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Roth, N.

Publications and source records attributed to Roth, N..

18 recordsLinked to original sources

A flexible quality metric for electrophysiological recordings across brain regions and species

The increasing size of electrophysiological datasets has heightened the need for quality metrics that automatically reject neurons whose activity was recorded with low sensitivity or specificity. One key approach estimates artifactual contamination by assuming that each neuron has a refractory period (RP), a brief time interval following each action potential when further activity cannot occur. However, existing methods cannot be applied without prior knowledge of the neurons RP durations, limiting their usefulness in datasets that include neurons from brain regions or species in which RP durations have not been systematically characterized. Here, we find that neurons in some brain regions (thalamus) and species (macaque) have shorter RP durations than commonly assumed, and we introduce a new metric, the Sliding Refractory Period metric, which is robust to variation in a neurons RP duration without tuning. We validate the method using simulations, demonstrating that it improves acceptance of uncontaminated spike trains with short or long RP durations while still rejecting contaminated ones. Moreover, by incorporating Poisson statistics into the calculation, the method also improves on prior work by allowing the user to approximately control the false acceptance rate. Our new metric improves quantification of contamination in electrophysiological recordings and enables application of a single tuning-free quality metric to data recorded from diverse brain regions and species.

neuroscience↗

Genetic Modifiers of Cognitive Function: Novel Genetic Associations with Memory, Executive Function, and Attention in the Long Life Family Study

Cognitive performance is central to health and quality of life. Studying the factors that sustain performance may offer insights into maintaining cognitive function into advanced ages and may inform strategies to promote healthy cognitive aging. To identify single nucleotide polymorphisms (SNPs) underlying cognitive function, we performed genome-wide association studies (GWAS) of nine neuropsychological test scores capturing performance in three cognitive domains in 2,455 participants of the Long Life Family Study (LLFS). We identified 12 variants in seven tests and three domains that reached genome-wide significance (p < 5x10-). Three rare (minor allele frequency, European population MAF<0.01) protective, intronic variants, rs190287985 (CCSER1), rs75730801 (FHOD3), and rs552842447 (LINC00508), were uniquely associated with semantic fluency, phonemic fluency and number span forward, respectively. Two rare deleterious variants, rs556333682 and rs188304645, were associated with performance on the Hopkins Verbal Learning Test-Revised (HVLT-R) learning trials and lie in ischemia-related genes SH3TC1 and RPH3A. Another variant, rs180691759, associated with HVLT-R delayed recall, was proximal to RSPO3 and linked to decreased ECHDC1 expression, implicating ischemic and unexplained Ethylmalonic acid (EMA) pathways. We compared the results with GWASs of a general cognitive factor (GCF) and reaction time (RT) in the UK Biobank and meta-analysis results of the UK Biobank, CHARGE and COGENT by Davies et al. We found that rs535509651 associates with HVLT-R delayed recall in the LLFS and nominally associates (p<0.05) with GCF, and that rs10424537 associates with Immediate Logical Memory in the LLFS and nominally associates with RT. Furthermore, we identified 5 genome-wide significant loci in Davies et al. that reached loci adjusted significance in the LLFS (GCF p<0.05/128 and RT p<0.05/39). Each locus was associated with a single cognitive domain in the LLFS. We annotated the genome-wide significant results with quantitative trait loci (QTL) analyses of whole blood transcriptomic, serum metabolomic data, and gene set enrichment analyses (GSEA) using all nominally significant transcripts (p < 0.05/12). QTL analyses discovered 1 SNP-transcript (ECHDC1, p < 3 x 10-6), no SNP-lipid (p < 2 x 10-4), and no SNP-polar metabolite (p < 2 x 10-4) associations. Gene set enrichment analyses identified three pathways at FDR < 0.05. Our findings provide insight into the domain-specific genetic architecture of cognitive function.

