Biology subjects

Moore, T.

Publications and source records attributed to Moore, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Potency of nucleoside analogs against Powassan virus replication and identification of 4'-fluorouridine as a therapeutic candidate for tick-borne orthoflavivirus encephalitis

Powassan virus (POWV) is an emerging tick-borne orthoflavivirus that causes severe encephalitis, long-term neurologic sequelae, and death, yet no approved antiviral therapies exist. Here, we evaluated several previously characterized nucleoside analogs as candidate countermeasures for POWV encephalitis. Favipiravir, molnupiravir, 4'-fluorouridine (4'-FlU), and GS-441524 inhibited POWV replication in vitro and demonstrated comparable activity against West Nile virus (WNV). We established C3H/HeNCrl mice as a stringent POWV disease model, showing increased susceptibility, higher day 7 brain titers, and more pronounced neurologic signs resembling severe human disease, compared with C57BL/6 mice. In prophylactic and therapeutic studies, 4'-fluorouridine was the most efficacious compound tested, significantly reducing brain viral burden even when treatment was delayed. Direct comparison with molnupiravir, favipiravir, and GS-441524 in mice confirmed superior survival benefit and antiviral activity for 4'-FlU against both POWV and WNV. These data identify 4'-fluorouridine as a promising therapeutic candidate for neurotropic flavivirus disease.

microbiology↗

bioRxiv2026

Extracellular vesicles derived from cells overexpressing HGSNAT rescue defects in Mucopolysaccharidosis IIIC neurons

Mucopolysaccharidosis III type C (MPS IIIC) is a rare neurological lysosomal storage disorder caused by genetic deficiency of the lysosomal membrane enzyme, heparan--glucosaminide N-acetyltransferase (HGSNAT). To assess the feasibility of therapeutic strategies based on cross-correction of neurons by HGSNAT secreted from transplanted cells overexpressing the enzyme, we generated induced cortical neurons (iCN) from induced pluripotent stem cells (iPSCs) derived from MPS IIIC patients. The neurons were treated with extracellular vesicles (EV) purified from the culture medium conditioned by human endothelial cells transduced with a lentiviral vector encoding EGFP-tagged HGSNAT (LV-HGSNAT-EGFP). The isolated EV showed supraphysiologic HGSNAT activity levels and efficiently delivered the enzyme to the lysosomes of MPS IIIC iCN reducing lysosomal size and restoring normal synaptic protein levels. EV-mediated delivery of HGSNAT to neurons was further confirmed by the analysis of MPS IIIC iCN either co-cultured with iPSC-derived MPS IIIC microglia (iMGL) transduced with LV-HGSNAT-EGFP or treated with the iMGL conditioned medium. MPS IIIC iCN co-cultured with iMGL overexpressing HGSNAT achieved a complete phenotypic rescue, including normalization of lysosomal size, and the levels of heparan sulfate, GM2-ganglioside, synaptic proteins and brain-derived neurotropic factor. Treatment of MPS IIIC iCNs with conditioned medium led to a partial defects correction. Our findings reveal the translational potential of EV-mediated enzyme delivery in MPS IIIC patients treated with LV-mediated haematopoietic progenitor stem cell gene therapy.

biochemistry↗

bioRxiv2026

A modular neural circuit for computing the motion of objects

Computing the direction of a moving object requires integrating motion signals from its component edges into coherent patterns. The representation of pattern motion in visual cortex has been extensively studied, yet its underlying neural circuitry remains unknown. Using high-density recordings in macaque area MT, we show that selectivity to pattern motion emerges from a functionally and anatomically distinct cortical circuit. We demonstrate that neurons specialized for encoding component and pattern motion comprise distinct cell types arranged in a hierarchical circuit in which pattern neurons integrate inputs from a range of component neurons. Furthermore, we show that component and pattern neurons are spatially segregated into modules arranged systematically across cortical columns encoding direction of motion. This architecture and circuit align with a classic solution to the problem of computing the motion of objects.

