bioRxiv Subject Collection: Neuroscience's Journal

Relating Monosynaptic and Functional Connectivity - Complementary Perspectives on Neural Computation -
Information processing in the brain is thought to result from the coordination of large-scale neuronal activity, but this occurs on a fine neural circuit. Here, we investigate their relationship. First, we estimate monosynaptic connectivity by applying an advanced analysis method to spike trains recorded with high-density microelectrodes and confirm that the estimated neuronal wiring is largely consistent with neuroanatomical and neurophysiological evidence. Second, we simulate calcium imaging signals from the same dataset and confirm that the estimated functional connectivity is influenced by shared inputs and population synchronization on slower timescales. Notably, even with unrealistically fast calcium dynamics, the functional connectivity is only partially consistent with the monosynaptic connectivity. These findings suggest the complementary roles for monosynaptic and functional connectivity: the former provides circuit-level specificity, while the latter reflects emergent system-wide patterns of activity. We propose that an integrative approach combining both perspectives is essential for understanding circuit-level computation in the brain.

Microglial brain-derived neurotrophic factor (BDNF) supports the behavioral and synaptogenic effects of ketamine
Microglia have been implicated in the pathogenesis for several psychiatric disorders, yet comparatively little is known about their role in treatments for these conditions. Prior work showed that the rapid-acting antidepressant ketamine increases synaptic density in the prefrontal cortex (PFC), and that brain-derived neurotrophic factor (BDNF) signaling is required for its synaptic and behavioral effects. These studies assumed that neurons were the primary source of BDNF, but other studies have since demonstrated that microglia can produce BDNF in the brain. Still, it remains unclear if microglial BDNF is important for the antidepressant-like effects of ketamine. Our initial studies show that the behavioral and synaptic effects of ketamine are associated with increased Bdnf expression in sorted PFC microglia 24 hours after injection. We then demonstrate that conditional BDNF depletion in microglia (Cx3cr1Cre/+:Bdnffl/fl) reduces GluN2B levels in PFC synaptoneurosomes and attenuates antidepressant-like responses following ketamine treatment compared to genotype controls (Cx3cr1Cre/+:Bdnf+/+). Consistent with this, we found that Cx3cr1Cre/+:Bdnffl/fl mice show no change in dendritic spine density in the PFC following ketamine. These results indicate that microglial BDNF is important for the effects of ketamine on brain and behavior, expanding upon the role of microglia in pharmacological interventions for psychiatric disorders.

Intrinsic and TDP-43 dysfunction-induced catabolic stress elicit neuroprotective cellular degradation in ALS-vulnerable motor neurons
Selective neuronal vulnerability is a defining feature of neurodegenerative disorders, exemplified by motor neuron degeneration in amyotrophic lateral sclerosis (ALS). The nature of motor neurons underlying this selectivity remains unresolved. Here, by monitoring autophagy at single-cell resolution across the translucent zebrafish spinal cord, we identify motor neurons as the cell population with the highest autophagic flux. Large spinal motor neurons (SMNs), most susceptible to ALS, exhibit higher flux compared to smaller SMNs and ALS-resistant ocular motor neurons. Notably, large SMNs accelerates both autophagy and proteasome-mediated degradation, which are further augmented by TDP-43 loss. Additionally, acceleration of multiple unfolded protein response pathways indicates their innate tendency to accumulate misfolded proteins. Enhanced cellular degradation in large SMNs is neuroprotective as its inhibition halts axon outgrowth. These findings propose that cell size-associated degradation load underlies selective neuronal vulnerability in ALS, highlighting the alleviation of catabolic stress as a target of therapy and prevention.

Measuring neurofilament light in human plasma and cerebrospinal fluid: a comparison of five analytical immunoassays
Objectives: Neurofilament light (NfL) is an established biofluid marker of neuroaxonal injury for neurological diseases. Several high-throughput and sensitive immunoassays have been developed to quantify NfL in blood and cerebrospinal fluid (CSF), facilitating the use of NfL as a biomarker in research and clinical practice. However, because of the lack of rigorous comparisons of assays, it has been difficult to determine whether data are comparable and whether assay performance differs. Here, we compared the performance of five NfL immunoassays. Methods: To assess the five NfL immunoassays (Fujirebio, ProteinSimple, Quanterix, Roche and Siemens), we used pooled plasma or pooled CSF, as well as unique samples from 20 healthy controls and 20 individuals with El Escorial defined probable or definite amyotrophic lateral sclerosis (ALS), to evaluate precision, parallelism and/or bias. We also examined correlations between plasma and CSF NfL concentrations within and across assays and evaluated their ability to differentiate healthy controls from individuals with ALS. Results: Four of the five assays demonstrated exemplary performance based on our analyses of precision and parallelism. Across the five assays, NfL concentrations were lower in plasma than in CSF, although they displayed a high degree of correlation. We noted bias across assays; plasma NfL concentrations were lowest for the Roche assay and highest for the ProteinSimple assay. In addition, all assays reliably distinguished healthy controls from individuals with ALS using plasma or CSF NfL. Conclusions: Four NfL assays demonstrated similar analytic performance. Alongside performance, other factors such as costs, accessibility, useability, footprint, and intended use, should be considered. Keywords: amyotrophic lateral sclerosis; biomarker; cerebrospinal fluid; immunoassays; neurofilament light chain; plasma

