PLOS Biology

When experiencing music, humans readily perceive and move along with a periodic beat. This ability has been proposed to rely on an enhanced representation of the beat periodicity in brain activity. However, whether this beat representation is achieved in sensory areas or whether it involves associative brain regions remains debated. Here, we addressed this question using intracerebral depth electrodes implanted in 13 human individuals to record local field potentials directly inside the brain. Participants were presented with an acoustic rhythm known to induce perception of a consistent beat across Western adults. The rhythmic stimulus elicited significant responses in a number of areas, especially superior temporal, parietal and frontal cortices located along the dorsal auditory pathway. Notably, these regions, including the primary auditory cortex but also frontal motor regions, showed significantly enhanced beat periodicity as compared to a biomimetic model of subcortical auditory processing. This beat representation was further sharpened in the inferior parietal lobe, indicating that this associative region may play a key role in the mapping between rhythmic inputs and perceptual templates of beat, in line with its posited function as a sensory-motor interface. Together, these findings provide direct evidence for a gradual transformation of rhythmic sensory input into an abstract representation of beat periodicity. This process appears to rely on the dorsal auditory pathway as a functional network supporting the categorization of rhythmic stimuli into behaviorally relevant timing templates that may be experienced as the beat.

Amidst the COVID-19 pandemic, preprints in the biomedical sciences are being posted and accessed at unprecedented rates, drawing widespread attention from the general public, press and policymakers for the first time. This phenomenon has sharpened longstanding questions about the reliability of information shared prior to journal peer review. Does the information shared in preprints typically withstand the scrutiny of peer review, or are conclusions likely to change in the version of record? We assessed preprints from bioRxiv and medRxiv that had been posted and subsequently published in a journal through 30th April 2020, representing the initial phase of the pandemic response. We utilised a combination of automatic and manual annotations to quantify how an article changed between the preprinted and published version. We found that the total number of figure panels and tables changed little between preprint and published articles. Moreover, the conclusions of 7.2% of non-COVID-19-related and 17.2% of COVID-19-related abstracts undergo a discrete change by the time of publication, but the majority of these changes do not qualitatively change the conclusions of the paper.

Perceptual experience is influenced by alpha-band oscillations (8-14 Hz) that dominate parietal and sensory cortices. However, there is uncertainty around the perceptual mechanisms that are affected by oscillatory power and phase. Previous work has linked power and phase to behaviour separately despite their theorised common effects via pulsed-inhibition, potentially misrepresenting or conflating their effects. Here we recorded brain activity using electroencephalography to investigate how alpha oscillations affect the psychometric function over visual contrast in both detection and discrimination tasks. We found that prestimulus power and phase predicted the strength of subsequent evoked neural responses and behavioural accuracy. We then combined power and phase into a joint model of pulsed-inhibition and estimated its effects within a signal detection model of behaviour. The model revealed response gain modulation of visual sensitivity in both tasks, and perceptual bias modulation in detection. Critically, oscillatory power suppressed visual sensitivity more strongly than phase, suggesting a sustained effect of alpha oscillations that is not accounted for by the pulsed-inhibition hypothesis. We conclude that alpha-band activity shapes visual perception by divisively suppressing sensory evidence and baseline sensory noise, with joint power-phase modelling revealing asymmetric contributions to visual sensitivity.