neuroscience↗

bioRxiv2026

Condition-Dependent Noise Correlations without Condition-Dependent Spike Counts

The ability of the brain to encode information and control behavior depends on the coordinated activity of large and distributed neuronal populations. Correlations in neuronal spiking activity across trials of the same condition, or noise correlations (NCs), have been interpreted as a reflection of shared synaptic connectivity and as a contributing factor to the information capacity of neuronal populations. The impact of NCs on coding is most often considered in populations of neurons exhibiting robust condition-dependent information in their spike counts (SCs). However, theoretical work suggests that NCs could provide a source of condition-dependent information separate from SCs. We examined the activity of large neuronal populations in prefrontal cortex of macaques while they performed a spatial delayed response task composed of visual, memory, and motor epochs. We found that pairs of neurons that displayed visual, memory, and motor selectivity in their SCs often exhibited selectivity in their NCs, independent of spike count. However, we also found that pairs of neurons without SC selectivity during the different task epochs nonetheless exhibited condition-dependent NCs. Moreover, we found that the prevalence of condition-dependent NCs were largely comparable across neuronal pairs with or without SC selectivity. These results demonstrate that correlated variability in spiking activity can be condition-dependent even in the absence of condition-dependent SCs.

neuroscience↗

bioRxiv2026

The 3D Ultrastructure of C. elegans Gut Granules

We identify an endoderm-restricted organelle in published volume electron microscopy datasets of C. elegans embryos. The organelle consists of a tubular ring surrounding a membrane-bound compartment harboring a prominent dense particle and exhibits a basal polarity and size concordant with canonical gut granules. This finding offers ultrastructural detail to recent evidence that gut granules are bi-lobed organelles with two distinct compartments.

cell biology↗

bioRxiv2026

Synthetic analogue of adrenocorticotropic hormone, ACTH(4-7)PGP delays neurological manifestations in diseases of mucopolysaccharidosis III spectrum by reducing neuroinflammation and rescuing neurotransmission, synaptogenesis, and axonal demyelination

Mucopolysaccharidosis III (MPS III or Sanfilippo disease) is a spectrum of 4 genetic disorders (MPS IIIA-D), caused by defects in the genes SGSH, NAGLU, HGSNAT and GNS encoding enzymes involved in degradation of heparan sulfate (HS). HS accumulates in brain tissues and causes neuronal dysfunction and neurodegeneration leading to neuropsychiatric problems, developmental delays, childhood dementia, blindness and death during the second decade of life. Previously, we demonstrated that pathophysiological mechanisms, underlying MPS IIIC in mouse models, involves functional pathological changes, affecting synaptogenesis and synaptic transmission and leading to learning and memory deficits. These results suggested that a treatment for MPS III could be developed by using compounds inducing synaptogenesis. In the current study, we tested the efficacy of a synthetic peptide ACTH(4-7)PGP, an analog of adrenocorticotropic hormone fragment, previously used as a neuroprotective and anti-inflammatory medication for treatment of acute neurological conditions, including stroke. We show that intranasal administration of ACTH(4-7)PGP restores defective synaptic transmission in CA1 pyramidal neurons of MPS IIIA and MPS IIIC mouse models and rescues the decrease in synaptic proteins in cultured MPS IIIC mouse hippocampal neurons and iPSC-derived neurons of human MPS IIIA, MPS IIIB and MPS IIIC patients. Furthermore, daily intranasal administration of ACTH(4-7)PGP to MPS IIIC and MPS IIIA mice reduces hyperactivity and rescues defects in working and spatial memory, delays progression of CNS pathology including neuroinflammation and axonal demyelination, and increases the lifespan. Together with the absence of any adverse reactions to ACTH(4-7)PGP in the MPS III and WT mice, our results justify testing the drugs efficacy in clinical settings.

