Biology subjects

Wilson, M.

Publications and source records attributed to Wilson, M..

At least 37 records · Page 2Linked to original sources

bioRxiv2024

Punishing temporal judgement boosts sense of agency and modulates its underlying neural correlates

Feeling in control of ones actions is fundamental to the formation of action-outcome relationships. Reinforcement and its valence also change the action-outcome relationship, either through behavior promotion or diminishment. In this study we evaluated how reward and punishment reinforcement modulate sense of agency, as measured by intentional binding. Moreover, using electroencephalography (EEG) we evaluated how reward and punishment reinforcement changes outcome event related potentials associated with the accuracy of participants judgement of the time interval between a key press and audio tone. We found that punishment reinforcement increased intentional binding between the action and outcome more than reward and control feedback. This was also reflected in the outcome event related potentials, where punishment elicited greater P300s and Late Positive Potentials compared to reward and control. We also found increased N100s and diminished P300s and Late Positive Potentials when the participants did not actively participate in evoking the tone. Taken together, our findings showcase that punishment reinforcement boosts sense of agency and modulates associated neural activity more than reward and no reinforcement, as a function of increasing attention and arousal. These findings illuminate the greater effect punishment reinforcement has on behavior and brain activity by its modification of sense of agency, which is important for the development of treatments in psychiatric and neurological diseases.

neuroscience↗

bioRxiv2024

Unraveling SARS-CoV-2 Host-Response Heterogeneity through Longitudinal Molecular Subtyping

Hospitalized COVID-19 patients exhibit diverse immune responses during acute infection, which are associated with a wide range of clinical outcomes. However, understanding these immune heterogeneities and their links to various clinical complications, especially long COVID, remains a challenge. In this study, we performed unsupervised subtyping of longitudinal multi-omics immunophenotyping in over 1,000 hospitalized patients, identifying two critical subtypes linked to mortality or mechanical ventilation with prolonged hospital stay and three severe subtypes associated with timely acute recovery. We confirmed that unresolved systemic inflammation and T-cell dysfunctions were hallmarks of increased severity and further distinguished patients with similar acute respiratory severity by their distinct immune profiles, which correlated with differences in demographic and clinical complications. Notably, one critical subtype (SubF) was uniquely characterized by early excessive inflammation, insufficient anticoagulation, and fatty acid dysregulation, alongside higher incidences of hematologic, cardiac, and renal complications, and an elevated risk of long COVID. Among the severe subtypes, significant differences in viral clearance and early antiviral responses were observed, with one subtype (SubC) showing strong early T-cell cytotoxicity but a poor humoral response, slower viral clearance, and greater risks of chronic organ dysfunction and long COVID. These findings provide crucial insights into the complex and context-dependent nature of COVID-19 immune responses, highlighting the importance of personalized therapeutic strategies to improve both acute and long-term outcomes.

immunology↗

bioRxiv2024

Improved Allele Frequencies in gnomAD through Local Ancestry Inference

The Genome Aggregation Database (gnomAD) is a foundational resource for allele frequency data, widely used in genomic research and clinical interpretation. However, traditional estimates rely on individual-level genetic ancestry groupings that may obscure variation in recently admixed populations. To improve resolution, we applied local ancestry inference (LAI) to over 27 million variants in two admixed groups: Admixed American (n = 7,612) and African/African American (n = 20,250), deriving ancestry-specific allele frequencies. We show that 78.5% and 85.1% of variants in these groups, respectively, exhibit at least a twofold difference in ancestry-specific frequencies. Moreover, 81.49% of variants with LAI information would be assigned a higher gnomAD-wide maximum frequency after incorporating LAI, potentially altering clinical interpretations. This LAI-informed release reveals clinically relevant frequency differences that are masked in aggregate estimates and may support reclassifying some variants from Uncertain Significance to Benign or Likely Benign.

genomics↗

bioRxiv2024

5-methylcytosine and 5-hydroxymethylcytosine are synergistic biomarkers for early detection of colorectal cancer

