Cortical signatures of precision grip force control in children, adolescents, and adults

Frontiers in Aging Neuroscience

Manual motor performance declines with age, but the extent to which age influences the acquisition of new skills remains a topic of debate. Here, we examined whether older healthy adults show less training-dependent performance improvements during a single session of a bimanual pinch task than younger adults. We also explored whether physical and cognitive factors, such as grip strength or motor-cognitive ability, are associated with performance improvements. Healthy younger (n = 16) and older (n = 20) adults performed three training blocks separated by short breaks. Participants were tasked with producing visually instructed changes in pinch force using their right and left thumb and index fingers. Task complexity was varied by shifting between bimanual mirror-symmetric and inverse-asymmetric changes in pinch force. Older adults generally displayed higher visuomotor force tracking errors during the more complex inverse-asymmetric task compared to younger adults. Both groups showed a comparable net decrease in visuomotor force tracking error over the entire session, but their improvement trajectories differed. Young adults showed enhanced visuomotor tracking error only in the first block, while older adults exhibited a more gradual improvement over the three training blocks. Furthermore, grip strength and performance on a motor-cognitive test battery scaled positively with individual performance improvements during the first block in both age groups. Together, the results show subtle age-dependent differences in the rate of bimanual visuomotor skill acquisition, while overall short-term learning ability is maintained.

bioRxiv

Background Transcranial magnetic stimulation (TMS) triggers time-locked cortical activity that can be recorded with electroencephalography (EEG). Transcranial evoked potentials (TEPs) are widely used to probe brain responses to TMS. Methods Here, we systematically reviewed 137 published experiments that studied TEPs elicited from TMS to the human primary motor cortex (M1) in healthy individuals to investigate the impact of methodological choices. We scrutinized prevalent methodological choices and assessed how consistently they were reported in published papers. We extracted amplitudes and latencies from reported TEPs and compared total cortical activation and specific TEP peaks and components. Results Reporting of methodological details was overall sufficient, but some relevant information regarding the TMS settings and the recording and pre-processing of EEG data were missing in more than 25% of the included experiments. The published TEP latencies and amplitudes confirm the "prototypical" TEP waveform of M1, comprising distinct N15, P30, N45, P60, N100, and P180 peaks. However, variations in amplitude and latencies were evident across studies. Higher stimulation intensities were associated with overall larger TEP amplitudes. Active noise masking during TMS generally resulted in lower TEP amplitudes compared to no or passive masking but did not specifically impact those TEP peaks linked to long-latency sensory processing. Studies implementing independent component analysis (ICA) for artifact removal generally reported lower TEP amplitudes. Conclusion Some aspects of reporting practices could be …

Frontiers in Aging Neuroscience

Manual motor performance declines with age, but the extent to which age influences the acquisition of new skills remains a topic of debate. Here, we examined whether older healthy adults show less training-dependent performance improvements during a single session of a bimanual pinch task than younger adults. We also explored whether physical and cognitive factors, such as grip strength or motor-cognitive ability, are associated with performance improvements. Healthy younger (n = 16) and older (n = 20) adults performed three training blocks separated by short breaks. Participants were tasked with producing visually instructed changes in pinch force using their right and left thumb and index fingers. Task complexity was varied by shifting between bimanual mirror-symmetric and inverse-asymmetric changes in pinch force. Older adults generally displayed higher visuomotor force tracking errors during the more complex inverse-asymmetric task compared to younger adults. Both groups showed a comparable net decrease in visuomotor force tracking error over the entire session, but their improvement trajectories differed. Young adults showed enhanced visuomotor tracking error only in the first block, while older adults exhibited a more gradual improvement over the three training blocks. Furthermore, grip strength and performance on a motor-cognitive test battery scaled positively with individual performance improvements during the first block in both age groups. Together, the results show subtle age-dependent differences in the rate of bimanual visuomotor skill acquisition, while overall short-term learning ability is maintained.

bioRxiv

Identifying which movement parameters are reflected in the corticospinal excitability (CSE) will improve our understanding human motor control. Change in CSE measured with transcranial magnetic stimulation (TMS)-induced motor evoked potentials (MEPs) can probe the content of the signal from primary motor cortex (M1) through the corticospinal pathway and spinal motoneurons to the muscle. Here we used MEPs to investigate which movement- related parameters are reflected in CSE in 33 healthy adults. In three separate tasks, we evaluated which movement parameter(s), force, angle, and velocity, are reflected in the MEP amplitude during movement preparation and movement execution. Bayesian model comparison in a forward feature selection framework identified force and velocity measures as reflected in the MEP amplitude during movement preparation, and force, angle, and velocity measures as reflected in the MEP amplitude during movement execution. Importantly, we included measures of electromyography (EMG) in the forward feature selection, and the parameter measures are included only if they add explanatory power of MEP amplitude in addition to the EMG. These findings show that when taking EMG measures into account, all three movement parameters force, angle, and velocity are reflected in CSE. These findings propose a flexible and task-dependent form of signaling in the motor system that allows parameter-specific modulation of CSE to accurately control finger movements.