genetics↗

bioRxiv2026

A System for Live Sorting of Neuronal Spiking Activity from Large-scale Recordings

Online monitoring of neuronal activity has tremendous value for closed-loop control in both experimental and clinical settings, yet established methods rely primarily on thresholded neural activity, rather than sorted single-neuron spikes. The recent introduction of large-scale electrophysiological tools has greatly expanded single-neuron recording capacity in animals and humans highlighting the need to sort spikes during data collection. Here, we describe a system for live spike sorting (LSS) populations of hundreds of neurons with millisecond-scale latency. Using neurophysiological recordings from macaque visual cortex with Neuropixels probes, we show that LSS closely replicates the temporal responses and tuning of single neurons obtained using offline sorting. We further show that decoding neural signals with LSS achieves the same performance as that obtained from offline sorting. Lastly, we demonstrate the capacity of LSS to enable closed-loop interventions based on the activity of specific neuronal subclasses.

neuroscience↗

bioRxiv2025

Ensemble Coding of Hidden Objects in Visual Cortex

Many species exhibit the understanding that visual objects that become hidden by others nonetheless still exist, a property known as object permanence. Previous studies in human and nonhuman primates have provided evidence that neurons within visual cortex encode objects that are remembered but not seen. However, past neurophysiological studies have generally failed to find evidence of visual cortical representations of hidden objects. We measured the activity of large populations of neurons within dorsal extrastriate cortex of macaques trained to monitor the identity of visual objects that moved behind an irrelevant occluder. We found that although the firing rates of neuronal populations signaled the trajectory of hidden objects throughout the occlusion period, coding of object identity in the same activity decayed to chance before the behavioral trial ended. Nevertheless, information about the hidden object was present in the coordinated activity of neuronal populations. Specifically, the strength and presence of pairwise cross-correlations reliably depended on the identity of the hidden object. These results demonstrate that ensembles of visual cortical neurons preserve information about hidden objects independent of single neuron firing rates.

neuroscience↗

bioRxiv2025

Identification and Characterization of Novel Chikungunya Virus Polymerase Inhibitors

Chikungunya virus (CHIKV) and other alphaviruses in the Togaviridae family are positive-sense RNA viruses and major human pathogens, causing millions of infections worldwide. In humans, alphaviruses such as CHIKV, Mayaro and Ross River viruses typically cause arthritogenic disease characterized by debilitating arthralgia, joint inflammation, fever, and rash. Although a vaccine was recently approved for use against CHIKV, no vaccines are licensed against other alphaviruses. No antiviral treatments are available to prevent or treat infections by any alphavirus. To address this unmet need, we used a CHIKV nanoluciferase reporter virus to develop a high-throughput screening assay for novel small-molecule inhibitors. From this campaign, we identified several unique inhibitors of CHIKV replication. Mechanistic characterization of two inhibitors revealed that both target the nsP4 RNA-dependent RNA polymerase, while susceptibility profiling pinpointed unique nsP4 mutations that specifically confer resistance. In silico docking analyses indicated potential binding poses of the inhibitors near the polymerase active site. Collectively, these results define multiple chemotypes for further development and highlight novel molecular targets within nsP4 for CHIKV inhibition. IMPORTANCEChikungunya virus is a mosquito-borne pathogen that has caused millions of human infections worldwide, producing severe fever, rash, and long-lasting joint pain that can persist for months. Related viruses such as Mayaro and Ross River viruses also cause debilitating disease, yet no antiviral drugs are available to treat any infection caused by this family of viruses. In this study, we developed a high-throughput assay that allowed us to rapidly identify compounds capable of blocking chikungunya virus replication. We discovered new hit compounds that inhibit virus growth. In addition, we determined that two of the most promising hit candidates target the viral nsP4 polymerase. By identifying these novel inhibitors and characterizing both their mechanisms of action and resistance profiles, we have established the groundwork for future efforts to develop much needed therapies against chikungunya virus and related pathogens.