genetics↗

Interactive data exploration websites for large-scale electrophysiology

Methodological advances in neuroscience have enabled the collection of massive datasets which demand innovative approaches for scientific communication. Existing platforms for data storage lack intuitive tools for data exploration, limiting our ability to interact effectively with these brain-wide datasets. We introduce two public websites: (Data and Atlas) developed for the International Brain Laboratory which provide access to millions of behavioral trials and hundreds of thousands of individual neurons. These interfaces allow users to discover both the raw and processed brain-wide data released by the IBL at the scale of the whole brain, individual sessions, trials, and neurons. By hosting these data interfaces as websites they are available cross-platform with no installation. By releasing each sites code as a modular open-source framework, other researchers can easily develop their own web interfaces and explore their own data. As neuroscience datasets continue to expand, customizable web interfaces offer a glimpse into a future of streamlined data exploration and act as blueprints for future tools.

neuroscience↗

Dissecting the Complexities of Learning With Infinite Hidden Markov Models

Learning to exploit the contingencies of a complex experiment is not an easy task for animals. Individuals learn in an idiosyncratic manner, revising their approaches multiple times as they are shaped, or shape themselves, and potentially end up with different strategies. Their long-run learning curves are therefore a tantalizing target for the sort of individualized quantitative characterizations that sophisticated modelling can provide. However, any such model requires a flexible and extensible structure which can capture radically new behaviours as well as slow changes in existing ones. To this end, we suggest a dynamic input-output infinite hidden semi-Markov model, whose latent states are associated with specific components of behaviour. This model includes an infinite number of potential states and so has the capacity to describe substantially new behaviours by unearthing extra states; while dynamics in the model allow it to capture more modest adaptations to existing behaviours. We individually fit the model to data collected from more than 100 mice as they learned a contrast detection task over tens of sessions and around fifteen thousand trials each. Despite large individual differences, we found that most animals progressed through three major stages of learning, the transitions between which were marked by distinct additions to task understanding. We furthermore showed that marked changes in behaviour are much more likely to occur at the very beginning of sessions, i.e. after a period of rest, and that response biases in earlier stages are not predictive of biases later on in this task.

animal behavior and cognition↗

Bypassing spike sorting: Density-based decoding using spike localization from dense multielectrode probes

Neural decoding and its applications to brain computer interfaces (BCI) are essential for understanding the association between neural activity and behavior. A prerequisite for many decoding approaches is spike sorting, the assignment of action potentials (spikes) to individual neurons. Current spike sorting algorithms, however, can be inaccurate and do not properly model uncertainty of spike assignments, therefore discarding information that could potentially improve decoding performance. Recent advances in high-density probes (e.g., Neuropixels) and computational methods now allow for extracting a rich set of spike features from unsorted data; these features can in turn be used to directly decode behavioral correlates. To this end, we propose a spike sorting-free decoding method that directly models the distribution of extracted spike features using a mixture of Gaussians (MoG) encoding the uncertainty of spike assignments, without aiming to solve the spike clustering problem explicitly. We allow the mixing proportion of the MoG to change over time in response to the behavior and develop variational inference methods to fit the resulting model and to perform decoding. We benchmark our method with an extensive suite of recordings from different animals and probe geometries, demonstrating that our proposed decoder can consistently outperform current methods based on thresholding (i.e. multi-unit activity) and spike sorting. Open source code is available at https://github.com/yzhang511/density_decoding.

neuroscience↗

A Brain-Wide Map of Neural Activity during Complex Behaviour

A key challenge in neuroscience is understanding how neurons in hundreds of interconnected brain regions integrate sensory inputs with prior expectations to initiate movements and thereby make decisions. It is difficult to meet this challenge if different laboratories apply different analyses to different recordings in different regions during different behaviours. Here, we report a comprehensive set of recordings from 621733 neurons across 139 mice in 12 labs performing a decision-making task with sensory, motor, and cognitive components, obtained with 699 Neuropixels probe insertions covering 279 brain areas in the left forebrain and midbrain and the right hindbrain and cerebellum. We provide an initial appraisal of this brain-wide map, assessing how neural activity encoded key task variables. Representations of visual stimuli appeared transiently in classical visual areas after stimulus onset and then spread to ramp-like activity in a collection of mid- and hindbrain regions that also encoded choices. Neural responses correlated with motor action almost everywhere in the brain. Responses to reward delivery and consumption versus negative feedback were also widespread. This publicly available dataset represents an unprecedented resource for understanding how computations distributed across and within brain areas drive behaviour.

