA virus evolution and ecology, highlighting the importance of extreme environments in uncovering hidden viral diversity, and further shed light into their potential ecological implications, particularly in the context of climate change. Significance StatementThis study unveils the hidden diversity and complexity of RNA viruses in the high-altitude ecosystem of Lake Nam Co, significantly expanding the known RNA virome. The discovery of novel viral clades, expanded potential host ranges, and unique evolutionary adaptations emphasizes the importance of exploring extreme environments to uncover viral diversity and evolutionary pathways. Our findings offer critical insights into viral evolution, host-virus interactions, and the ecological roles of RNA viruses, particularly in the context of climate change and environmental resilience.

microbiology↗

bioRxiv2024

Adhesive interactions within microbial consortia can be differentiated at the single-cell level through expansion microscopy

SignificanceA single-cell understanding of microbe-microbe interactions is critical for unraveling the organization and dynamics of microbial communities. Through an unconventional application of expansion microscopy, we oppose the adhesive force holding microbes together by an expansion force pulling them apart, resulting in microbial separation dependent on the strength of microbial adhesion. Our new approach establishes a proof-of-principle for differentiating adhesive interactions within microbial consortia at the single-cell level. AbstractInvestigating microbe-microbe interactions at the single-cell level is critical to unraveling the ecology and dynamics of microbial communities. In many situations, microbes assemble themselves into densely packed multi-species biofilms. The density and complexity pose acute difficulties for visualizing individual cells and analyzing their interactions. Here, we address this problem through an unconventional application of expansion microscopy, which allows for the decrowding of individual bacterial cells within a multispecies community. Expansion microscopy generally has been carried out under isotropic expansion conditions and used as a resolution-enhancing method. In our variation of expansion microscopy, we carry out expansion under heterotropic conditions; that is, we expand the space between bacterial cells but not the space within individual cells. The separation of individual bacterial cells from each other reflects the competition between the expansion force pulling them apart and the adhesion force holding them together. We employed heterotropic expansion microscopy to study the relative strength of adhesion in model biofilm communities. These included mono and dual-species Streptococcus biofilms, and a three-species synthetic community (Fusobacterium nucleatum, Streptococcus mutans, and Streptococcus sanguinis) under conditions that facilitated interspecies coaggregation. Using adhesion mutants, we investigated the interplay between F. nucleatum outer membrane protein RadD and different Streptococcus species. We also examined the Schaalia-TM7 epibiont association. Quantitative proximity analysis was used to evaluate the separation of individual microbial members. Our study demonstrates that heterotropic expansion microscopy can decrowd dense biofilm communities, improve visualization of individual bacterial members, and enable analysis of microbe-microbe adhesive interactions at the single-cell level.

microbiology↗

bioRxiv2024

CCSer2 gates dynein activity at the cell periphery

Cytoplasmic dynein-1 (dynein) is a microtubule-associated, minus end-directed motor that traffics hundreds of different cargos. Dynein must discriminate between cargos and traffic them at the appropriate time from the correct cellular region. How dyneins trafficking activity is regulated in time or cellular space remains poorly understood. Here, we identify CCSer2 as the first known protein to gate dynein activity in the spatial dimension. CCSer2 promotes the migration of developing zebrafish primordium cells and of cultured human cells by facilitating the trafficking of cargos that are acted on by cortically localized dynein. CCSer2 inhibits the interaction between dynein and its regulator Ndel1 exclusively at the cell periphery, resulting in localized dynein activation. Our findings suggest that the spatial specificity of dynein is achieved by the localization of proteins that disinhibit Ndel1. We propose that CCSer2 defines a broader class of proteins that activate dynein in distinct microenvironments via Ndel1 inhibition.

cell biology↗

bioRxiv2024

Viral diversiy within marine biofilms and their potential roles in microbially influenced corrosion

In marine environments, a wide variety of microbes exert an important influence on the corrosion of materials. Viruses are widely distributed in biofilms formed on materials and may influence the corrosion process through interactions with key corrosive microbes. However, our understanding of the viral communities within biofilms and their implications for corrosion remains notably limited. To fill this knowledge gap, we utilized 53 publicly metagenomes to investigate the ecological dynamics of viruses within biofilms on 8 different materials and their potential roles in the corrosion of materials. In biofilms, the type of materials may be the primary factor driving differences in the diversity of viral communities. Viruses within biofilms predominantly belong to Caudoviricetes, and phylogenetic analysis of Caudoviricetes and protein-sharing networks with other environments revealed the presence of numerous novel viral clades in biofilms. The presence of virus-host linkages revealed a close association between viruses and corrosive microbes in biofilms. Viruses play a key role in corrosion by modulating host corrosion-related metabolism. It was observed that viruses could enhance host resistance to metals and antibiotics via horizontal gene transfer. Furthermore, viruses can protect themselves from host antiviral systems through anti-defense systems. Overall, this work illustrates the diversity of viruses within biofilms formed on materials and the intricate interactions between viruses and corrosive microbes, revealing the potential roles of viruses in microbially influenced corrosion.

microbiology↗

bioRxiv2024

Transcription network of SLC7A11 (xCT) in colon cancer provides clinical targets for metabolic regulation and cell proliferation