Orienting covert attention to a target location improves performance across a wide array of visual tasks [1, 2]. Whereas fMRI studies have identified partially overlapping frontoparietal networks underlying endogenous (voluntary) and exogenous (involuntary) covert attention, these correlational methods cannot establish whether a given region is functionally necessary. Prior neurostimulation studies have established that early visual cortex (V1/V2) is critical for exogenous [3, 4] but not endogenous attention [5], whereas the right frontal eye field (rFEF+) is critical for endogenous attention [5]. Here, we used a combined psychophysical-TMS protocol to investigate whether rFEF+ is also required for exogenous attention. Participants performed an orientation discrimination task, in which a peripheral cue (valid, neutral, or invalid) preceded a target and a distractor stimulus. We applied two successive TMS pulses to rFEF+ during stimulus presentation and measured contrast-response functions (CRFs) to quantify perceptual sensitivity (d') across all attention cueing and stimulation conditions. When the distractor was stimulated, exogenous attention yielded a characteristic response gain at the target--with performance benefits for valid cues and costs for invalid cues at high contrast levels. Crucially, this response gain was entirely preserved when the target was stimulated. This pattern contrasts with previous findings demonstrating that TMS to V1/V2 eliminates exogenous attentional effects at the stimulated location. These results indicate that rFEF+ is not necessary for exogenous attention, and together with previous studies [3-5] complete a double dissociation: rFEF+ is critical for endogenous but not exogenous attention, whereas V1/V2 is critical for exogenous but not endogenous attention. These findings reveal a distinct causal cortical architecture for voluntary and involuntary spatial attention, suggesting that they rely on different cortical scaffolds.

Posterior parietal cortex (PPC), specifically right supramarginal gyrus, is involved in transsaccadic memory of object orientation for both perception and action. Here, we investigated whether PPC is involved in transsaccadic memory of other features, namely spatial frequency. We employed a functional magnetic resonance imaging paradigm where participants briefly viewed a grating stimulus with a specific spatial frequency that later reappeared with the same or different frequency, after a saccade or continuous fixation. Post-saccadic frequency modulation activated a region in the right hemisphere spanning medial PPC (ventral precuneus) and posterior cingulate cortex. Importantly, the site of peak precuneus activation showed saccade-specific feature modulation (compared to fixation) and task-specific saccade modulation (compared to a saccade localizer task). Psychophysiological interaction analysis revealed functional connectivity between this precuneus site and the precentral gyrus (M1), lingual gyrus (V1/V2), and medial occipitotemporal sulcus. This differed from the transsaccadic orientation network, perhaps because spatial frequency signaled changes in object identity. Overall, this experiment supports a general role for PPC in transsaccadic vision, but suggests that different networks are employed for specific features.

We conducted an international cross-sectional survey of biomedical researchers perspectives on the reproducibility of research. This study builds on a widely cited 2016 survey on reproducibility, and provides a biomedical-specific and contemporary perspective on reproducibility. To sample the community, we randomly selected 400 journals indexed in MEDLINE, from which we extracted the author names and e-mails from all articles published between October 1, 2020 and October 1, 2021. We invited participants to complete an anonymous online survey which collected basic demographic information, perceptions about a reproducibility crisis, perceived causes of irreproducibility of research results, experience conducting replication studies, and knowledge of funding and training for research on reproducibility. A total of 1924 participants accessed our survey, of which 1630 provided useable responses (response rate 7% of 23,234). Key findings include that 72% of participants agreed there was a reproducibility crisis in biomedicine, with 27% of participants indicating the crisis was significant. The leading perceived cause of irreproducibility was a pressure to publish with 62% of participants indicating it always or very often contributes. About half of the participants (54%) had run a replication of their own previously published study while slightly more (57%) had run a replication of another researchers study. Just 16% of participants indicated their institution had established procedures to enhance the reproducibility of biomedical research; and 67% felt their institution valued new research over replication studies. Participants also reported few opportunities to obtain funding to attempt to reproduce a study and 83% perceived it would be harder to do so than to get funding to do a novel study. Our results may be used to guide training and interventions to improve research reproducibility and to monitor rates of reproducibility over time. The findings are also relevant to policy makers and academic leadership looking to create incentives and research cultures that support reproducibility and value research quality.