Neural and Computational Mechanisms Underlying One-shot Perceptual Learning in Humans
The ability to quickly learn and generalize is one of the brain's most impressive feats and recreating it remains a major challenge for modern artificial intelligence research. One of the most mysterious one-shot learning abilities displayed by humans is one-shot perceptual learning, whereby a single viewing experience drastically alters visual perception in a long-lasting manner. Where in the brain one-shot perceptual learning occurs and what mechanisms support it remain enigmatic. Combining psychophysics, 7T fMRI, and intracranial recordings, we identify high-level visual cortex as the most likely neural substrate wherein neural plasticity supports one-shot perceptual learning. We further develop a novel deep neural network model incorporating top-down feedback into a vision transformer, which recapitulates and predicts human behavior. The prior knowledge learnt by this model is highly similar to the neural code in the human high-level visual cortex. These results reveal the neurocomputational mechanisms underlying one-shot perceptual learning in humans.

A Spinal Circuit for Hypoxia-Evoked Motor Output in Zebrafish Larvae
Oxygen availability is a critical environmental variable that shapes animal physiology and behavior. In larval zebrafish, acute hypoxia elicits a distinct increase in rhythmic pectoral fin movements, a behavior thought to facilitate oxygen uptake. While peripheral oxygen sensors such as neuroepithelial cells (NECs) and Merkel-like cells (MLCs) have been well characterized, the motor circuits responsible for executing this behavior remain unknown. Four distinct lower motor nerve branches in the spinal cord have been shown to innervate the pectoral fin muscles and are candidate effectors of hypoxia-induced behaviors. Here, we identify the neural pathways that transform hypoxia detection into a dedicated motor output. Using high-speed behavioral tracking, we confirm that hypoxia reliably increases pectoral fin beat frequency without affecting locomotor tail activity or visually guided swimming. Two-photon calcium imaging in Tg(ChaTa:Gal4;UAS:GCaMP6s) larvae reveals that a subset of cholinergic spinal motor neurons is selectively active during hypoxia-induced fin movements. Targeted laser ablation of pectoral fin motor nerves abolishes the response, demonstrating the necessity of descending input for this behavior. Our findings define a distributed, partially redundant motor circuit that implements a homeostatic fin response to hypoxia. By establishing a mechanistic framework for this behavior in a genetically accessible vertebrate model, this work enables future studies of oxygen sensing, sensorimotor integration, and the neural basis of homeostatic motor control.

NAD+ reduction in glutamatergic neurons triggers fatty acid catabolism and neuroinflammation in the brain, mitigated by SARM1 deletion
The importance of NAD+ homeostasis for neuronal health has been emphasized by studies on nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2), a NAD+-synthesizing enzyme, and sterile alpha and TIR motif-containing protein 1 (SARM1), a NAD+ hydrolase. NMNAT2 declines caused by neurodegenerative insults activate SARM1 to degenerate axons. To elucidate the impact of the NMNAT2-SARM1 axis on brain energy metabolism, we employed multi-omics approaches to investigate the metabolic effects caused by neuronal NMNAT2 loss. The loss of NMNAT2 in glutamatergic neurons results in a striking metabolic shift in the cerebral cortex from glucose to lipid catabolism, reduced lipid abundance, and pronounced neurodegenerative phenotypes. Proteomic analysis found that neuronal NMNAT2 loss altered levels of glial enzymes central to glucose and lipid metabolism. Genetic deletion of SARM1 in NMNAT2-deficient mice restores lipid metabolism and mitigates neurodegeneration. Taken together, we show that neuronal NAD+ reduction leads to SARM1-dependent maladaptive adaptations in both neurons and glia.

A compact multisensory representation of self-motion is sufficient for computing an external world variable
External forces shape navigation, but cannot be directly measured by an animal in motion. How the brain integrates multi-modal cues to estimate external forces remains unclear. Here we investigated the representation of multi-modal self-motion cues across columnar inputs to the fly navigation center, known as PFNs. We find that one type integrates optic flow and airflow direction signals with distinct dynamics. We reveal airspeed encoding by a different type. Based on these data, we construct and validate models of how multi-sensory dynamics are encoded across PFNs, allowing us to simulate neural responses during rapid flight maneuvers. Applying a nonlinear observability analysis to these responses, we show that PFN representations during active maneuvers are sufficient to decode the direction of an external force (wind) during free flight. Our work provides evidence that active sensation, combined with multisensory encoding, can allow a compact nervous system to infer a property of the external world that cannot be directly measured by a single sensory system.