neuroscience↗

Brain-wide representations of prior information in mouse decision-making

The neural representations of prior information about the state of the world are poorly understood. To investigate them, we examined brain-wide Neuropixels recordings and widefield calcium imaging collected by the International Brain Laboratory. Mice were trained to indicate the location of a visual grating stimulus, which appeared on the left or right with prior probability alternating between 0.2 and 0.8 in blocks of variable length. We found that mice estimate this prior probability and thereby improve their decision accuracy. Furthermore, we report that this subjective prior is encoded in at least 20% to 30% of brain regions which, remarkably, span all levels of processing, from early sensory areas (LGd, VISp) to motor regions (MOs, MOp, GRN) and high level cortical regions (ACAd, ORBvl). This widespread representation of the prior is consistent with a neural model of Bayesian inference involving loops between areas, as opposed to a model in which the prior is incorporated only in decision-making areas. This study offers the first brain-wide perspective on prior encoding at cellular resolution, underscoring the importance of using large scale recordings on a single standardized task.

neuroscience↗

Objects Guide Human Gaze Behavior in Dynamic Real-World Scenes

The complexity of natural scenes makes it challenging to experimentally study the mechanisms behind human gaze behavior when viewing dynamic environments. Historically, eye movements were believed to be driven primarily by space-based attention towards locations with salient features. Increasing evidence suggests, however, that visual attention does not select locations with high saliency but operates on attentional units given by the objects in the scene. We present a new computational framework to investigate the importance of objects for attentional guidance. This framework is designed to simulate realistic scanpaths for dynamic real-world scenes, including saccade timing and smooth pursuit behavior. Individual model components are based on psychophysically uncovered mechanisms of visual attention and saccadic decision-making. All mechanisms are implemented in a modular fashion with a small number of well-interpretable parameters. To systematically analyze the importance of objects in guiding gaze behavior, we implemented five different models within this framework: two purely spatial models, where one is based on low-level saliency and one on high-level saliency, two object-based models, with one incorporating low-level saliency for each object and the other one not using any saliency information, and a mixed model with object-based attention and selection but space-based inhibition of return. We optimized each models parameters to reproduce the saccade amplitude and fixation duration distributions of human scanpaths using evolutionary algorithms. We compared model performance with respect to spatial and temporal fixation behavior, including the proportion of fixations exploring the background, as well as detecting, inspecting, and returning to objects. A model with object-based attention and inhibition, which uses saliency information to prioritize between objects for saccadic selection, leads to scanpath statistics with the highest similarity to the human data. This demonstrates that scanpath models benefit from object-based attention and selection, suggesting that object-level attentional units play an important role in guiding attentional processing. Author summaryThere has long been an interest in understanding how we decide when and where to move our eyes, and psychophysical experiments have uncovered many underlying mechanisms. Under controlled laboratory conditions, objects in the scene play an important role in guiding our attention. Due to the visual complexity of the world around us, however, it is hard to assess experimentally how objects influence eye movements when observing dynamic real-world scenes. Computational models have proved to be a powerful tool for investigating visual attention, but existing models are either only applicable to images or restricted to predicting where humans look on average. Here, we present a computational framework for simulating where and when humans decide to move their eyes when observing dynamic real-world scenes. Using our framework, we can assess the influence of objects on the model predictions. We find that including object-based attention in the modeling increases the resemblance of simulated eye movements to human gaze behavior, showing that objects play indeed an important role in guiding our gaze when exploring the world around us. We hope that the availability of this framework encourages more research on attention in dynamic real-world scenes.

neuroscience↗

Assessment of Immunogenicity and Efficacy of CV0501 mRNA-based Omicron COVID-19 Vaccination in Small Animal Models