molecular biology↗

bioRxiv2025

Impact of Mutations Affecting 4'-Fluorouridine Susceptibility on Fitness and Treatment Outcomes for Venezuelan Equine Encephalitis Virus

Venezuelan equine encephalitis virus (VEEV) is a prototypical encephalitic alphavirus. Members of the Alphavirus genus are found across the globe, transmitted by arthropod vectors, and cause significant disease burdens in humans and animals. There are currently no FDA-approved antivirals against any member of the Alphavirus genus. While a vaccine exists against chikungunya virus (CHIKV), a member of the arthitogenic alphaviruses, FDA-approved vaccines are not available for other members of this genus, particularly the encephalitic alphaviruses such as VEEV, Eastern equine encephalitis virus (EEEV) and Western equine encephalitis virus (WEEV). 4-Fluorouridine (4-FlU, EIDD-2749) was recently identified as a broad-spectrum antiviral against multiple RNA viruses, including alphaviruses. 4-FlU can potently inhibit VEEV-TC83 replication, with submicromolar potency in cell culture. However, the emergence of antiviral resistance represents a hurdle for antiviral drug development and the implementation of effective treatment strategies. Here, we have identified novel mutations in the VEEV nsP4 RNA-dependent RNA polymerase that reduce susceptibility to 4-FlU, including P187A, Q191L, L289F, and T296I. We rebuilt each mutation in recombinant VEEV-TC83 and characterized the effects of these mutations on fitness and pathogenicity. In addition, we assessed the impact of mutations reducing sensitivity to 4-FlU in a mouse model. Although mutations against 4-FlU arise quickly in vitro, treatment can still alleviate severe disease and lethal encephalitis. Together, these data highlight the promising therapeutic potential of 4-FlU for the treatment of alphavirus encephalitis. ImportanceVEEV is one of several mosquito-spread viruses that can cause serious brain infections in people and animals. Unlike CHIKV, against which an approved vaccine exists, there are no countermeasures to prevent or treat VEEV infections or block its close relatives, EEEV and WEEV. 4-FlU inhibits many different RNA viruses, including VEEV, and is currently being developed to treat multiple viral infections. A major problem with small-molecule antivirals is the appearance of virus populations that are less susceptible to treatment. In this study, we identified mutations in VEEVs RNA-dependent RNA polymerase (nsP4) that confer reduced susceptibility to 4-FlU. We then engineered these mutations into full-length infectious clones and assessed if viruses encoding for these mutations were still pathogenic. In addition, we treated infected mice with 4-FlU and measured how well the compound inhibited virus replication and prevented severe disease, even when mice were infected with viruses harboring mutations that reduced susceptibility to 4-FlU. Although VEEV can develop moderate resistance to 4-FlU in vitro, administration of 4-FlU still reduced severe disease and prevented lethality in the animals infected with viruses that possess mutations that decrease susceptibility to 4-FlU. These results suggest that 4-FlU has strong potential as a future treatment for alphavirus infections like VEEV encephalitis.

microbiology↗

bioRxiv2025

High-resolution laminar recordings reveal structure-function relationships in monkey V1

The relationship between structural properties of diverse neuronal populations in monkey primary visual cortex (V1) and their in vivo functional responses is not fully understood. We combined high-density Neuropixels recordings across cortical layers of macaque V1 with non-linear dimensionality reduction on waveform shape to delineate nine putative cell classes: 4 narrow-spiking (NS), 4 broad-spiking (BS) and 1 tri-phasic (TP). Using targeted analyses of laminar organization, spike amplitude, multichannel waveforms, functional properties, and network connectivity of these cell classes, we demonstrate four aspects of the V1 microcircuit predicted by anatomical studies but never fully demonstrated in vivo. First, NS neurons were concentrated in layer 4. Second, a large-amplitude NS cell class in layer 4B showed strong direction selectivity. Third, another layer 4B NS class exhibited robust bursting and orientation selectivity. Finally, cross-correlation analysis revealed functional interactions between cells in different layers. Our results highlight how high-resolution electrophysiology can reveal novel relationships between in vivo function of neurons and the underlying circuit. TeaserHigh-resolution electrophysiology used with machine learning reveals links between function and the underlying neural circuitry.