Early cancer detection has the potential to significantly improve treatment outcomes and survival rates. This study investigates the roles of 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) as biomarkers for early-stage colorectal cancer (CRC) detection in cell-free DNA (cfDNA). Using whole genome sequencing, we analyzed cfDNA from 37 treatment-naive CRC patients and 32 healthy controls. Our findings indicate that combining measurements of 5mC and 5hmC significantly enhances diagnostic accuracy (AUC = 0.95) compared to traditional approaches that conflate these markers (modified C, AUC = 0.66). Notably, 71.7% of differentially methylated regions (DMRs) exhibiting an increase in 5hmC in stage I cfDNA also showed a corresponding decrease in 5mC in stage IV, suggesting that 5hmC can effectively track regions undergoing demethylation during tumor development. These results support the hypothesis that distinguishing between 5mC and 5hmC can improve the sensitivity of liquid biopsy tests for early cancer detection.

cancer biology↗

bioRxiv2024

A novel epigenetic clock for rhesus macaques unveils an association between early life adversity and epigenetic age acceleration

Because DNA methylation changes reliably with age, machine learning models called epigenetic clocks can estimate an individuals age based on their DNA methylation profile. This epigenetic measure of age can deviate from ones true age, and the difference between the epigenetic age and true age, known as epigenetic age acceleration (EAA), has been found to directly correlate with morbidity and mortality in adults. Emerging evidence suggests that EAA is also associated with aberrant health outcomes in children, making epigenetic clocks useful tools for studying aging and development. We developed two highly accurate epigenetic clocks for the rhesus macaque, utilizing 1,008 blood samples from 690 macaques between 2 days and 23.4 years of age with diverse genetic backgrounds and exposure to environmental conditions. The first clock, which is trained on all samples, achieves a Pearson correlation between true age and predicted age of 0.983 and median absolute error of 0.210 years. To study phenotypes during development, the second clock is optimized for macaques younger than 6 years and achieves a Pearson correlation of 0.974 and a median absolute error of 0.148 years. Using the latter clock, we investigated whether epigenetic aging is affected by early life adversity in the form of infant maltreatment. Our data suggests that maltreatment and increased hair cortisol levels are associated with epigenetic age acceleration right after the period of maltreatment.

neuroscience↗

bioRxiv2024

Soil organic carbon stocks and stabilization mechanisms in tidal marshes along estuarine gradients

Tidal marshes store large amounts of soil organic carbon (SOC), however, little is known on SOC stabilization mechanisms in these ecosystems. In estuarine marshes, SOC storage is dominated by a complex interaction of tidal inundation and salinity with biotic ecosystem components, leading to strong spatio-temporal variations within estuaries. Our aim was to assess (i) SOC stocks, (ii) SOC stabilization mechanisms (aggregation and mineral-association), and (iii) their environmental drivers along estuarine gradients. We analyzed SOC stocks and SOC density fractions in topsoil (0-10 cm) and subsoil (10-30 cm) of three marsh zones representing three flooding regimes (daily, monthly, yearly) in three marsh types along the salinity gradient (salt, brackish, freshwater) of the Elbe Estuary, Germany. Increasing salinity and flooding reduced SOC stocks 0-30 cm (9.3-74.6 t ha-1), which was related to decreasing plant biomass and soil texture. Mineral-associated organic matter (CMAOM) was the largest SOC fraction (59% of total SOC), followed by aggregate-occluded organic matter (CoPOM) (24%) and free particulate organic matter (CfPOM) (16%). The CMAOM amount in topsoils decreased downstream with increasing salinity, reflecting decreasing fine-texture along the estuary. The amount of CoPOM was higher in topsoils and high marshes, indicating negative effects of flooding on aggregation. The relative proportion of CfPOM (% of total SOC) increased with increasing flooding frequency and reducing soil conditions. Our results underline the importance of estuarine gradients as drivers of SOC storage and stabilization. Climate-change induced sea-level rise and variations in salinity might reduce SOC storage and stabilization in estuaries.