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron and its subvariants (BA.2, BA.4, BA.5) represent the most commonly circulating variants of concern (VOC) in the coronavirus disease 2019 (COVID-19) pandemic in 2022. Despite high vaccination rates with approved SARS-CoV-2 vaccines encoding the ancestral spike (S) protein, these Omicron subvariants have collectively resulted in increased viral transmission and disease incidence. This necessitates the development and characterization of vaccines incorporating later emerging S proteins to enhance protection against VOC. In this context, bivalent vaccine formulations may induce broad protection against VOC and potential future SARS-CoV-2 variants. Here, we report preclinical data for a lipid nanoparticle (LNP)-formulated RNActive(R) N1-methylpseudouridine (N1m{Psi}) modified mRNA vaccine (CV0501) based on our second-generation SARS-CoV-2 vaccine CV2CoV, encoding the S protein of Omicron BA.1. The immunogenicity of CV0501, alone or in combination with a corresponding vaccine encoding the ancestral S protein (ancestral N1m{Psi}), was first measured in dose-response and booster immunization studies performed in Wistar rats. Both monovalent CV0501 and bivalent CV0501/ancestral N1m{Psi} immunization induced robust neutralizing antibody titers against the BA.1, BA.2 and BA.5 Omicron subvariants, in addition to other SARS-CoV-2 variants in a booster immunization study. The protective efficacy of monovalent CV0501 against live SARS-CoV-2 BA.2 infection was then assessed in hamsters. Monovalent CV0501 significantly reduced SARS-CoV-2 BA.2 viral loads in the airways, demonstrating protection induced by CV0501 vaccination. CV0501 has now advanced into human Phase 1 clinical trials (ClinicalTrials.gov Identifier: NCT05477186).

immunology↗

Extracellular ATP drives pancreatic cancer cell invasion via purinergic receptor-integrin interactions

Pancreatic ductal adenocarcinoma (PDAC) is a cancer of unmet clinical need. Given the elevated ATP levels seen in PDAC, the purinergic axis represents an attractive therapeutic target. Mediated in part by highly druggable extracellular proteins, it plays essential roles in fibrosis, inflammation response and immune function. We have analysed the PDAC purinome using publicly available databases to discern which members may impact patient survival. We identified P2RY2 to be the purinergic gene with the strongest association to hypoxia, the highest cancer cell specific expression and the strongest impact on overall survival. Invasion assays using a 3D spheroid model revealed P2Y2 to be critical in facilitating invasion driven by extracellular ATP. Using genetic modification or pharmacological strategies we identify the mechanism of this ATP-driven invasion to require direct protein-protein interactions between P2Y2 and V integrins. Using DNA-PAINT super-resolution fluorescence microscopy, we found that P2Y2 regulates the amount and distribution of integrin V in the plasma membrane. This work highlights a novel GPCR-integrin interaction in cancer invasion and its potential for therapeutic targeting.

cancer biology↗

Reproducibility of in-vivo electrophysiological measurements in mice

Understanding brain function relies on the collective work of many labs generating reproducible results. However, reproducibility has not been systematically assessed within the context of electrophysiological recordings during cognitive behaviors. To address this, we formed a multi-lab collaboration using a shared, open-source behavioral task and experimental apparatus. Experimenters in ten laboratories repeatedly targeted Neuropixels probes to the same location (spanning secondary visual areas, hippocampus, and thalamus) in mice making decisions; this generated a total of 121 experimental replicates, a unique dataset for evaluating reproducibility of electrophysiology experiments. Despite standardizing both behavioral and electrophysiological procedures, some experimental outcomes were highly variable. A closer analysis uncovered that variability in electrode targeting hindered reproducibility, as did the limited statistical power of some routinely used electrophysiological analyses, such as single-neuron tests of modulation by individual task parameters. Reproducibility was enhanced by histological and electrophysiological quality-control criteria. Our observations suggest that data from systems neuroscience is vulnerable to a lack of reproducibility, but that across-lab standardization, including metrics we propose, can serve to mitigate this.

neuroscience↗

Low-dose bivalent mRNA vaccine is highly effective against different SARS-CoV-2 variants in a transgenic mouse model

Combining optimized spike (S) protein-encoding mRNA vaccines to target multiple SARS-CoV-2 variants could improve COVID-19 control. We compared monovalent and bivalent mRNA vaccines encoding B.1.351 (Beta) and/or B.1.617.2 (Delta) SARS-CoV-2 S-protein, primarily in a transgenic mouse model and a Wistar rat model. The low-dose bivalent mRNA vaccine contained half the mRNA of each respective monovalent vaccine, but induced comparable neutralizing antibody titres, enrichment of lung-resident memory CD8+ T cells, specific CD4+ and CD8+ responses, and fully protected transgenic mice from SARS-CoV-2 lethality. The bivalent mRNA vaccine significantly reduced viral replication in both Beta- and Delta-challenged mice. Sera from bivalent mRNA vaccine immunized Wistar rats also contained neutralizing antibodies against the B.1.1.529 (Omicron BA.1) variant. These data suggest that low-dose and fit-for-purpose multivalent mRNA vaccines encoding distinct S-proteins is a feasible approach for increasing the potency of vaccines against emerging and co-circulating SARS-CoV-2 variants.