Frontiers in Human Neuroscience

The central nervous system has a remarkable ability to plan motor actions, to predict and monitor the sensory consequences during and following motor actions and integrate these into future actions. Numerous studies investigating human motor learning have employed tasks involving either force control during isometric contractions or position control during dynamic tasks. To our knowledge, it remains to be elucidated how motor practice with an emphasis on position control influences force control and vice versa. Furthermore, it remains unexplored whether these distinct types of motor practice are accompanied by differential effects on corticospinal excitability. In this study, we tested motor accuracy and effects of motor practice in a force or position control task allowing wrist flexions of the non-dominant hand in the absence of online visual feedback. For each trial, motor performance was quantified as errors (pixels) between the displayed target and the movement endpoint. In the main experiment, 46 young adults were randomized into three groups: position control motor practice (PC), force control motor practice (FC), and a resting control group (CON). Following assessment of baseline motor performance in the position and force control tasks, intervention groups performed motor practice with, augmented visual feedback on performance. Motor performance in both tasks was assessed following motor practice. In a supplementary experiment, measures of corticospinal excitability were obtained in twenty additional participants by application of transcranial magnetic stimulation to the primary motor cortex hot spot of the flexor carpi radialis muscle …

Pre-programmed hamstring activation during a sidecutting is associated with reflexive response during a single-legged pertubation test — The Capital Region of Denmark's Research Portal Skip to main navigation Skip to search Skip to main content The Capital Region of Denmark's Research Portal Home The Capital Region of Denmark's Research Portal Logo Help & FAQ Dansk English Home Hospitals/departments Researchers Research output Activities Prizes Search by expertise, name or affiliation Pre-programmed hamstring activation during a sidecutting is associated with reflexive response during a single-legged pertubation test Jesper Bencke * , Mette K Zebis, Jesper Lundbye-Jensen, Anke Karabanov, Merete Brink Speedtsberg, Niels Jensby Nedergaard * Corresponding author for this work Department of Orthopaedic Surgery Sports Orthopedic Research Center - Copenhagen Overview Original …

Trials

BackgroundMany patients do not fully regain motor function after ischemic stroke. Transcranial direct current stimulation (TDCS) targeting the motor cortex may improve motor outcome as an add-on intervention to physical rehabilitation. However, beneficial effects on motor function vary largely among patients within and across TDCS trials. In addition to a large heterogeneity of study designs, this variability may be caused by the fact that TDCS was given as a one-size-fits-all protocol without accounting for anatomical differences between subjects. The efficacy and consistency of TDCS might be improved by a patient-tailored design that ensures precise targeting of a physiologically relevant area with an appropriate current strength.MethodsIn a randomized, double-blinded, sham-controlled trial, patients with subacute ischemic stroke and residual upper-extremity paresis will receive two times 20 min of focal TDCS of …

Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation

Background: Sensorimotor integration can be investigated with transcranial magnetic stimulation (TMS) by measuring short-latency afferent inhibition (SAI). SAI reflects the inhibitory effects of peripheral nerve stimulation (PNS) of the hand on the response to a TMS pulse delivered∼ 25ms later to contralateral primary motor cortex (M1). Repeated pairing of the peripheral and transcranial stimuli (Paired Associative Stimulation, PAS) can produce facilitatory after-effects on corticomotor excitability. Since conventional PAS protocols involve mixed nerve stimulation, after-effects might be mediated by both proprioceptive and cutaneous afferent signals. Here, we investigated the after-effects of a 5Hz PAS protocol that selectively paired cutaneous inputs from a single digit with TMS of M1 hand representation (M1HAND).Material and methods: On two separate days, we mapped corticomotor representation of three hand …

Neurobiology of learning and memory

Performing a single bout of exercise can enhance motor learning and long-term retention of motor skills. Parameters such as the intensity and when the exercise bout is performed in relation to skill practice (i.e., timing) likely influence the effectiveness. However, it is still not fully understood how exercise should be administered to maximize its effects and how exercise interacts with distinct components of skill learning. Here, we expand this knowledge by investigating the potential synergistic effects of performing acute exercise both prior to and following motor practice. Sixty-four, able-bodied, young adult male participants practiced a sequential visuomotor accuracy tracking (SVAT) task requiring rapid and accurate force modulation and high levels of precision control using intrinsic hand muscles. The task also contained a repeated pattern of targets that allowed sequence-specific skill improvements. Sequential and …