Colorectal cancer (CRC) represents the third leading cause of cancer-related deaths. Knowledge covering diverse cellular and molecular data from individual patients has become valuable for diagnosis, prognosis, and treatment selection. Here, we present in-depth comparative RNA-seq analysis of 32 CRC patients pairing tumor and healthy tissues (total of 73 samples). Strict thresholds for differential expression genes (DEG) analysis revealed an interconnection between nutrients, metabolic program, and cell cycle pathways. Among the upregulated DEGs, we focused on the Xc- system, composed of the proteins from SLC7A11 (xCT) and SLC3A2 genes, along with several interacting genes. To assess the oncogenic potency of the Xc- system in a cellular setting, we applied a knowledge-based approach, analyzing gene perturbations from CRISPR screens. The study focused on a set of 27 co-dependent genes that were strongly correlated with the fitness of SLC7A11 and SLC3A2 across many cell types. Alterations in these genes in 13 large-scale studies (e.g., by mutations and copy number variation) were found to enhance overall survival and progression-free survival in CRC patients. In agreement, the overexpression of these genes in cancer cells drives cancer progression by allowing effective management of the redox level, induction of stress response mechanisms, and most notably, enhanced activity of ion/amino acid transporters, and enzymes acting in de novo nucleotide synthesis. We also highlight the positive correlation between the Xc- system gene expression level, patient responsiveness to different chemotherapy treatments, and immune cell infiltration (e.g., myeloid-derived suppressor cells) in CRC tumors as a measure for their immunosuppressive activity. This study illustrates that knowledge-based interpretation by synthesizing multiple layers of data leads to functional and mechanistic insights into the role of SLC7A11 and its associated genes in CRC tumorigenesis and therapeutics.

cancer biology↗

bioRxiv2024

Advancing the genetic engineering toolbox by combining AsCas12a knock-in mice with ultra-compact screening

Cas12a is a gene-editing tool that simplifies multiplexed gene targeting through its RNase activity, enabling maturation of individual crRNAs from a pre-crRNA-encoding RNA. Here, we present a mouse model that constitutively expresses enhanced Acidaminococcus sp. Cas12a (enAsCas12a) linked to an mCherry fluorescent reporter. We demonstrate efficient single and multiplexed gene-editing in cells from enAsCas12aKI mice. To test in vivo activity, we transduced haematopoietic stem cells from E-MycT/+;enAsCas12aKI/+animals with Trp53-targeting pre-crRNAs followed by transplantation into irradiated recipient animals. Tumour development was accelerated and TRP53 protein lost. We generated compact, genome-wide Cas12a knockout libraries targeting each gene with four guide RNAs encoded on two (Menuetto) or one (Scherzo) vector. Introducing these libraries into E-MycT/+;enAsCas12aKI/+lymphoma cells followed by treatment with an MCL-1 inhibitor (S63845) or TRP53-inducer (nutlin-3a) identified known and novel drug resistance genes. Finally, we demonstrate simultaneous gene knockouts (Trp53 or combined Bax/Bak) and activation (Cd19) in primary T cells and mouse dermal fibroblasts from crosses of our enAsCas12a and CRISPR activation models (dCas9a-SAM). Our enAsCas12a mouse model and accompanying libraries enhance genome engineering capabilities and complements current CRISPR technologies.

molecular biology↗

bioRxiv2024

The Prefrontal Cortex to the Hippocampus Glutamatergic Pathway Regulates Reward Effects of Methamphetamine

Methamphetamine (METH) induces reward effects. The prefrontal cortex (PFC) plays a role in regulating top-down. The hippocampus is closely involved reward memory. However, the direct projects from the PFC to the hippocampus have not been studied well. Here, we use conditioned place preference (CPP), a recombinant adeno-associated virus 2/9 (rAAV2/9) and optogenetic approaches to explore a role in METH-CPP for a novel pathway projecting from the medial prefrontal prelimbic cortex (PrL) directly to the dorsal hippocampus CA1 (dCA1). Expressing CaMKII-ChR2 or CaMKII-eNpHR3.0 in the PrL and optically stimulating in the dCA1 blocks or enhances METH-CPP, respectively. Moreover, silencing the PrL to dCA1 glutamatergic pathway with tetanus neurotoxin (TeNT) enhances METH-CPP. These results identify a novel PrL-to-dCA1 glutamatergic pathway regulating METH-CPP.

neuroscience↗

bioRxiv2024

Impaired sleep-dependent memory consolidation predicted by reduced sleep spindles in Rolandic epilepsy

Background and ObjectivesSleep spindles are prominent thalamocortical brain oscillations during sleep that have been mechanistically linked to sleep-dependent memory consolidation in animal models and healthy controls. Sleep spindles are decreased in Rolandic epilepsy and related sleep-activated epileptic encephalopathies. We investigate the relationship between sleep spindle deficits and deficient sleep dependent memory consolidation in children with Rolandic epilepsy. MethodsIn this prospective case-control study, children were trained and tested on a validated probe of memory consolidation, the motor sequence task (MST). Sleep spindles were measured from high-density EEG during a 90-minute nap opportunity between MST training and testing using a validated automated detector. ResultsTwenty-three children with Rolandic epilepsy (14 with resolved disease), and 19 age- and sex-matched controls were enrolled. Children with active Rolandic epilepsy had decreased memory consolidation compared to control children (p=0.001, mean percentage reduction: 25.7%, 95% CI [10.3, 41.2]%) and compared to children with resolved Rolandic epilepsy (p=0.007, mean percentage reduction: 21.9%, 95% CI [6.2, 37.6]%). Children with active Rolandic epilepsy had decreased sleep spindle rates in the centrotemporal region compared to controls (p=0.008, mean decrease 2.5 spindles/min, 95% CI [0.7, 4.4] spindles/min). Spindle rate positively predicted sleep-dependent memory consolidation (p=0.004, mean MST improvement of 3.9%, 95% CI [1.3, 6.4]%, for each unit increase in spindles per minute). DiscussionChildren with Rolandic epilepsy have a sleep spindle deficit during the active period of disease which predicts deficits in sleep dependent memory consolidation. This finding provides a mechanism and noninvasive biomarker to aid diagnosis and therapeutic discovery for cognitive dysfunction in Rolandic epilepsy and related sleep activated epilepsy syndromes.

neuroscience↗