ecology↗

bioRxiv2024

Functional Magnetic Resonance Spectroscopy of Prolonged Motor Activation using Conventional and Spectral GLM Analyses

BackgroundFunctional MRS (fMRS) is a technique used to measure metabolic changes in response to increased neuronal activity, providing unique insights into neurotransmitter dynamics and neuroenergetics. In this study we investigate the response of lactate and glutamate levels in the motor cortex during a sustained motor task using conventional spectral fitting and explore the use of a novel analysis approach based on the application of linear modelling directly to the spectro-temporal fMRS data. MethodsfMRS data were acquired at a field strength of 3 Tesla from 23 healthy participants using a short echo-time (28ms) semi-LASER sequence. The functional task involved rhythmic hand clenching over a duration of 8 minutes and standard MRS preprocessing steps, including frequency and phase alignment, were employed. Both conventional spectral fitting and direct linear modelling were applied, and results from participant-averaged spectra and metabolite-averaged individual analyses were compared. ResultsWe observed a 20% increase in lactate in response to the motor task, consistent with findings at higher magnetic field strengths. However, statistical testing showed some variability between the two averaging schemes and fitting algorithms. While lactate changes were supported by the direct spectral modelling approach, smaller increases in glutamate (2%) were inconsistent. Exploratory spectral modelling identified a 4% decrease in aspartate, aligning with conventional fitting and observations from prolonged visual stimulation. ConclusionWe demonstrate that lactate dynamics in response to a prolonged motor task are observed using short-echo time semi-LASER at 3 Tesla, and that direct linear modelling of fMRS data is a useful complement to conventional analysis. Future work includes mitigating spectral confounds, such as scalp lipid contamination and lineshape drift, and further validation of our novel direct linear modelling approach through experimental and simulated datasets.

neuroscience↗

bioRxiv2024

Partitioning biota along the Elbe River estuary: where are the community transitions?

Estuarine zonation and community assemblages are frequently correlated with salinity, although the extent or nature of this correlation varies considerably among the published studies. While a smooth transition in biological communities is often conceptualized in association with estuarine fresh, brackish, and marine conditions, many studies have shown more distinct communities and the altogether absence of a brackish community. We explore these viewpoints in light of plant observations and soil and aquatic microbial analyses from permanent plots established on the Elbe River Estuary of northern Germany. Generally, two distinct communities were observed, a polyhaline assemblage towards the mouth of the system, and another that was associated with both the fresh and brackish mesohaline regimes further upriver. This was most pronounced among plant and soil bacteria communities, while aquatic 16S assemblages reflected little distinction at all. The proportion of marine classified taxa declined from the mouth to upriver and suggests that while the transition from marine to brackish or fresh vegetation falls within the sampled area, the same transition for microbial taxa could not be observed and may be further upriver. Thus, although we were able to identify two distinct communities, the "limit" of marine taxa was only evident for vegetation. While tidal and weather-related hydrology, as well as soil properties were also influential in distinguishing the communities, much of the variance remains unexplained. Further sampling, classification, and partitioning is necessary to determine the origin and/or autochthonous habitat, if any, for the Elbe River estuarine taxa. Geographic boundsbottom left: 53.556216{degrees}N, 8.824398{degrees}E top right: 53.917760 {degrees}N, 10.155669 {degrees}E

ecology↗

bioRxiv2024

Local cryptic diversity in salinity adaptation mechanisms in a wild outcrossing Brassica