immunology↗

mRNA Vaccines Induce Rapid Antibody Responses in Mice

mRNA vaccines can be developed and produced quickly, making them attractive for immediate outbreak responses. Furthermore, clinical trials have demonstrated rapid protection following mRNA vaccination. We sought to investigate how quickly mRNA vaccines elicit antibody responses compared to other vaccine modalities. We first examined immune kinetics of mRNA and DNA vaccines expressing SARS-CoV-2 spike in mice. We observed rapid induction of antigen-specific binding and neutralizing antibodies by day 5 following mRNA, but not DNA, immunization. The mRNA vaccine also induced increased levels of IL-5, IL-6 and MCP-1. We then evaluated immune kinetics of an HIV-1 mRNA vaccine in comparison to DNA, protein, and rhesus adenovirus 52 (RhAd52) vaccines with the same HIV-1 envelope antigen in mice. Induction of envelope-specific antibodies was observed by day 5 following mRNA vaccination, whereas antibodies were detected by day 7-14 following DNA, protein, and RhAd52 vaccination. Eliciting rapid humoral immunity may be an advantageous property of mRNA vaccines for controlling infectious disease outbreaks. IMPORTANCEmRNA vaccines can be developed and produced in record time. Here we demonstrate induction of rapid antibody responses by mRNA vaccines encoding two different viral antigens by day 5 following immunization in mice. The rapid immune kinetics of mRNA vaccines can be an advantageous property that makes them well suited for rapid control of infectious disease outbreaks.

microbiology↗

Optimization of Non-Coding Regions Improves Protective Efficacy of an mRNA SARS-CoV-2 Vaccine in Nonhuman Primates

The CVnCoV (CureVac) mRNA vaccine for SARS-CoV-2 has recently been evaluated in a phase 2b/3 efficacy trial in humans. CV2CoV is a second-generation mRNA vaccine with optimized non-coding regions and enhanced antigen expression. Here we report a head-to-head study of the immunogenicity and protective efficacy of CVnCoV and CV2CoV in nonhuman primates. We immunized 18 cynomolgus macaques with two doses of 12 ug of lipid nanoparticle formulated CVnCoV, CV2CoV, or sham (N=6/group). CV2CoV induced substantially higher binding and neutralizing antibodies, memory B cell responses, and T cell responses as compared with CVnCoV. CV2CoV also induced more potent neutralizing antibody responses against SARS-CoV-2 variants, including B.1.351 (beta), B.1.617.2 (delta), and C.37 (lambda). While CVnCoV provided partial protection against SARS-CoV-2 challenge, CV2CoV afforded robust protection with markedly lower viral loads in the upper and lower respiratory tract. Antibody responses correlated with protective efficacy. These data demonstrate that optimization of non-coding regions can greatly improve the immunogenicity and protective efficacy of an mRNA SARS-CoV-2 vaccine in nonhuman primates.

immunology↗

CV2CoV, an enhanced mRNA-based SARS-CoV-2 vaccine candidate, supports higher protein expression and improved immunogenicity in rats

More than two years after the emergence of SARS-CoV-2, 33 COVID-19 vaccines, based on different platforms, have been approved in 197 countries. Novel variants that are less efficiently neutralised by antibodies raised against ancestral SARS-CoV-2 are circulating, highlighting the need to adapt vaccination strategies. Here, we compare the immunogenicity of a first-generation mRNA vaccine candidate, CVnCoV, with a second-generation mRNA vaccine candidate, CV2CoV, in rats. Higher levels of spike (S) protein expression were observed in cell culture with CV2CoV mRNA than with CVnCoV mRNA. Vaccination with CV2CoV also induced higher titres of virus neutralising antibodies with accelerated kinetics in rats compared with CVnCoV. Significant cross-neutralization of the SARS-CoV-2 variants, Alpha (B.1.1.7), Beta (B.1.351), and the mink variant (B1.1.298) that were circulating at the time in early 2021 was also demonstrated. In addition, CV2CoV induced higher levels of antibodies at lower doses than CVnCoV, suggesting that dose-sparing could be possible with the next generation SARS-CoV-2 vaccine which could improve worldwide vaccine supply.