neuroscience↗

bioRxiv2024

U1 snRNP-Specific U1C Acts as the Gatekeeper of the Survival of Motor Neurons (SMN) Complex in snRNP Biogenesis

The stability and abundance of spliceosomal snRNPs are determined by the assembly of an Sm protein ring (Sm core) on each snRNA, a process facilitated by the survival of motor neuron (SMN) complex. Whereas the SMN complexs role as a chaperone is well-established, the mechanisms that regulate its activity remain unclear. Our study identifies U1C, a U1 snRNP-specific protein, as a key regulator of the SMN complex. U1C together with U1-70K facilitates U1 snRNP formation, rendering the SMN complex accessible for other snRNAs to assemble Sm cores. Remarkably, a prevalent cancer-associated mutation in U1 snRNA near the U1C binding site not only disrupts Sm core assembly but also sequesters the SMN complex, inhibiting canonical snRNP formation. Our findings provide mechanistic insights into how snRNP-specific proteins regulate the SMN complex and suggest that U1 snRNA mutations in numerous cancers disrupt the SMN complex, leading to perturbation in various RNA metabolism pathways. HighlightsO_LIU1C facilitates the formation of Sm core not only on U1 snRNA but also on other snRNAs. C_LIO_LIU1C together with U1-70K promotes U1 snRNP formation, enabling the SMN complex to recruit Gemin5/other snRNAs complex. C_LIO_LIThe divalent binding of U1C to the SMN complex is mediated by U1Cs N-terminus helix, interacting with U1-70K, and its arginine-methylated C-terminus domain, binding to the SMN protein. C_LIO_LIMultiple U1 snRNA mutations in cancer patients defect in Sm core assembly and potentially sequester the SMN complex, thereby inhibiting canonical snRNP formation. C_LI

biochemistry↗

bioRxiv2024

Neural mechanisms underlying robust target selection in response to microstimulation of the oculomotor system

Despite its prevalence in studying the causal roles of different brain circuits in cognitive processes, electrical microstimulation often results in inconsistent behavioral effects. These inconsistencies are assumed to be due to multiple mechanisms, including habituation, compensation by other brain circuits, and contralateral suppression. Considering the presence of reinforcement in most experimental paradigms, we hypothesized that interactions between reward feedback and microstimulation could contribute to inconsistencies in behavioral effects of microstimulation. To test this, we analyzed data from electrical microstimulation of the frontal eye field of male macaques during a value-based decision-making task and constructed network models to capture choice behavior. We found evidence for microstimulation-dependent adaptation in saccadic choice, such that in stimulated trials, monkeys choices were biased toward the target in the response field of the microstimulated site (Tin). In contrast, monkeys showed a bias away from Tin in non-stimulated trials following microstimulation. Critically, this bias slowly decreased as a function of the time since the last stimulation. Moreover, microstimulation-dependent adaptation was influenced by reward outcomes in preceding trials. Despite these local effects, we found no evidence for the global effects of microstimulation on learning and sensitivity to the reward schedule. By simulating choice behavior across various network models, we found a model in which microstimulation and reward-value signals interact competitively through reward-dependent plasticity can best account for our observations. Our findings indicate a reward-dependent compensatory mechanism that enhances robustness to perturbations within the oculomotor system and could explain the inconsistent outcomes observed in previous microstimulation studies.

neuroscience↗

bioRxiv2024

Posterior Parietal Cortex Regulates Intrinsic Neural Timescales and Attentional Processing in Frontal Eye Field