It is generally assumed that populations of the same species should evolve shared mechanisms of adaptation to common stressors due to evolutionary constraint. Here, we describe a novel system of within-species local adaptation to coastal habitats, Brassica fruticulosa, and detail surprising mechanistic variability in adaptive responses to extreme salinity. These radically different adaptive responses in neighbouring populations are evidenced by transcriptomes, diverse physiological outputs, and completely distinct genomic selective landscapes. In response to high salinity Northern Catalonian populations restrict root-to-shoot Na+ transport, favouring K+ uptake. Contrastingly, Central Catalonian populations accumulate Na+ in leaves and compensate for the osmotic imbalance with compatible solutes such as proline and elevated Ca2+. Despite contrasting responses, both metapopulations were salinity tolerant relative to all inland accessions. To characterise the genomic basis of these two divergent adaptive strategies in an otherwise non-saline-tolerant endemic, we generate a long-read-based genome and population sequencing of 18 populations (9 inland, 9 coastal) across the B. fruticulosa species range. Results of genomic and transcriptomic approaches confirm the physiological observations of completely distinct underlying mechanisms of adaptation to extreme salinity and reveal potential genetic targets of these two recently evolved salinity adaptations. We therefore provide a new model of within-species salinity adaptation and reveal cryptic variation in neighbouring plant populations in the mechanisms of adaptation to an important natural stressor highly relevant to agriculture. SignificanceIts usually expected that closely related populations of a given species should adapt to the same environmental stressor in the same way due to genetic or physiological constraints. However, this is not commonly tested due to practical constraints. Here we show that, even at the level of neighbouring populations, contrasting adaptive mechanisms control adaptive responses to extreme coastal salinity in a new plant model, Brassica fruticulosa, a close wild relative of many crops of worldwide importance. This indicates multiple options for engineering an agriculturally crucial adaptation: soil salinization. These results will be of great interest to not only those studying fundamental mechanisms of adaptation, but also resilience improvement in Brassica species.

evolutionary biology↗

bioRxiv2024

Chromosome-scale genome assembly of bread wheat's wild relative Triticum timopheevii

Wheat (Triticum aestivum) is one of the most important food crops with an urgent need for increase in its production to feed the growing world. Triticum timopheevii (2n = 4x = 28) is an allotetraploid wheat wild relative species containing the At and G genomes that has been exploited in many pre-breeding programmes for wheat improvement. In this study, we report the generation of a chromosome-scale reference genome assembly of T. timopheevii accession PI 94760 based on PacBio HiFi reads and chromosome conformation capture (Hi-C). The assembly comprised a total size of 9.35 Gb, featuring a contig N50 of 42.4 Mb, and 166,325 predicted gene models. DNA methylation analysis showed that the G genome had on average more methylated bases than the At genome. The G genome was also more closely related to the S genome of Aegilops speltoides than to the B genome of hexaploid or tetraploid wheat. In summary, the T. timopheevii genome assembly provides a valuable resource for genome-informed discovery of agronomically important genes for food security.

plant biology↗

bioRxiv2023

Adherent reformed islets: a long-term primary cell-based platform for exploring mouse and human islet biology.

Pancreatic islets are 3-dimensional micro-organs that maintain {beta}-cell functionality via cell-cell and cell-matrix communication. Isolated primary islets are the gold standard for in vitro models. However, native islets present experimental challenges for long-term mechanistic studies owing to their short culture life (approximately 1 week). We developed a novel long-term protocol to study the function of primary islets. The protocol employed reformed islets following dispersion and a fine-tuned culture environment. Reformed islets are highly similar to their primary counterparts across various physiological characteristics. Long-term culture of reformed islets enables high-resolution imaging, repeated functional assessment, and the study of cell-cell communication. Unlike other platforms such as stem cell-derived organoids, reformed islets retain their resident immune populations, making them ideal for studying both resident and infiltrating immune cells and their interactions with hormone-producing islet cells. Qualitative and quantitative analyses revealed that the composition and cytoarchitecture of the reformed islets mimicked those found in primary islets, including the presence of macrophages and CD4+ and CD8+ T cells, which are the key resident immune cell types. Reformed islets secrete insulin and are glucose-responsive, and their {beta}-cells can be stimulated to proliferate using GLP-1 receptor agonism. Furthermore, a comparison of the transcriptomic landscape of isolated human islets and reformed islets generated from the same donor demonstrated a high degree of similarity. Our reformed islets provide an ideal platform to study diabetes pathology. We recapitulated both the T1DM and T2DM disease milieu and validated our model for studying islet immune trafficking and invasion using activated macrophages and T cells. Our data illustrates that reformed islets are an anatomical and functional alternative to native human and mouse islets. Moreover, reformed islets have an advantage over mouse and human {beta}-cell lines, including MIN6 and EndoC-{beta}H1cells, that lack the signalling input of non-{beta}-endocrine cells and immune cell crosstalk. In this study, we showed that reformed islets are a durable paradigm (cell-based model) for islet-based exploration and a means of target discovery/validation for diabetes research. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=141 SRC="FIGDIR/small/568245v2_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@1201151org.highwire.dtl.DTLVardef@510ea8org.highwire.dtl.DTLVardef@19937c1org.highwire.dtl.DTLVardef@1b85a6_HPS_FORMAT_FIGEXP M_FIG C_FIG