The nematode Caenorhabditis elegans is one of the best-studied model organisms in molecular biology; however, many aspects of its physiology and the functions of many genes remain poorly understood. In this study, we investigated the role of nematode-specific NSPC proteins, whose mRNAs were recently identified as primary targets of the poly(A) polymerase TENT-5. Surprisingly, we found that NSPCs are exclusively expressed in the excretory gland cell, a cell with still unclear functionality. Using an optogenetic approach, we precisely ablated the excretory gland cell and observed that nematodes exhibited no transcriptomic or physiological changes in its absence. Additionally, we generated and thoroughly studied a strain with a deletion of all 18 nspc genes, which revealed that, despite previous indications, NSPCs do not influence the worms defense response. Instead, the transcriptomic analysis showed that the absence of NSPCs strongly impacts DAF-2/DAF-16 insulin signaling, suggesting that NSPCs may function as neuropeptides influencing key C. elegans signaling pathways. Although further studies are required to elucidate the physiological effects of this regulation, our findings provide new insights into this unexplored part of nematode physiology.

Why are females still underrepresented in science? The social factors that affect career choices and trajectories are thought to be important but are poorly understood. We analyzed author gender in a sample of >61,000 scientific articles in the biological sciences to evaluate the factors that shape the formation of research teams. We find that authorship teams are more gender-assorted than expected by chance, with excess homotypic assortment accounting for up to 7% of published articles. One possible mechanism that could explain gender assortment and broader patterns of female representation is that women may focus on different research topics than men (i.e., the \"topic preference\" hypothesis). An alternative hypothesis is that researchers may consciously or unconsciously prefer to work within same-gender teams (the \"gender homophily\" hypothesis). Using network analysis, we find no evidence to support the topic preference hypothesis, because the topics of female-authored articles are no more similar to each other than expected within the broader research landscape. Instead, consistent with a model of moderate gender homophily, we find that the prevalence of matched-gender teams increases as a discipline moves towards gender parity. This can occur because latent preferences are more easily fulfilled in a gender-diverse environment. Finally, we show that female authors pay a substantial citation cost to work in gender-matched teams. Notably, the prevalence of homotypic assortment is predicted to increase in the future if more disciplines shift towards gender parity. These data indicate that social preferences can have important downstream consequences for the retention of women and other underrepresented groups in science.

Valproic acid (VPA) is a drug with both anticonvulsant and antimanic properties. It has been widely prescribed to treat epilepsy, bipolar disorder, and other neuropsychiatric conditions for decades, but prenatal exposure is linked to developmental anomalies, cognitive deficits, and an increased risk of autism. Remarkably, the molecular basis of VPA action in the brain is not fully understood. To determine VPAs effect on the nervous system without requiring systemic drug application that induce toxic effects, we exploited the well-characterized chemotaxis behavior of the nematode Caenorhabditis elegans. We found that C. elegans are attracted to VPA, and this behavior is missing in animals lacking the tax-4 ion channel and the tax-4-expressing AWC chemosensory neurons. To test the idea that VPA directly activates the AWC neurons, we performed calcium imaging studies in a line expressing GCaMP6s in all amphid chemosensory neurons in the head. We found that VPA evoked calcium transients consistently in the AWC neurons and variably in AWB and ASH. As cyclic nucleotide-gated channels, the active state of tax-4 increases upon the binding of cGMP. Within the worms chemosensory nervous system, receptor guanylate cyclases (rGCs) facilitate the synthesis of cGMP and serve as chemoreceptors for various chemical cues. By performing chemotaxis assays and calcium imaging experiments with rGC mutants against VPA, we found that odr-1 and gcy-28 are essential for mediating VPA attraction, as their absence disrupts both behavior and control AWC calcium transients. However, given their broad use in chemosensation, odr-1 and gcy-28 most likely act as downstream effectors rather than as direct targets. These findings compelled us to investigate whether chemoreceptors belonging to the G protein-coupled receptor (GPCR) family contribute to VPA sensing. We approached this hypothesis by conducting chemotaxis assays with G mutants and identified several (odr-3, egl-30, gpa-2;gpa-3) whose absence leads to a loss of VPA attraction. Thus, future studies should focus on elucidating the mechanisms by which GPCRs contribute to VPA sensing and cGMP signaling.

