PLoS Biology最新文献

Practice not only improves task performance but also changes task execution from rule- to memory-based processing by incorporating experiences from practice. However, how and when this change occurs is unclear. We test the hypothesis that strategy transitions in task learning can result from decision-making guided by cost-benefit analysis. Participants learn 2 task sequences and are then queried about the task type at a cued sequence and position. Behavioral improvement with practice can be accounted for by a computational model implementing cost-benefit analysis and the model-predicted strategy transition points align with the observed behavioral slowing. Model comparisons using behavioral data show that strategy transitions are better explained by a cost-benefit analysis across alternative strategies rather than solely on memory strength. Model-guided fMRI findings suggest that the brain encodes a decision variable reflecting the cost-benefit analysis and that different strategy representations are double-dissociated. Further analyses reveal that strategy transitions are associated with activation patterns in the dorsolateral prefrontal cortex and increased pattern separation in the ventromedial prefrontal cortex. Together, these findings support cost-benefit analysis as a mechanism of practice-induced strategy shift.

The basal ganglia (BG) play a key role in decision-making, preventing impulsive actions in some contexts while facilitating fast adaptations in others. The specific contributions of different BG structures to this nuanced behavior remain unclear, particularly under varying situations of noisy and conflicting information that necessitate ongoing adjustments in the balance between speed and accuracy. Theoretical accounts suggest that dynamic regulation of the amount of evidence required to commit to a decision (a dynamic "decision boundary") may be necessary to meet these competing demands. Through the application of novel computational modeling tools in tandem with direct neural recordings from human BG areas, we find that neural dynamics in the theta band manifest as variations in a collapsing decision boundary as a function of conflict and uncertainty. We collected intracranial recordings from patients diagnosed with either Parkinson's disease (PD) (n = 14) or dystonia (n = 3) in the subthalamic nucleus (STN), globus pallidus internus (GPi), and globus pallidus externus (GPe) during their performance of a novel perceptual discrimination task in which we independently manipulated uncertainty and conflict. To formally characterize whether these task and neural components influenced decision dynamics, we leveraged modified diffusion decision models (DDMs). Behavioral choices and response time distributions were best characterized by a modified DDM in which the decision boundary collapsed over time, but where the onset and shape of this collapse varied with conflict. Moreover, theta dynamics in BG structures modulated the onset and shape of this collapse but differentially across task conditions. In STN, theta activity was related to a prolonged decision boundary (indexed by slower collapse and therefore more deliberate choices) during high conflict situations. Conversely, rapid declines in GPe theta during low conflict conditions were related to rapidly collapsing boundaries and expedited choices, with additional complementary decision bound adjustments during high uncertainty situations. Finally, GPi theta effects were uniform across conditions, with increases in theta associated with a prolongation of decision bound collapses. Together, these findings provide a nuanced understanding of how our brain thwarts impulsive actions while nonetheless enabling behavioral adaptation amidst noisy and conflicting information.

Pain is closely linked to alpha oscillations (8 < 13 Hz) which are thought to represent a supra-modal, top-down mediated gating mechanism that shapes sensory processing. Consequently, alpha oscillations might also shape the cerebral processing of nociceptive input and eventually the perception of pain. To test this mechanistic hypothesis, we designed a sham-controlled and double-blind electroencephalography (EEG)-based neurofeedback study. In a short-term neurofeedback training protocol, healthy participants learned to up- and down-regulate somatosensory alpha oscillations using attention. Subsequently, we investigated how this manipulation impacts experimental pain applied during neurofeedback. Using Bayesian statistics and mediation analysis, we aimed to test whether alpha oscillations mediate attention effects on pain perception. The results showed that attention and neurofeedback successfully up- and down-regulated the asymmetry of somatosensory alpha oscillations. However, attention and neurofeedback did not modulate pain ratings or related brain responses. Accordingly, somatosensory alpha oscillations did not mediate attention effects on pain perception. Thus, our results challenge the hypothesis that somatosensory alpha oscillations shape pain perception. A causal relationship between alpha oscillations and pain perception might not exist or be more complex than hypothesized. Trial registration: Following Stage 1 acceptance, the study was registered at ClinicalTrials.gov NCT05570695.