physiology↗

bioRxiv2023

Integrated longitudinal multi-omics study identifies immune programs associated with COVID-19 severity and mortality in 1152 hospitalized participants

Hospitalized COVID-19 patients exhibit diverse clinical outcomes, with some individuals diverging over time even though their initial disease severity appears similar. A systematic evaluation of molecular and cellular profiles over the full disease course can link immune programs and their coordination with progression heterogeneity. In this study, we carried out deep immunophenotyping and conducted longitudinal multi-omics modeling integrating ten distinct assays on a total of 1,152 IMPACC participants and identified several immune cascades that were significant drivers of differential clinical outcomes. Increasing disease severity was driven by a temporal pattern that began with the early upregulation of immunosuppressive metabolites and then elevated levels of inflammatory cytokines, signatures of coagulation, NETosis, and T-cell functional dysregulation. A second immune cascade, predictive of 28-day mortality among critically ill patients, was characterized by reduced total plasma immunoglobulins and B cells, as well as dysregulated IFN responsiveness. We demonstrated that the balance disruption between IFN-stimulated genes and IFN inhibitors is a crucial biomarker of COVID-19 mortality, potentially contributing to the failure of viral clearance in patients with fatal illness. Our longitudinal multi-omics profiling study revealed novel temporal coordination across diverse omics that potentially explain disease progression, providing insights that inform the targeted development of therapies for hospitalized COVID-19 patients, especially those critically ill.

immunology↗

bioRxiv2023

Small variant benchmark from a complete assembly of X and Y chromosomes

The sex chromosomes contain complex, important genes impacting medical phenotypes, but differ from the autosomes in their ploidy and large repetitive regions. To evaluate variant detection on chromosomes X and Y, we created an 111,725 variant benchmark for the Genome in a Bottle HG002 reference material. We show how complete assemblies can expand benchmarks to difficult regions, but highlight remaining challenges benchmarking complex gene conversions, copy number variable gene arrays, and human satellites.

genomics↗

bioRxiv2023

Peripherally derived LGI1-reactive monoclonal antibodies cause epileptic seizures in vivo

One striking clinical hallmark in patients with autoantibodies to leucine-rich glioma inactivated 1 (LGI1) is the very frequent focal seizure semiologies, including faciobrachial dystonic seizures (FBDS), in addition to the amnesia. Polyclonal serum IgGs have successfully modelled the cognitive changes in vivo but not seizures. Hence, it remains unclear whether LGI1-autoantibodies are sufficient to cause seizures. We tested this with the molecularly precise monoclonal antibodies directed against LGI1 (LGI1-mAbs), derived from patient circulating B cells. These were directed towards both major domains of LGI1, LRR (n=5) and EPTP (n=5) and infused intracerebroventricularly over 7 days into juvenile male Wistar rats using osmotic pumps. Continuous wireless EEG was recorded from a depth electrode placed in hippocampal CA3 plus behavioural tests for memory and hyperexcitability were performed. Following infusion completion (Day 9), post-mortem brain slices were studied using electrophysiology and immunostaining. By comparison to control-mAb injected rats (n=6), video-EEG analysis over 9 days revealed convulsive and non-convulsive seizure activity in rats infused with LGI1-mAbs, with a significant number of ictal events (245{+/-}83 vs. 7.8{+/-}7.8 in controls; p=0.002). Memory was not impaired in the novel object recognition test. Local field potential recordings from postmortem brain slices showed spontaneous ictal-like spike activity in the CA3 region (p=0.03). The LGI1-mAbs bound most strongly in the hippocampal CA3 region and induced a significant reduction in Kv1.1 cluster number in this subfield (6 controls; 7 LGI1-mAbs; p=0.01) Peripherally-derived human LGI1-mAbs infused into rodent CSF provide strong evidence of direct in vivo epileptogenesis with molecular correlations. These findings fulfill criteria for LGI1-antibodies in seizure causation.