Intrinsic neural timescales quantify how long spontaneous neuronal activity patterns persist, reflecting dynamics of endogenous fluctuations. We measured intrinsic timescales of frontal eye field (FEF) neurons and examined their changes during posterior parietal cortex (PPC) inactivation. We observed two distinct classes of FEF neurons based on their intrinsic timescales: short-timescale neurons ([~]25 ms) or long-timescale neurons ([~]100 ms). Short-timescale neurons showed stronger transient visual responses, suggesting their role in rapid visual processing, whereas long-timescale neurons exhibited pronounced sustained attentional modulation, suggesting their role in maintaining stimulus-driven attention. During PPC inactivation, intrinsic timescales increased in both neuron types, with a significantly larger effect in short-timescale neurons. In addition, PPC inactivation reduced attentional modulation, particularly in long-timescale neurons. Our findings provide the first causal evidence linking intrinsic local neural timescales to long-range inter-area communications. These findings also suggest the presence of at least two distinct network motifs that support different neuronal dynamics and functional computations within the FEF.

neuroscience↗

bioRxiv2024

Antigen-specificity of clonally-enriched CD8+ T cells in multiple sclerosis

CD8+ T cells are the dominant lymphocyte population in multiple sclerosis (MS) lesions where they are highly clonally expanded. The clonal identity, function, and antigen specificity of CD8+ T cells in MS are not well understood. Here we report a comprehensive single-cell RNA-seq and T cell receptor (TCR)-seq analysis of the cerebrospinal fluid (CSF) and blood from a cohort of treatment-naive MS patients and control participants. A small subset of highly expanded and activated CD8+ T cells were enriched in the CSF in MS that displayed high activation, cytotoxicity and tissue-homing transcriptional profiles. Using a combination of unbiased and targeted antigen discovery approaches, MS-derived CD8+ T cell clonotypes recognizing Epstein-Barr virus (EBV) antigens and multiple novel mimotopes were identified. These findings shed vital insight into the role of CD8+ T cells in MS and pave the way towards disease biomarkers and therapeutic targets. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/611010v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1a0b738org.highwire.dtl.DTLVardef@5cf5c2org.highwire.dtl.DTLVardef@10abdccorg.highwire.dtl.DTLVardef@32c7b2_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical SummaryC_FLOATNO Created in BioRender. Sabatino, J. (2024) BioRender.com/e66l598 C_FIG

immunology↗

bioRxiv2024

Tree diversity increases carbon stocks and fluxes above- but not belowground in a tropical forest experiment

International commitments advocate large-scale forest restoration as a nature-based solution to climate change mitigation through carbon (C) sequestration. Mounting evidence suggests that mixed compared to monospecific planted forests may sequester more C, exhibit lower susceptibility to climate extremes and offer a broader range of ecosystem services. However, experimental studies comprehensively examining the control of tree diversity on multiple C stocks and fluxes above- and belowground are lacking. To address this gap, we leverage data from the Sardinilla experiment in Panama, the oldest tropical tree diversity experiment which features a gradient of one-, two-, three- and five-species mixtures of native tree species. Over 16 years, we measured multiple above- and belowground C stocks and fluxes, ranging from tree aboveground C, over leaf litter C production, to soil organic carbon (SOC). We show that tree diversity significantly increased aboveground C stocks and fluxes, with a 57% higher gain in aboveground tree C in five-species mixtures compared to monocultures (35.7{+/-}1.8 vs 22.8{+/-}3.4 Mg C ha-1) 16 years after planting. In contrast, we observed a net reduction in SOC (on average -11.2{+/-}1.1 Mg C ha-1) and no significant difference in SOC3 stocks (the predominantly tree-derived, i.e., C3 plant-derived SOC fraction) between five-species mixtures and monocultures (13.0{+/-}0.9 vs 15.1{+/-}1.3 Mg C ha-1). Positive tree diversity effects persisted despite repeated climate extremes and strengthened over time for aboveground tree growth. Structural equation models showed that higher tree growth in mixtures enhanced leaf litter and coarse woody debris C fluxes to the soil, resulting in a tightly linked C cycle aboveground. However, we did not observe significant links between above- and belowground C stocks and fluxes. Our study elucidates the mechanisms through which higher tree diversity bolsters the climate mitigation potential of tropical forest restoration. Restoration schemes should prioritize mixed over monospecific planted forests.