immunology↗

CVnCoV protects human ACE2 transgenic mice from ancestral B BavPat1 and emerging B.1.351 SARS-CoV-2

The ongoing severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic necessitates the fast development of vaccines as the primary control option. Recently, viral mutants termed "variants of concern" (VOC) have emerged with the potential to escape host immunity. VOC B.1.351 was first discovered in South Africa in late 2020, and causes global concern due to poor neutralization with propensity to evade preexisting immunity from ancestral strains. We tested the efficacy of a spike encoding mRNA vaccine (CVnCoV) against the ancestral strain BavPat1 and the novel VOC B.1.351 in a K18-hACE2 transgenic mouse model. Naive mice and mice immunized with formalin-inactivated SARS-CoV-2 preparation were used as controls. mRNA-immunized mice developed elevated SARS-CoV-2 RBD-specific antibody as well as neutralization titers against the ancestral strain BavPat1. Neutralization titers against VOC B.1.351 were readily detectable but significantly reduced compared to BavPat1. VOC B.1.351-infected control animals experienced a delayed course of disease, yet nearly all SARS-CoV-2 challenged naive mice succumbed with virus dissemination and high viral loads. CVnCoV vaccine completely protected the animals from disease and mortality caused by either viral strain. Moreover, SARS-CoV-2 was not detected in oral swabs, lung, or brain in these groups. Only partial protection was observed in mice receiving the formalin-inactivated virus preparation. Despite lower neutralizing antibody titers compared to the ancestral strain BavPat1, CVnCoV shows complete disease protection against the novel VOC B.1.351 in our studies.

microbiology↗

mRNA based SARS-CoV-2 vaccine candidate CVnCoV induces high levels of virus neutralizing antibodies and mediates protection in rodents

mRNA technologies have recently proven clinical efficacy against coronavirus disease 2019 (COVID-19) and are among the most promising technologies to address the current pandemic. Here, we show preclinical data for our clinical candidate CVnCoV, a lipid nanoparticle encapsulated mRNA vaccine that encodes full length, pre-fusion stabilised severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Spike protein. In contrast to previously published approaches, CVnCoV is exclusively composed of naturally occurring nucleotides. Immunisation with CVnCoV induced strong humoral responses with high titres of virus neutralizing antibodies and robust T cell responses. CVnCoV vaccination protected hamsters from challenge with wild type SARS-CoV-2, demonstrated by the absence of viral replication in the lungs. Hamsters vaccinated with a suboptimal dose of CVnCoV leading to breakthrough viral replication exhibited no evidence of vaccine enhanced disease. Overall, data presented here provide evidence that CVnCoV represents a potent and safe vaccine candidate against SARS-CoV-2.

immunology↗

Large nuisance modulation has little impact on IT target match performance

Finding a sought visual target object requires combining visual information about a scene with a remembered representation of the target to create a \"target match\" signal that indicates when a target is in view. Target match signals have been reported to exist within high-level visual brain areas including inferotemporal cortex (IT), where they are mixed with representations of image and object identity. However, these signals are not well understood, particularly in the context of the real-world challenge that the objects we search for typically appear at different positions, sizes, and within different background contexts. To investigate these signals, we recorded neural responses in IT as two rhesus monkeys performed a delayed-match-to-sample object search task in which target objects could appear at a variety of identity-preserving transformations. Consistent with the existence of behaviorally-relevant target match signals in IT, we found that IT contained a linearly separable target match representation that reflected behavioral confusions on trials in which the monkeys made errors. Additionally, target match signals were highly distributed across the IT population, and while a small fraction of units reflected target match signals as target match suppression, most units reflected target match signals as target match enhancement. Finally, we found that the potentially detrimental impact of target match signals on visual representations was mitigated by target match modulation that was approximately (albeit imperfectly) multiplicative. Together, these results support the existence of a robust, behaviorally-relevant target match representation in IT that is configured to minimally interfere with IT visual representations.

neuroscience↗