bioRxiv

Learning or relearning of motor skills requires plasticity in relevant neural circuits. Motor recovery following lesions to the corticospinal system can be augmented through neuromodulation techniques targeting the affected or compensatory neural circuits. By repeatedly pairing transcranial magnetic stimulation of the primary motor cortex (M1) and motoneuronal electrical stimulation (i.e., paired corticomotoneuronal stimulation, PCMS) timed to arrive at the corticomotoneuronal (CM) synapses in close temporal proximity, spike-timing-dependent bidirectional changes in CM transmission can be induced in humans . PCMS-induced increases in CM transmission have been demonstrated to transiently improve motor control in patients with spinal cord injury , whereas effects on the malleability of neural circuits are entirely unexplored. We hypothesized that PCMS can prime mechanisms of subsequent motor learning exclusively when directed to the neural circuitry underpinning the motor behavior. In three experiments, we provide the first evidence (‘Experiment I’) and a double-blinded, sham-controlled replication (‘Experiment II’) that PCMS targeting the spinal CM synapses can prime subsequent learning of rapid finger movements relying on spinal neuroplasticity. Finally, we demonstrate that the effects of PCMS are circuit-specific and bidirectional. When PCMS was timed to arrive at a facilitatory interval in M1 but an inhibitory interval at the CM synapses subsequent learning was transiently impeded (‘Experiment III’). Taken together, our results provide proof-of-principle that non-invasively induced plasticity governed by Hebbian learning rules interacts …

Neuroscience Letters

Raffalt, PC, Sommerfeld, JH, Stergiou, N & Likens, AD 2023,'Stride-to-stride time intervals are independently affected by the temporal pattern and probability distribution of visual cues', Neuroscience Letters, vol. 792, 136909. https://doi. org/10.1016/j. neulet. 2022.136909

Journal of Neurophysiology

Single-pulse transcranial magnetic stimulation (TMS) of the precentral hand representation (M1HAND) can elicit indirect waves in the corticospinal tract at a periodicity of ∼660 Hz, called I-waves. These descending volleys are produced by transsynaptic excitation of fast-conducting corticospinal axons in M1HAND. Paired-pulse TMS can induce short-interval intracortical facilitation (SICF) of motor evoked potentials (MEPs) at interpulse intervals that match I-wave periodicity. This study examined whether short-latency corticospinal facilitation engages additional mechanisms independently of I-wave periodicity. In 19 volunteers, one to four biphasic TMS pulses were applied to left M1HAND with interpulse intervals adjusted to the first peak or trough of the individual SICF curve at different intensities to probe the intensity-response relationship. Multipulse TMSHAND at individual peak latency facilitated MEP amplitudes …

Human Movement Science

In this study, we investigated the effects of motor practice with an emphasis on either position or force control on motor performance, motor accuracy and variability in preadolescent children. Furthermore, we investigated corticomuscular coherence and potential changes following motor practice.We designed a setup allowing discrete wrist flexions of the non-dominant hand and tested motor accuracy and variability when the task was to generate specific movement endpoints (15–75 deg) or force levels (5–25% MVC). All participants were tested in both tasks at baseline and post motor practice without augmented feedback on performance. Following baseline assessment, participants (44 children aged 9–11 years) were randomly assigned to either position (PC) or force control (FC) motor practice or a resting control group (CON). The PC and FC groups performed four blocks of 40 trials motor practice with augmented …

BackgroundChildhood obesity can have significant negative consequences for children’s wellbeing and long-term physical health. In Denmark, the prevalence of overweight and obesity increases from 13% to 18% during elementary school and reaches 53% among adults, underscoring the importance of early prevention. Prior school-based interventions have shown limited effects on child weight development, which highlights the necessity for comprehensive approaches addressing the complex drivers of childhood obesity.“Generation Healthy Kids”(GHK) is a multi-setting, multi-component intervention aiming to promote healthy weight development, health and wellbeing in Danish children aged 6–11 years. This protocol describes the GHK main trial, which is a cluster-randomized trial evaluating the effectiveness and implementation of the GHK intervention.MethodsDuring December 2022–May 2023, we recruited 24 schools (Capital, Zealand and Southern Denmark Regions) and randomly allocated them 1: 1 to intervention or control. The intervention will run for two school years (October 2023–June 2025) and will include children in 1 st–2 nd grade at baseline (approx. n= 1,600 children). The intervention will target multiple settings, including families, schools, after-school clubs, and local communities. Within four focus areas–diet, physical activity, screen media use, and sleep habits–the intervention incorporates several fixed elements, including a free school lunch program and three weekly sessions of physical activity at school. Furthermore, building on whole-systems thinking, the intervention will encompass co-created elements developed …

Cerebral Cortex

The cortical mechanisms underlying the act of taking a step—including planning, execution, and modification—are not well understood. We hypothesized that oscillatory communication in a parieto-frontal and corticomuscular network is involved in the neural control of visually guided steps. We addressed this hypothesis using source reconstruction and lagged coherence analysis of electroencephalographic and electromyographic recordings during visually guided stepping and 2 control tasks that aimed to investigate processes involved in (i) preparing and taking a step and (ii) adjusting a step based on visual information. Steps were divided into planning, initiation, and execution phases. Taking a step was characterized by an upregulation of beta/gamma coherence within the parieto-frontal network during planning followed by a downregulation of alpha and beta/gamma coherence during initiation and …