Parental care is widespread across the animal kingdom and plays a critical role in offspring development. Yet, its broader genetic and evolutionary impacts remain underexplored. Here, using the biparental burying beetle Nicrophorus vespilloides as a model, we show that parental care acts as a genetic capacitor: it allows genetic variation to accumulate while care is present and releases it when care is disrupted. By experimentally manipulating care, we demonstrate that parental care suppresses genetic variation associated with offspring body size, which is released when care is lost. To investigate the underlying molecular mechanisms, we generate a chromosome-scale genome assembly for N. vespilloides, alongside a single-nucleus gene expression atlas and epigenomic datasets from larvae reared with and without parental care. We find that the loss of parental care induces molecular stress, disrupting the expression of the protein chaperone Hsp83, which is a well-known molecular capacitor, alongside other putative mRNA chaperones. Moreover, our results suggest that parental care buffers development by maintaining an open, responsive chromatin landscape and redundant gene regulatory interactions. Overall, our work reveals that parental care shapes the storage, expression and release of genetic variation with broad implications for adaptation and evolution.

Decoding human speech requires the brain to segment the incoming acoustic signal into meaningful linguistic units, ranging from syllables and words to phrases. Integrating these linguistic constituents into a coherent percept sets the root of compositional meaning and hence understanding. One important cue for segmentation in natural speech are prosodic cues, such as pauses, but their interplay with higher-level linguistic processing is still unknown. Here we dissociate the neural tracking of prosodic pauses from the segmentation of multi-word chunks using magnetoencephalography (MEG). We find that manipulating the regularity of pauses disrupts slow speech-brain tracking bilaterally in auditory areas (below 2 Hz) and in turn increases left-lateralized coherence of higher frequency auditory activity at speech onsets (around 25 - 45 Hz). Critically, we also find that multi-word chunks--defined as short, coherent bundles of inter-word dependencies--are processed through the rhythmic fluctuations of low frequency activity (below 2 Hz) bilaterally and independently of prosodic cues. Importantly, low-frequency alignment at chunk onsets increases the accuracy of an encoding model in bilateral auditory and frontal areas, while controlling for the effect of acoustics. Our findings provide novel insights into the neural basis of speech perception, demonstrating that both acoustic features (prosodic cues) and abstract processing at the multi-word timescale are underpinned independently by low-frequency electrophysiological brain activity.

The brain must guide immediate responses to beneficial and harmful stimuli while simultaneously writing memories for future reference. While both immediate actions and reinforcement learning are instructed by dopamine, how dopaminergic systems maintain coherence between these two reward functions is unknown. Through optogenetic activation experiments, we showed that the dopamine neurons that inform olfactory memory in Drosophila have a distinct, parallel function driving attraction and aversion (valence). Sensory neurons required for olfactory memory were dispensable to dopaminergic valence. A broadly projecting set of dopaminergic cells had valence that was dependent on dopamine, glutamate, and octopamine. Similarly, a more restricted dopaminergic cluster with attractive valence was reliant on dopamine and glutamate; flies avoided opto-inhibition of this narrow subset, indicating the role of this cluster in controlling ongoing behavior. Dopamine valence was distinct from output-neuron opto-valence in locomotor pattern, strength, and polarity. Overall our data suggest that dopamines acute effect on valence provides a mechanism by which a dopaminergic system can coherently write memories to influence future responses while guiding immediate attraction and aversion.

It is widely recognized that funding for biomedical research supports the development of major medical advances. However, little systematic effort has been made to determine whether a link exists between the types of funding opportunities that are available to scientists and progress towards new treatments in the clinic. To better understand this relationship, we analyzed the funding opportunities offered by the National Institutes of Health (NIH) over a span of thirty-two years, together with the resulting portfolio of applications and awards. We found NIH funding opportunity announcements became more numerous and increasingly clinically oriented over that span, following a trend that parallels the increasing clinical and translational orientation of both NIH grant applications and NIH-funded publications. Surprisingly, this increase appears to be independent of the representation of clinician-scientists in the NIH workforce.