neuroscience↗

bioRxiv2023

Cellular Calcium Activity at Depth Predicted from Surface Potential Recordings using Ultra-high Density Transparent Graphene Arrays

Recording brain activity with high spatial and high temporal resolution across deeper layers of cortex has been a long-sought methodology to study how neural information is coded, stored, and processed by neural circuits and how it leads to cognition and behavior. Electrical and optical neural recording technologies have been the key tools in neurophysiology studies toward a comprehensive understanding of the neural dynamics. The advent of optically transparent neural microelectrodes has facilitated multimodal experiments combining simultaneous electrophysiological recordings from the brain surface with optical imaging and stimulation of neural activity. A remaining challenge is to scale down electrode dimensions to single -cell size and increase the density to record neural activity with high spatial resolution across large areas to capture nonlinear neural dynamics at multiple spatial and temporal scales. Here, we developed microfabrication techniques to create transparent graphene microelectrodes with ultra-small openings and a large, completely transparent recording area. We achieved this by using long graphene microwires without any gold extensions in the field of view. To overcome the quantum capacitance limit of graphene and scale down the microelectrode diameter to 20 m, we used Pt nanoparticles. To prevent open circuit failure due to defects and disconnections in long graphene wires, we employed interlayer doped double layer graphene (id-DLG) and demonstrated cm-scale long transparent graphene wires with microscale width and low resistance. Combining these two advances, we fabricated high-density microelectrode arrays up to 256 channels. We conducted multimodal experiments, combining recordings of cortical potentials with high-density transparent arrays with two-photon calcium imaging from layer 1 (L1) and layer 2/3 (L2/3) of the V1 area of mouse visual cortex. High-density recordings showed that the visual evoked responses are more spatially localized for high-frequency bands, particularly for the multi-unit activity (MUA) band. The MUA power was found to be strongly correlated with the cellular calcium activity. Leveraging this strong correlation, we applied dimensionality reduction techniques and neural networks to demonstrate that single-cell (L2/3) and average (L1 and L2/3) calcium activities can be decoded from surface potentials recorded by high-density transparent graphene arrays. Our high-density transparent graphene electrodes, in combination with multimodal experiments and computational methods, could lead to the development of minimally invasive neural interfaces capable of recording neural activity from deeper layers without requiring depth electrodes that cause damage to the tissue. This could potentially improve brain computer interfaces and enable less invasive treatments for neurological disorders.

neuroscience↗

bioRxiv2023

Lung-innervating neurons expressing Tmc3 can induce broncho-constriction and dilation with direct consequences for the respiratory cycle