Research in Developmental Disabilities

BackgroundIndividuals with Down syndrome (DS) have impaired general motor skills compared to typically developed (TD) individuals.AimsTo gain knowledge on how young adults with DS learn and retain new motor skills.Methods and ProceduresA DS-group (mean age = 23.9 ± 3 years, N = 11), and an age-matched TD-group (mean age 22.8 ± 1.8, N = 14) were recruited. The participants practiced a visuomotor accuracy tracking task (VATT) in seven blocks (10.6 min). Online and offline effects of practice were assessed based on tests of motor performance at baseline immediate and 7-day retention.Outcomes and ResultsThe TD-group performed better than the DS-group on all blocks (all P < 0.001). Both groups improved VATT-performance online from baseline to immediate retention, (all P < 0.001) with no difference in online effect between groups. A significant between-group difference was observed in the …

Does female handball players with low hip external rotation strength display higher knee abduction moments during side-cutting than players with high strength? — The Capital Region of Denmark's Research Portal Skip to main navigation Skip to search Skip to main content The Capital Region of Denmark's Research Portal Home The Capital Region of Denmark's Research Portal Logo Help & FAQ Dansk English Home Hospitals/departments Researchers Research output Activities Prizes Search by expertise, name or affiliation Does female handball players with low hip external rotation strength display higher knee abduction moments during side-cutting than players with high strength? Niels Jensby Nedergaard * , Mette K Zebis, Louise W. Nielsen, Andreas Henneberg, Jesper Lundbye-Jensen, Anke Karabanov, Jesper Bencke * Corresponding author for this work Department of Orthopaedic Surgery Overview …

Introduction Heavy‐load free‐flow resistance exercise (HL‐FFRE) is a widely used training modality. Recently, low‐load blood‐flow restricted resistance exercise (LL‐BFRRE) has gained attention in both athletic and clinical settings as an alternative when conventional HL‐FFRE is contraindicated or not tolerated. LL‐BFRRE has been shown to result in physiological adaptations in muscle and connective tissue that are comparable to those induced by HL‐FFRE. The underlying mechanisms remain unclear; however, evidence suggests that LL‐BFRRE involves elevated metabolic stress compared to conventional free‐flow resistance exercise (FFRE). Aim The aim was to evaluate the initial (<10 min post‐exercise), intermediate (10–20 min), and late (>30 min) hormonal, immune, and oxidative stress responses observed following acute sessions of LL‐BFRRE compared to FFRE in healthy adults. Methods A …

bioRxiv

Background Transcranial evoked potentials (TEPs) measured via electroencephalography (EEG) are widely used to study the cortical responses to transcranial magnetic stimulation (TMS). Immediate transcranial evoked potentials (i-TEPs) have been obscured by pulse and muscular artifacts. Thus, the TEP peaks that are commonly reported have latencies that are too long to be caused by direct excitation of cortical neurons. Methods In 14 healthy individuals, we recorded i-TEPs evoked by a single biphasic TMS pulse targeting the primary motor hand area (M1_HAND) or parietal or midline control sites. Sampling EEG at 50 kHz enabled us to reduce the duration of the TMS pulse artifact to a few milliseconds, while minor adjustments of the TMS coil tilt or position enabled us to avoid cranial muscular twitches during the experiment. Results We observed an early positive EEG deflection starting after approx. 2 ms followed by a series of superimposed peaks with an inter-peak interval of ~1.1-1.4 ms in multiple electrodes overlying the stimulated sensorimotor region. This multi-peak i-TEP response was only evoked by TMS of the M1_HAND region and was modified by changes in stimulation intensity and current direction. Discussion Single-pulse TMS of the M1_HAND evokes an immediate local multi-peak response at the cortical site of stimulation. Our results suggest that the observed i-TEP patterns are genuine cortical responses evoked by TMS caused by synchronized excitation of pyramidal neurons in the targeted precentral cortex. This notion needs to be corroborated in future studies, including further investigations into the potential …

International Journal of Clinical and Health Psychology

Background/objectivePatients with major depressive disorder (MDD) have altered learning rates for rewards and losses in non-social learning paradigms. However, it is not well understood whether the ability to learn from social interactions is altered in MDD patients. Using reinforcement learning during the repeated Trust Game (rTG), we investigated how MDD patients learn to trust newly-met partners in MDD patients.MethodSixty-eight MDD patients and fifty-four controls each played as ‘investor’ and interacted with ten different partners. We manipulated both the level of trustworthiness by varying the chance of reciprocity (10, 30, 50, 70 and 90%) and reputation disclosure, where partners’ reputation was either pre-disclosed or hidden.ResultsOur reinforcement learning model revealed that MDD patients had significantly higher learning rates for losses than the controls in both the reputation disclosure and non …