Antibodies are extensively used in biomedical research, clinical fields, and disease treatment. However, to enhance the reproducibility and reliability of antibody-based experiments, it is crucial to have a detailed understanding of the antibody's target specificity and epitope. In this study, we developed a high-throughput and precise epitope analysis method, DECODE (Decoding Epitope Composition by Optimized-mRNA-display, Data analysis, and Expression sequencing). This method allowed identifying patterns of epitopes recognized by monoclonal or polyclonal antibodies at single amino acid resolution and predicted cross-reactivity against the entire protein database. By applying the obtained epitope information, it has become possible to develop a new 3D immunostaining method that increases the penetration of antibodies deep into tissues. Furthermore, to demonstrate the applicability of DECODE to more complex blood antibodies, we performed epitope analysis using serum antibodies from mice with experimental autoimmune encephalomyelitis (EAE). As a result, we were able to successfully identify an epitope that matched the sequence of the peptide inducing the disease model without relying on existing antigen information. These results demonstrate that DECODE can provide high-quality epitope information, improve the reproducibility of antibody-dependent experiments, diagnostics and therapeutics, and contribute to discover pathogenic epitopes from antibodies in the blood.

Studies of perception have long shown that the brain adds information to its sensory analysis of the physical environment. A touchstone example for humans is language use: to comprehend a physical signal like speech, the brain must add linguistic knowledge, including syntax. Yet, syntactic rules and representations are widely assumed to be atemporal (i.e., abstract and not bound by time), so they must be translated into time-varying signals for speech comprehension and production. Here, we test 3 different models of the temporal spell-out of syntactic structure against brain activity of people listening to Dutch stories: an integratory bottom-up parser, a predictive top-down parser, and a mildly predictive left-corner parser. These models build exactly the same structure but differ in when syntactic information is added by the brain-this difference is captured in the (temporal distribution of the) complexity metric "incremental node count." Using temporal response function models with both acoustic and information-theoretic control predictors, node counts were regressed against source-reconstructed delta-band activity acquired with magnetoencephalography. Neural dynamics in left frontal and temporal regions most strongly reflect node counts derived by the top-down method, which postulates syntax early in time, suggesting that predictive structure building is an important component of Dutch sentence comprehension. The absence of strong effects of the left-corner model further suggests that its mildly predictive strategy does not represent Dutch language comprehension well, in contrast to what has been found for English. Understanding when the brain projects its knowledge of syntax onto speech, and whether this is done in language-specific ways, will inform and constrain the development of mechanistic models of syntactic structure building in the brain.

Coronaviruses express their structural and accessory genes via a set of subgenomic RNAs, whose synthesis is directed by transcription regulatory sequences (TRSs) in the 5' genomic leader and upstream of each body open reading frame. In SARS-CoV-2, the TRS has the consensus AAACGAAC; upon searching for emergence of this motif in the global SARS-CoV-2 sequences, we find that it evolves frequently, especially in the 3' end of the genome. We show well-supported examples upstream of the Spike gene-within the nsp16 coding region of ORF1b-which is expressed during human infection, and upstream of the canonical Envelope gene TRS, both of which have evolved convergently in multiple lineages. The most frequent neo-TRS is within the coding region of the Nucleocapsid gene, and is present in virtually all viruses from the B.1.1 lineage, including the variants of concern Alpha, Gamma, Omicron and descendants thereof. Here, we demonstrate that this TRS leads to the expression of a novel subgenomic mRNA encoding a truncated C-terminal portion of Nucleocapsid, which is an antagonist of type I interferon production and contributes to viral fitness during infection. We observe distinct phenotypes when the Nucleocapsid coding sequence is mutated compared to when the TRS alone is ablated. Our findings demonstrate that SARS-CoV-2 is undergoing evolutionary changes at the functional RNA level in addition to the amino acid level.

A single exposure to a stressful event can result in enduring changes in behaviour. Long-term modifications in neuronal networks induced by stress are well explored but the initial steps leading to these alterations remain incompletely understood. In this study, we found that acute stress exposure triggers an immediate increase in the firing activity of calretinin-positive neurons in the paraventricular thalamic nucleus (PVT/CR+) that persists for several days in mice. This increase in activity had a causal role in stress-induced changes in spontaneous behaviour. Attenuating PVT/CR+ neuronal activity for only 1 h after the stress event rescued both the protracted increase in PVT/CR+ firing rate and the stress-induced behavioural alterations. Activation of the key forebrain targets (basolateral amygdala, prelimbic cortex, and nucleus accumbens) that mediate defensive behaviour has also been reduced by this post-stress inhibition. Reduction of PVT/CR+ cell activity 5 days later remained still effective in ameliorating stress-induced changes in spontaneous behaviour. The results demonstrate a critical role of the prolonged, post-stress changes in firing activity of PVT/CR+ neurons in shaping the behavioural changes associated with stress. Our data proposes a therapeutic window for intervention in acute stress-related disorders, offering potential avenues for targeted treatment strategies.