Peer review serves as the cornerstone of scientific quality control. Yet, the current journal-centric system is hindered by long timelines, high publication costs, inconsistent review quality, systemic biases, and editorial gatekeeping. Notably, the system is built around misaligned measures of impact that are tethered to journal branding and conflate scientific rigor (Quality) with perceived significance (Impact). Here, we report findings from the Discovery Stack Pilot Study, which tested a scientist-designed, journal-independent peer review model. The Discovery Stack model integrates in-line reviewer comments to promote constructive, improvement-focused feedback and generates separate, multimodal assessments of scientific Quality and Impact. To examine its feasibility and effectiveness, manuscripts enrolled in the pilot were reviewed in parallel with traditional journal review. A total of 162 reviews were completed, and survey data from 86 participants were analyzed to evaluate the experience of both authors and reviewers. The results showed that reviewers effectively evaluated Quality and Impact as separate dimensions, with Quality scores being more consistent across reviewers than Impact scores. Importantly, participants strongly supported the core elements of the Discovery Stack model and expressed enthusiasm for its broader adoption to enhance transparency, efficiency, and value in peer review. Future studies will explore integrating this model into a digital platform for reviewing and curating scientific discoveries to improve the production and dissemination of high-quality research.

Throughout history, humans have relied on plants as a source of medication, flavoring, and food. Plants synthesize large chemical libraries and release many of these compounds into the rhizosphere and atmosphere where they affect animal and microbe behavior. To survive, nematodes must have evolved the sensory capacity to distinguish plant-made small molecules (SMs) that are harmful and must be avoided from those that are beneficial and should be sought. This ability to classify chemical cues as a function of their value is fundamental to olfaction, and represents a capacity shared by many animals, including humans. Here, we present an efficient platform based on multi-well plates, liquid handling instrumentation, inexpensive optical scanners, and bespoke software that can efficiently determine the valence (attraction or repulsion) of single SMs in the model nematode, Caenorhabditis elegans. Using this integrated hardware-wetware-software platform, we screened 90 plant SMs and identified 37 that attracted or repelled wild-type animals, but had no effect on mutants defective in chemosensory transduction. Genetic dissection indicates that for at least 10 of these SMs, response valence emerges from the integration of opposing signals, arguing that olfactory valence is often determined by integrating chemosensory signals over multiple lines of information. This study establishes that C. elegans is an effective discovery engine for determining chemotaxis valence and for identifying natural products detected by the chemosensory nervous system.

The coronavirus pandemic introduced many changes to our society, and deeply affected the established in biomedical sciences publication practices. In this article, we present a comprehensive study of the changes in scholarly publication landscape for biomedical sciences during the COVID-19 pandemic, with special emphasis on preprints posted on bioRxiv and medRxiv servers. We observe the emergence of a new category of preprint authors working in the fields of immunology, microbiology, infectious diseases, and epidemiology, who extensively used preprint platforms during the pandemic for sharing their immediate findings. The majority of these findings were works-in-progress unfitting for a prompt acceptance by refereed journals. The COVID-19 preprints that became peer-reviewed journal articles were often submitted to journals concurrently with the posting on a preprint server, and the entire publication cycle, from preprint to the online journal article, took on average 63 days. This included an expedited peer-review process of 43 days and journals production stage of 15 days, however there was a wide variation in publication delays between journals. Only one third of COVID-19 preprints posted during the first nine months of the pandemic appeared as peer-reviewed journal articles. These journal articles display high Altmetric Attention Scores further emphasizing a significance of COVID-19 research during 2020. This article will be relevant to editors, publishers, open science enthusiasts, and anyone interested in changes that the 2020 crisis transpired to publication practices and a culture of preprints in life sciences.