Elife

Chemoresistance is a major cause of treatment failure in many cancers. However, the life cycle of cancer cells as they respond to and survive environmental and therapeutic stress is understudied. In this study, we utilized a microfluidic device to induce the development of doxorubicin-resistant (DOXR) cells from triple negative breast cancer (TNBC) cells within 11 days by generating gradients of DOX and medium. In vivo chemoresistant xenograft models, an unbiased genome-wide transcriptome analysis, and a patient data/tissue analysis all showed that chemoresistance arose from failed epigenetic control of the nuclear protein-1 (NUPR1)/histone deacetylase 11 (HDAC11) axis, and high NUPR1 expression correlated with poor clinical outcomes. These results suggest that the chip can rapidly induce resistant cells that increase tumor heterogeneity and chemoresistance, highlighting the need for further studies on the epigenetic control of the NUPR1/HDAC11 axis in TNBC.

Elife

Accurate prediction of contacting residue pairs between interacting proteins is very useful for structural characterization of protein–protein interactions. Although significant improvement has been made in inter-protein contact prediction recently, there is still a large room for improving the prediction accuracy. Here we present a new deep learning method referred to as PLMGraph-Inter for inter-protein contact prediction. Specifically, we employ rotationally and translationally invariant geometric graphs obtained from structures of interacting proteins to integrate multiple protein language models, which are successively transformed by graph encoders formed by geometric vector perceptrons and residual networks formed by dimensional hybrid residual blocks to predict inter-protein contacts. Extensive evaluation on multiple test sets illustrates that PLMGraph-Inter outperforms five top inter-protein contact prediction methods, including DeepHomo, GLINTER, CDPred, DeepHomo2, and DRN-1D2D_Inter, by large margins. In addition, we also show that the prediction of PLMGraph-Inter can complement the result of AlphaFold-Multimer. Finally, we show leveraging the contacts predicted by PLMGraph-Inter as constraints for protein–protein docking can dramatically improve its performance for protein complex structure prediction.

Elife

Partial reprogramming by cyclic short-term expression of Yamanaka factors holds promise for shifting cells to younger states and consequently delaying the onset of many diseases of aging. However, the delivery of transgenes and potential risk of teratoma formation present challenges for in vivo applications. Recent advances include the use of cocktails of compounds to reprogram somatic cells, but the characteristics and mechanisms of partial cellular reprogramming by chemicals remain unclear. Here, we report a multi-omics characterization of partial chemical reprogramming in fibroblasts from young and aged mice. We measured the effects of partial chemical reprogramming on the epigenome, transcriptome, proteome, phosphoproteome, and metabolome. At the transcriptome, proteome, and phosphoproteome levels, we saw widescale changes induced by this treatment, with the most notable signature being an upregulation of mitochondrial oxidative phosphorylation. Furthermore, at the metabolome level, we observed a reduction in the accumulation of aging-related metabolites. Using both transcriptomic and epigenetic clock-based analyses, we show that partial chemical reprogramming reduces the biological age of mouse fibroblasts. We demonstrate that these changes have functional impacts, as evidenced by changes in cellular respiration and mitochondrial membrane potential. Taken together, these results illuminate the potential for chemical reprogramming reagents to rejuvenate aged biological systems and warrant further investigation into adapting these approaches for in vivo age reversal.

Elife

Altered brain energy metabolism associated with increase in lactate levels and the resultant decrease in pH have been increasingly implicated in multiple neuropsychiatric disorders, such as schizophrenia, bipolar disorder, autism spectrum disorder and neurodegenerative disorders. Although it is controversial, change of pH/ lactate level as a primary feature of these diseases, rather than a result of confounding factors such as medication and agonal state, has been evidenced. Animal models that can be studied without such confounding factors inherent to humans are a suitable alternative to understand the controversy. However, the knowledge in animal models regarding brain pH and lactate and their relation to behavioral outcomes is limited in the context of neuropsychiatric disease conditions. In this study, we investigated the common occurrence of changes in the pH and lactate levels in the brain in animal models by analyzing 65 animal models related to neuropsychiatric and neurodegenerative diseases with 1,239 animals. Additionally, we evaluated the behavioral phenotypes relative to the chemical changes in the brain. Among the models, 27 and 24 had significant changes in brain pH and lactate levels, respectively, including Shank2 KO mice, Clock mutant mice, serotonin transporter KO mice, mice with a paternal duplication of human chromosome 15q11-13, Fmr1 KO mice, BTBR mice, APP-J20 Tg mice, social defeat stress-exposed mice, corticosterone-treated mice, and streptozotocin-induced diabetic mice. Meta-analysis of the data revealed a highly significant negative correlation between brain pH and lactate levels, suggestive of …

eLife

The genetic basis of severe COVID-19 has been thoroughly studied and many genetic risk factors shared between populations have been identified. However, reduced sample sizes from non-European groups have limited the discovery of population-specific common risk loci. In this second study nested in the SCOURGE consortium, we have conducted the largest GWAS meta-analysis for COVID-19 hospitalization in admixed Americans, comprising a total of 4,702 hospitalized cases recruited by SCOURGE and other seven participating studies in the COVID-19 Host Genetic Initiative. We identified four genome-wide significant associations, two of which constitute novel loci and first discovered in Latin-American populations (BAZ2B and DDIAS). A trans-ethnic meta-analysis revealed another novel cross-population risk locus in CREBBP. Finally, we assessed the performance of a cross-ancestry polygenic risk score in the SCOURGE admixed American cohort.