ecology↗

bioRxiv2024

Secondary deficiency of neuraminidase 1 contributes to CNS pathology in neurological mucopolysaccharidoses via hypersialylation of brain glycoproteins

Mucopolysaccharidoses (MPS) are lysosomal storage diseases caused by defects in catabolism of glycosaminoglycans. MPS I, II, III and VII are associated with lysosomal accumulation of heparan sulphate and manifest with neurological deterioration. Most of these neurological MPS currently lack effective treatments. Here, we report that, compared to controls, neuraminidase 1 (NEU1) activity is drastically reduced in brain tissues of neurological MPS patients and in mouse models of MPS I, II, IIIA, IIIB and IIIC, but not of other neurological lysosomal disorders not presenting with heparan sulphate storage. We further show that accumulated heparan sulphate disrupts the lysosomal multienzyme complex of NEU1 with cathepsin A (CTSA), {beta}-galactosidase (GLB1) and glucosamine-6-sulfate sulfatase (GALNS) necessary to maintain enzyme activity, and that NEU1 deficiency is linked to partial deficiencies of GLB1 and GALNS in cortical tissues and iPSC-derived cortical neurons of neurological MPS patients. Increased sialylation of N-linked glycans in brain samples of human MPS III patients and MPS IIIC mice implicated insufficient processing of brain N-linked sialylated glycans, except for polysialic acid, which was reduced in the brains of MPS IIIC mice. Correction of NEU1 activity in MPS IIIC mice by lentiviral gene transfer ameliorated previously identified hallmarks of the disease, including memory impairment, behavioural traits, and reduced levels of the excitatory synapse markers VGLUT1 and PSD95. Overexpression of NEU1 also restored levels of VGLUT1-/PSD95-positive puncta in cortical neurons derived from iPSC of an MPS IIIA patient. Together, our data demonstrate that heparan sulphate-induced secondary NEU1 deficiency and aberrant sialylation of glycoproteins implicated in synaptogenesis, memory, and behaviour constitute a novel pathological pathway in neurological MPS spectrum crucially contributing to CNS pathology. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=89 SRC="FIGDIR/small/587986v1_ufig1.gif" ALT="Figure 1"> View larger version (21K): org.highwire.dtl.DTLVardef@3905c3org.highwire.dtl.DTLVardef@1a9672corg.highwire.dtl.DTLVardef@b4911forg.highwire.dtl.DTLVardef@a3b190_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

Dependence of Contextual Modulation in Macaque V1 on Interlaminar Signal Flow

In visual cortex, neural correlates of subjective perception can be generated by modulation of activity from beyond the classical receptive field (CRF). In macaque V1, activity generated by nonclassical receptive field (nCRF) stimulation involves different intracortical circuitry than activity generated by CRF stimulation, suggesting that interactions between neurons across V1 layers differ under CRF and nCRF stimulus conditions. Using Neuropixels probes, we measured border ownership modulation within large, local populations of V1 neurons. We found that neurons in single columns preferred the same side of objects located outside of the CRF. In addition, we found that cross-correlations between pairs of neurons situated across feedback/horizontal and input layers differed between CRF and nCRF stimulation. Furthermore, independent of the comparison with CRF stimulation, we observed that the magnitude of border ownership modulation increased with the proportion of information flow from feedback/horizontal layers to input layers. These results demonstrate that the flow of signals between layers covaries with the degree to which neurons integrate information from beyond the CRF.

neuroscience↗