Bacteriophages infect gram-negative bacteria by attaching to molecules present on the bacterial surface, often lipopolysaccharides (LPS). Modification of LPS can lead to resistance to phage infection. In addition, LPS modifications can impact antibiotic susceptibility, allowing for phage-antibiotic synergism. The evolutionary mechanism(s) behind such synergistic interactions remain largely unclear. Here, we show that the presence of antibiotics can affect the evolution of resistance to phage infection, using phage ΦX174 and Escherichia coli C. We use a collection of 34 E. coli C LPS strains, each of which is resistant to ΦX174, and has either a "rough" or "deep rough" LPS phenotype. Growth of the bacterial strains with the deep rough phenotype is inhibited at low concentrations of chloramphenicol and, to a much lesser degree, gentamicin. Treating E. coli C wild type with ΦX174 and chloramphenicol eliminates the emergence of mutants with the deep rough phenotype, and thereby slows the evolution of resistance to phage infection. At slightly lower chloramphenicol concentrations, phage resistance rates are similar to those observed at high concentrations; yet, we show that the diversity of possible mutants is much larger than at higher chloramphenicol concentrations. These data suggest that specific antibiotic concentrations can lead to synergistic phage-antibiotic interactions that disappear at higher antibiotic concentrations. Overall, we show that the change in survival of various ΦX174-resistant E. coli C mutants in the presence of antibiotics can explain the observed phage-antibiotic synergism.

Human papillomavirus (HPV) infections drive one in 20 new cancer cases, exerting a particularly high burden on women. Most anogenital HPV infections are cleared in less than two years, but the underlying mechanisms that favour persistence in around 10% of women remain largely unknown. Notwithstanding, it is precisely this information that is crucial for improving treatment, screening, and vaccination strategies. To understand viral and immune dynamics in non-persisting HPV infections, we set up an observational longitudinal cohort study with frequent on-site visits for biological sample collection. We enrolled 189 women aged from 18 to 25 and living in the area of Montpellier (France) between 2016 and 2020. We performed 974 on-site visits for a total of 1,619 months of follow-up. We collected data on virus load, local immune cell populations, local concentrations of cytokines, and circulating antibody titres. Using hierarchical Bayesian statistical modelling to simultaneously analyse the data from 164 HPV infections from 76 participants, we show that in two months after infection, HPV viral load in non-persisting infections reaches a plateau that lasts on average for 13 to 20 months (95% credibility interval) and is then followed by a rapid clearance phase. This first description of the dynamics of HPV infections comes with the identification of immune correlates associated with infection clearance, especially gamma-delta T cells and CXCL10 concentration. A limitation of this study on HPV kinetics is that many infection follow-ups are censored. Furthermore, some immune cell populations are difficult to label because cervical immunity is less well characterised than systemic immunity. These results open new perspectives for understanding the frontier between acute and chronic infections, and for controlling HPV-associated diseases, as well as for research on human cancers of infectious origin. Trial Registration: This trial was registered is registered at ClinicalTrials.gov under the ID NCT02946346. This study has been approved by the Comité de Protection des Personnes (CPP) Sud Méditerranée I (reference number 2016-A00712-49); by the Comité Consultatif sur le Traitement de l'Information en matière de Recherche dans le domaine de la Santé (reference number 16.504); by the Commission Nationale Informatique et Libertés (reference number MMS/ABD/ AR1612278, decision number DR-2016-488), by the Agence Nationale de Sécurité du Médicament et des Produits de Santé (reference 20160072000007).

Perceptual awareness results from an intricate interaction between external sensory input and the brain's spontaneous activity. Pre-stimulus ongoing activity influencing conscious perception includes both brain oscillations in the alpha (7 to 14 Hz) and beta (14 to 30 Hz) frequency ranges and aperiodic activity in the slow cortical potential (SCP, <5 Hz) range. However, whether brain oscillations and SCPs independently influence conscious perception or do so through shared mechanisms remains unknown. Here, we addressed this question in 2 independent magnetoencephalography (MEG) data sets involving near-threshold visual perception tasks in humans using low-level (Gabor patches) and high-level (objects, faces, houses, animals) stimuli, respectively. We found that oscillatory power and large-scale SCP activity influence conscious perception through independent mechanisms that do not have shared variance. In addition, through mediation analysis, we show that pre-stimulus oscillatory power and SCP activity have different relations to pupil size-an index of arousal-in their influences on conscious perception. Together, these findings suggest that oscillatory power and SCPs independently contribute to perceptual awareness, with distinct relations to pupil-linked arousal.