Elife

Previously, we showed that a massively parallel reporter assay, mSTARR-seq, could be used to simultaneously test for both enhancer-like activity and DNA methylation-dependent enhancer activity for millions of loci in a single experiment (Lea et al., 2018). Here, we apply mSTARR-seq to query nearly the entire human genome, including almost all CpG sites profiled either on the commonly used Illumina Infinium MethylationEPIC array or via reduced representation bisulfite sequencing. We show that fragments containing these sites are enriched for regulatory capacity, and that methylation-dependent regulatory activity is in turn sensitive to the cellular environment. In particular, regulatory responses to interferon alpha (IFNA) stimulation are strongly attenuated by methyl marks, indicating widespread DNA methylation-environment interactions. In agreement, methylation-dependent responses to IFNA identified via mSTARR-seq predict methylation-dependent transcriptional responses to challenge with influenza virus in human macrophages. Our observations support the idea that pre-existing DNA methylation patterns can influence the response to subsequent environmental exposures—one of the tenets of biological embedding. However, we also find that, on average, sites previously associated with early life adversity are not more likely to functionally influence gene regulation than expected by chance. eLife assessmentThis important paper uses a genome-wide, massively parallel reporter assay to determine how CpG methylation affects regulatory sequences that control the expression of human genes. The authors provide compelling evidence …

Elife

The nuclear pore complex (NPC) regulates the selective transport of large biomolecules through the nuclear envelope. As a model system for nuclear transport, we construct NPC mimics by functionalizing the pore walls of freestanding palladium zero-mode waveguides with the FG-nucleoporin Nsp1. This approach enables the measurement of single-molecule translocations through individual pores using optical detection. We probe the selectivity of Nsp1-coated pores by quantitatively comparing the translocation rates of the nuclear transport receptor Kap95 to the inert probe BSA over a wide range of pore sizes from 35 nm to 160 nm. Pores below 55±5 nm show significant selectivity that gradually decreases for larger pores. This finding is corroborated by coarse-grained molecular dynamics simulations of the Nsp1 mesh within the pore, which suggest that leakage of BSA occurs by diffusion through transient openings within the dynamic mesh. Furthermore, we experimentally observe a modulation of the BSA permeation when varying the concentration of Kap95. The results demonstrate the potential of single-molecule fluorescence measurements on biomimetic NPCs to elucidate the principles of nuclear transport. eLife assessmentThis important study reports on a new method for the fabrication and the analysis of the transport through nuclear pore complexes mimic. Methods, data, and analyses are convincing and show a clear correlation between the size of the nuclear pore complex mimic and its transport selectivity. This work will be of high interest to biologists and biophysicists working on the mechanosensitivity of nucleocytoplasmic transport.

Elife

Understanding how plants adapt to changing environments and the potential contribution of transposable elements (TEs) to this process is a key question in evolutionary genomics. While TEs have recently been put forward as active players in the context of adaptation, few studies have thoroughly investigated their precise role in plant evolution. Here, we used the wild Mediterranean grass Brachypodium distachyon as a model species to identify and quantify the forces acting on TEs during the adaptation of this species to various conditions, across its entire geographic range. Using sequencing data from more than 320 natural B. distachyon accessions and a suite of population genomics approaches, we reveal that putatively adaptive TE polymorphisms are rare in wild B. distachyon populations. After accounting for changes in past TE activity, we show that only a small proportion of TE polymorphisms evolved neutrally (< 10%), while the vast majority of them are under moderate purifying selection regardless of their distance to genes. TE polymorphisms should not be ignored when conducting evolutionary studies, as they can be linked to adaptation. However, our study clearly shows that while they have a large potential to cause phenotypic variation in B. distachyon, they are not favored during evolution and adaptation over other types of mutations (such as point mutations) in this species.

Elife

Genetic variants in gene regulatory sequences can modify gene expression and mediate the molecular response to environmental stimuli. In addition, genotype-environment interactions (GxE) contribute to complex traits such as cardiovascular disease. Caffeine is the most widely consumed stimulant and is known to produce a vascular response. To investigate GxE for caffeine, we treated vascular endothelial cells with caffeine and used a massively parallel reporter assay to measure allelic effects on gene regulation for over 43,000 genetic variants. We identified 665 variants with allelic effects on gene regulation and 29 variants that regulate the gene expression response to caffeine (GxE, FDR<10%). When overlapping our GxE results with eQTLs colocalized with CAD and hypertension, we dissected their regulatory mechanisms and showed a modulatory role for caffeine. Our results demonstrate that massively parallel reporter assay is a powerful approach to identify and molecularly characterize GxE in the specific context of caffeine consumption.