Sexually-dimorphic neural circuits play a critical role in shaping sex-specific animal behaviors. Maps of the structural dimorphisms in these circuits have been explored by analyzing "synaptic connectomes", electron micrograph reconstructions of synaptic connectivity. Nevertheless, recent studies in the model organism C. elegans have shown little to no correlation between the synaptic connectome and dynamic neural activity. Therefore, the extent of sexual dimorphism in functional neural activity remains unknown. To determine the extent of functional sexual-dimorphisms in C. elegans we compared activity, neuron-by-neuron, across all neurons in the heads of both sexes. To sample a broad view of responses to different sensory modalities, we tested a diverse panel of ethologically-relevant olfactory, gustatory, and chemical stimuli, representing both attractive and aversive cues. We found that nearly every sensory neuron responded dimorphically to at least one cue and monomorphically to other cues, indicating that sexually-dimorphic circuits are pervasive and stimulus dependent. This dimorphic and monomorphic activity was present to a lesser extent in downstream interneurons and even less so in motoneurons, implicating sensory neurons as the primary source and location of sexually-dimorphic activity. Comparing the functional activity we measured to the published synaptic connectomes of both sexes revealed that sexual dimorphism in functional connectivity was distinct from and complementary to sexual dimorphism in synaptic connectivity. Our results provide a first-of-its-kind comparison of whole-brain dynamics between sexes at the level of single neurons, serving as an extensive resource for further investigations of functional sex differences.

Honey bees visit food sources up to several kilometers away from their hives, which is underpinned by their sophisticated learning and memory, and cognitive abilities. However, the molecular and neural bases for these advanced brain functions remain obscure. Here, we focused on mKast, a gene preferentially expressed in the optic lobes, a visual center, and a specific Kenyon cell subtype in the mushroom bodies, a higher-order center, in the honey bee brain. We successfully produced homozygous mutant honey bee workers by crossing individuals mutated with CRISPR/Cas9 targeting mKast. Through behavioral analyses of mKast mutants using a new conditioning paradigm and a visual response assay, we found that mKast functions in bimodal learning and memory based on olfactory and visual information, and direction-specific motion sensing. We also found that mKast homozygous mutants have defects in survival outside the colony. These findings suggest that mKast modulate brain functions underlying homing ability that is essential for nidificating hymenopteran species.

Accurate localization of anatomical landmarks is a foundational skill in anatomy and imaging that is often taught informally through expert mentorship, requiring access to data and desktop software. There is no openly accessible, interactive resource that teaches neuroanatomy with quantitative feedback. We present the AFIDs-Validator (validator.afids.io), an open-access, browser-based platform that pairs guided instruction with quantitative assessment. The platform combines (1) a learning mode in which a language-model neuroanatomy tutor operates inside an MRI viewer, giving anatomy-first instruction that responds to the learner's current image slice, orientation, and cursor position; and (2) a validation engine that accepts a learner's landmark file and returns per-landmark Euclidean error against expert-annotated references spanning 21 brain templates. To make the feedback interpretable, we analyzed 15,000 landmark annotations across 132 human subjects and found that landmark difficulty varies fourfold (median error ranged from 0.37 mm at the anterior commissure to 1.50 mm at the temporal horns) with heavy-tailed distributions at every landmark. These distributions are compiled into per-landmark reliability priors, so learners are scored against the empirical spread of trained raters rather than an arbitrary threshold, and difficult landmarks are not mistaken for poor performance. The AFIDs-Validator requires no installation, licensed software, or local data, and all code, reference data, and tutor design are openly released.

Research on butterflies has uncovered a conserved "toolkit" of genes for color pattern development and evolution. One of these genes is optix, a homeobox transcription factor that regulates ommochrome and melanin pigmentation, as well as structural coloration, in nymphalid butterflies. It remains unclear, however, whether optix plays any roles in color patterning outside of the Nymphalidae. We used CRISPR-Cas9 to disrupt optix in the tobacco hornwormmoth Manduca sexta and observed a dramatic abdominal pigmentation phenotype, where orange pigmentation was replaced by black eumelanin. Chemical assays suggest that the orange pigment is not an ommochrome, indicating that optix modulates an alternative, uncharacterized pigment pathway in M. sexta. RNA-seq and chemical analyses of orange and black abdominal scales lead us to speculate that the orange pigment may be a type of melanin, perhaps N-{beta}-alanyldopamine (NBAD) sclerotin. Our results suggest that optix plays a deeply ancestral role in pigment regulation in Lepidoptera, and demonstrates evolutionary flexibility in how it interfaces with pigment chemistry across moths and butterflies.