Sensory neurons of the vagal ganglia (VG) innervate lungs and play a critical role in maintaining airway homeostasis. However, the specific VG neurons that innervate lungs, and the mechanisms by which these neurons sense and respond to airway insults, are not well understood. Here, we identify a subpopulation of lung-innervating VG neurons defined by their expression of Tmc3. Single cell transcriptomics illuminated several subpopulations of Tmc3+ sensory neurons, revealing distinct Piezo2- and Trpv1-expressing subclusters. Furthermore, Tmc3 deficiency in VG neurons leads to global and subcluster specific transcriptional changes related to metabolic and ion channel function. Importantly, we show that broncho-constriction and dilation can be modulated through inhibition or activation of Tmc3+ VG neurons resulting in a decrease or increase of end-expiratory lung volume, respectively. Together, our data show that Tmc3 is a marker of lung-innervating neurons and may play a pivotal role in maintaining fundamental inspiratory and expiratory processes. SignificanceHarnessing the neuronal mechanisms that regulate lung function offers potential alternatives to existing corticosteroid treatment regimens for respiratory illness associated with acute bronchoconstriction including asthma, COPD, and emphysema. Our findings define Transmembrane channel-like 3, Tmc3, as a marker of lung-innervating sensory neurons, identify distinct subpopulations of Tmc3+ neurons with unique transcriptional profiles, and show that activation or inhibition of these neurons has a significant impact on airway function. Our work highlights potential avenues of novel targeted intervention in respiratory conditions driven by dysfunctional neuronal reflexes.

neuroscience↗

bioRxiv2023

NaV1.6 inhibition drives the efficacy of voltage-gated sodium channel inhibitors to prevent electrically induced seizures in both wild type and Scn8aN1768D/+ gain-of-function mice

Inhibitors of voltage-gated sodium channels (NaVs) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are nonselective. We created a series of compounds with diverse selectivity profiles enabling block of NaV1.6 alone or together with NaV1.2. Mice with a heterozygous gain-of-function mutation (N1768D/+) in Scn8a (encoding NaV1.6) responded with a tonic-clonic seizure to a mild 6 Hz stimulus that was innocuous to wild-type mice. Pharmacologic inhibition of NaV1.6 in Scn8aN1768D/+ mice prevented seizures. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild-type mice. NaV1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS NaV isoforms. Our data suggest NaV1.6 inhibition is a driver of efficacy for NaV inhibitor anti-seizure medicines. Selective NaV1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and better tolerated treatments for idiopathic epilepsies. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=199 SRC="FIGDIR/small/551823v2_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@39c09borg.highwire.dtl.DTLVardef@19413b8org.highwire.dtl.DTLVardef@9aa226org.highwire.dtl.DTLVardef@b9207_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2023

Registered report: Age-preserved semantic memory and the CRUNCH effect manifested as differential semantic control networks: an fMRI study

Semantic memory representations are generally well maintained in aging, whereas semantic control is thought to be more affected. To explain this phenomenon, this study tested the predictions of the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH), focusing on task demands in aging as a possible framework. The CRUNCH effect would manifest itself in semantic tasks through a compensatory increase in neural activation in semantic control network regions but only up to a certain threshold of task demands. This study compares 39 younger (20-35 years old) with 39 older participants (60-75 years old) in a triad-based semantic judgment task performed in an fMRI scanner while manipulating task demand levels (low versus high) through semantic distance. In line with the CRUNCH predictions, differences in neurofunctional activation and behavioral performance (accuracy and response times) were expected in younger versus older participants in the low-versus high-demand conditions, which should be manifested in semantic control Regions of Interest (ROIs). Our older participants had intact behavioral performance, as proposed in the literature for semantic memory tasks (maintained accuracy and slower response times (RTs)). Age-invariant behavioral performance in the older group compared to the younger one is necessary to test the CRUNCH predictions. The older adults were also characterized by high cognitive reserve, as our neuropsychological tests showed. Our behavioral results confirmed that our task successfully manipulated task demands: error rates, RTs and perceived difficulty increased with increasing task demands in both age groups. We did not find an interaction between age group and task demand, or a statistically significant difference in activation between the low- and high-demand conditions for either RTs or accuracy. As for brain activation, we did not find the expected age group by task demand interaction, or a significant main effect of task demand. Overall, our results are compatible with neural activation in the semantic network and the semantic control network, largely in frontotemporoparietal regions. ROI analyses demonstrated significant effects (but no interactions) of task demand in the left and right inferior frontal gyrus, the left posterior middle temporal gyrus, the posterior inferior temporal gyrus and the prefrontal gyrus. Overall, our test did not confirm the CRUNCH predictions.

neuroscience↗