Elife

Cognitive control resolves conflicts between task-relevant and-irrelevant information to enable goal-directed behavior. As conflicts can arise from different sources (eg, sensory input, internal representations), how a limited set of cognitive control processes can effectively address diverse conflicts remains a major challenge. Based on the cognitive space theory, different conflicts can be parameterized and represented as distinct points in a (low-dimensional) cognitive space, which can then be resolved by a limited set of cognitive control processes working along the dimensions. It leads to a hypothesis that conflicts similar in their sources are also represented similarly in the cognitive space. We designed a task with five types of conflicts that could be conceptually parameterized. Both human performance and fMRI activity patterns in the right dorsolateral prefrontal cortex support that different types of conflicts are organized based on their similarity, thus suggesting cognitive space as a principle for representing conflicts.

eLife

Tissue clearing and labeling techniques have revolutionized brain-wide imaging and analysis, yet their application to clinical formalin-fixed paraffin-embedded (FFPE) blocks remains challenging. We introduce MOCAT, a novel method for efficiently clearing and labeling centimeter-thick FFPE specimens using elevated temperature and concentrated detergents. MOCAT with multi-round immunolabeling reveals neuron circuitry regulating multiple neurotransmitter systems in a whole FFPE mouse brain, and is able to be used as the evaluation of disease treatment efficiency. MOCAT also supports expansion microscopy and can be performed on a non-sectioned 15-year-old FFPE specimen. Thus, MOCAT represents a feasible approach for researching archived FFPE specimens for future neuroscientific and 3D neuropathological analyses.

Elife

Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.

eLife

Neurotransmission at synapses is mediated by the fusion and subsequent endocytosis of synaptic vesicle membranes. Actin has been suggested to be required for presynaptic endocytosis but the mechanisms that control actin polymerization and its mode of action within presynaptic nerve terminals remain poorly understood. We combine optical recordings of presynaptic membrane dynamics and ultrastructural analysis with genetic and pharmacological manipulations to demonstrate that presynaptic endocytosis is controlled by actin regulatory diaphanous-related formins mDia1/3 and Rho family GTPase signaling in mouse hippocampal neurons. We show that impaired presynaptic actin assembly in the near absence of mDia1/3 and reduced RhoA activity is partly compensated by hyperactivation of Rac1. Inhibition of Rac1 signaling further aggravates impaired presynaptic endocytosis elicited by loss of mDia1/3. Our data suggest that interdependent mDia1/3-Rho and Rac1 signaling pathways cooperatively act to facilitate synaptic vesicle endocytosis by controlling presynaptic F-actin.

eLife

The sensorimotor system can recalibrate itself without our conscious awareness, a type of procedural learning whose computational mechanism remains undefined. Recent findings on implicit motor adaptation, such as over-learning from minor perturbations and swift saturation for increasing perturbation size, challenge existing theories based on sensory errors. We argue that perceptual error, arising from the optimal combination of movement-related cues, is the primary driver of implicit adaptation. Central to our theory is the linear relationship between the sensory uncertainty of visual cues and perturbation, validated through perceptual psychophysics (Experiment 1). Our theory predicts diverse features of implicit adaptation across a spectrum of perturbation conditions on trial-by-trial basis (Experiment 2) and explains proprioception changes and their relation to visual perturbation (Experiment 3). By altering visual uncertainty in perturbation, we induced unique adaptation responses (Experiment 4). Overall, our perceptual error framework outperforms existing models, suggesting that Bayesian cue integration underpins the sensorimotor system's implicit adaptation.

Elife

Generating synthetic locomotory and neural data is a useful yet cumbersome step commonly required to study theoretical models of the brain’s role in spatial navigation. This process can be time consuming and, without a common framework, makes it difficult to reproduce or compare studies which each generate test data in different ways. In response, we present RatInABox, an open-source Python toolkit designed to model realistic rodent locomotion and generate synthetic neural data from spatially modulated cell types. This software provides users with (i) the ability to construct one-or two-dimensional environments with configurable barriers and visual cues,(ii) a physically realistic random motion model fitted to experimental data,(iii) rapid online calculation of neural data for many of the known self-location or velocity selective cell types in the hippocampal formation (including place cells, grid cells, boundary vector cells, head direction cells) and (iv) a framework for constructing custom cell types, multi-layer network models and data-or policy-controlled motion trajectories. The motion and neural models are spatially and temporally continuous as well as topographically sensitive to boundary conditions and walls. We demonstrate that out-of-the-box parameter settings replicate many aspects of rodent foraging behaviour such as velocity statistics and the tendency of rodents to over-explore walls. Numerous tutorial scripts are provided, including examples where RatInABox is used for decoding position from neural data or to solve a navigational reinforcement learning task. We hope this tool will significantly streamline computational research into the …

eLife

The complex of methyltransferase-like proteins 3 and 14 (METTL3-14) is the major enzyme that deposits N 6-methyladenosine (m 6 A) modifications on messenger RNA (mRNA) in humans. METTL3-14 plays key roles in various biological processes through its methyltransferase (MTase) activity. However, little is known about its substrate recognition and methyl transfer mechanism from its cofactor and methyl donor S-adenosylmethionine (SAM). Here, we study the MTase mechanism of METTL3-14 by a combined experimental and multiscale simulation approach using bisubstrate analogues (BAs), conjugates of a SAM-like moiety connected to the N 6-atom of adenosine. Molecular dynamics simulations based on crystal structures of METTL3-14 with BAs suggest that the Y406 side chain of METTL3 is involved in the recruitment of adenosine and release of m 6 A. A crystal structure with a BA representing the transition state of methyl transfer shows a direct involvement of the METTL3 side chains E481 and K513 in adenosine binding which is supported by mutational analysis. Quantum mechanics/molecular mechanics (QM/MM) free energy calculations indicate that methyl transfer occurs without prior deprotonation of adenosine-N 6. Furthermore, the QM/MM calculations provide further support for the role of electrostatic contributions of E481 and K513 to catalysis. The multidisciplinary approach used here sheds light on the (co) substrate binding mechanism, catalytic step, and (co) product release, and suggests that the latter step is rate-limiting for METTL3. The atomistic information on the substrate binding and methyl transfer reaction of METTL3 …

Elife

Neurostimulation of the hippocampal formation has shown promising results for modulating memory but the underlying mechanisms remain unclear. In particular, the effects on hippocampal theta-nested gamma oscillations and theta phase reset, which are both crucial for memory processes, are unknown. Moreover, these effects cannot be investigated using current computational models, which consider theta oscillations with a fixed amplitude and phase velocity. Here, we developed a novel computational model that includes the medial septum, represented as a set of abstract Kuramoto oscillators producing a dynamical theta rhythm with phase reset, and the hippocampal formation, composed of biophysically realistic neurons and able to generate theta-nested gamma oscillations under theta drive. We showed that, for theta inputs just below the threshold to induce self-sustained theta-nested gamma oscillations, a single stimulation pulse could switch the network behavior from non-oscillatory to a state producing sustained oscillations. Next, we demonstrated that, for a weaker theta input, pulse train stimulation at the theta frequency could transiently restore seemingly physiological oscillations. Importantly, the presence of phase reset influenced whether these two effects depended on the phase at which stimulation onset was delivered, which has practical implications for designing neurostimulation protocols that are triggered by the phase of ongoing theta oscillations. This novel model opens new avenues for studying the effects of neurostimulation on the hippocampal formation. Furthermore, our hybrid approach that combines different levels of …

Elife

The differential signaling of multiple FGF ligands through a single fibroblast growth factor (FGF) receptor (FGFR) plays an important role in embryonic development. Here, we use quantitative biophysical tools to uncover the mechanism behind differences in FGFR1c signaling in response to FGF4, FGF8, and FGF9, a process which is relevant for limb bud outgrowth. We find that FGF8 preferentially induces FRS2 phosphorylation and extracellular matrix loss, while FGF4 and FGF9 preferentially induce FGFR1c phosphorylation and cell growth arrest. Thus, we demonstrate that FGF8 is a biased FGFR1c ligand, as compared to FGF4 and FGF9. Förster resonance energy transfer experiments reveal a correlation between biased signaling and the conformation of the FGFR1c transmembrane domain dimer. Our findings expand the mechanistic understanding of FGF signaling during development and bring the poorly understood concept of receptor tyrosine kinase ligand bias into the spotlight.

Elife

The important paper provides compelling evidence that the gene hkb controls the development of the salivary gland of Drosophila by controlling a cell cycle and cell death. The work extends and corrects previous findings on the role of this transcription factor and will be important for scientists interested in organogenesis and in particular the coordination of cell cycle and cell death.

eLife

Humans face the challenge of making sense of a complex world. Learning where to find information is crucial to filter through the abundance of stimuli, distinguish relevant from irrelevant sources, and optimize our learning. Here, we examined the developmental roots of information-seeking by testing whether 8-month-old infants can predict where to find information. We presented infants with visual cues indicating whether they will later receive information about the location of a rewarding stimulus. We analyzed the dynamics of pupil dilation when the cues were presented, but before the actual information was delivered. By combining additive Bayesian models with reinforcement learning, we show that infants learn to successfully predict what cues have a greater informational value and that they generalize these predictions to novel cues that share the same perceptual features. These results reveal the fundamental learning processes that support information-seeking from early in life.