Early downregulation of HC-specific genes in the vestibular sensory epithelium during chronic ototoxicity
Exposure of mammals to ototoxic compounds causes hair cell (HC) loss in the vestibular sensory epithelia of the inner ear. In chronic exposure models, this loss often occurs by extrusion of the HC from the sensory epithelium towards the luminal cavity. HC extrusion is preceded by several steps that begin by detachment and synaptic uncoupling of the cells from the afferent terminals of their postsynaptic vestibular ganglion neurons. To identify gene expression programs driving these responses to chronic ototoxic stress, we performed five RNA-seq control versus treated comparisons involving two species (rat and mouse), two compounds (streptomycin and 3,3'-iminodipropionitrile, IDPN), and three time points in the rat/IDPN model. By comparing the differentially expressed genes and their associated Gene Ontology terms, we identified both common and model-unique expression responses. The earliest and most robust common response was a downregulation of HC-specific genes, including stereocilium (Atp2b2, Xirp2), synaptic (Nsg2), and ion channel genes (Kcnab1, Kcna10), together with new potential biomarkers of HC stress (Vsig10l2). This response was validated by in-situ hybridisation and immunofluorescence analyses. A second common response across species and compounds was the upregulation of the stress mediator Atf3. Model- or time- restricted responses included downregulation of cell-cell adhesion and mitochondrial ATP synthesis genes, and upregulation of interferon response, unfolded protein response and tRNA aminoacylation genes. The present results provide key insights on the responses of the vestibular sensory epithelium to chronic ototoxic stress, potentially relevant to other types of chronic stress.

Real-time affect decoding in the amygdalo-hippocampal circuit from dynamic auditory signals
Affect decoding from auditory signals requires the temporal tracking and neural processing of dynamic sound patterns, such as in affective speech. Affective speech is commonly expressed to maximize its emotional impact and its neural decoding in integrated medial limbic circuits of recipients. Here we examined how affective speech, which was live produced by speakers to maximize amygdala-hippocampal connectivity in listeners, can evoke significant intralimbic and cortico-limbic affect decoding mechanisms. Aggressive and joyful affective speech that was produced based on real-time feedback of amygdala-hippocampal couplings in listeners increased intralimbic connectivity as well as activity in auditory cortical nodes as parts of a broader affective sound processing network. Neural time courses in the auditory cortex also correlated with acoustic patterns of adaptive speech indicative of a communicative speaker-listener coupling. Affective speech can thus meaningfully influence limbic circuit synchronizations with a specific significance of the amygdala-hippocampal circuit for affect decoding from auditory signals.

Music as a real-time fMRI neurofeedback interface for modulating interhemispheric connectivity: effects on mood and recruitment of the putamen and insula
Music is a universal language that transcends cultures and is deeply rooted in human evolutionary history. Its creation and appreciation recruit the brain's limbic and reward systems, leading to the evocation of emotions ranging from happiness and sadness to tenderness and grief. Here, we explore the potential of music as an interventional tool in a novel neurofeedback experiment. This study introduces and validates a musical interface for real-time fMRI neurofeedback that is adaptable to various experimental paradigms. Using a previously developed motor imagery connectivity-based framework, we evaluate its feasibility and efficacy by comparing the modulation of bilateral premotor cortex (PMC) activity during functional runs with real versus sham (random) feedback in 22 healthy adults. We also assess its performance against a visual feedback interface. The experiment involves a 50-minute MRI session, including anatomical scans, a PMC functional localizer run, and four neurofeedback runs (two with active feedback and two with sham feedback). Pre- and post-session questionnaires assess mood (looking at the behavioral impact of the NF session), musical background (in search of predictors of NF success), and subjective feedback experiences. During neurofeedback, participants perform motor imagery of finger-tapping, with feedback delivered as a dynamic, pre-validated chord progression that evolves or regresses based on the correlation between left and right PMC activity. We found that our implementation of music-based feedback was successful, with participants managing to modulate their own connectivity using the proposed interface. The modulation performance was similar for active and sham NF runs, possible due to the power of music to boost neuromodulation, but the network recruitment was stronger for active NF, including in the insula, putamen, and target ROIs. Behaviorally, we found a decrease in tension and an improvement in the overall mood of the participants after the session. When comparing our results to previous NF data with a visual interface, we found stronger brain activations, in particular in NF-relevant regions such as the insula and the putamen. This work highlights the potential of musical feedback as a more intuitive and engaging interface in neurofeedback protocols, paving the way for enhanced participant experience and training outcomes.

A unified imaging-histology framework for superficial white matter architecture studies in the human brain
The superficial white matter (SWM), immediately beneath the cortical mantle, is thought to play a major role in cortico-cortical connectivity as well as large-scale brain function. Yet, this compartment remains rarely studied due to its complex organization. Our objectives were to develop and disseminate a robust computational framework to study SWM organization based on 3D histology and high-field 7T MRI. Using data from the BigBrain and Ahead 3D histology initiatives, we first interrogated variations in cell staining intensities across different cortical regions and different SWM depths. These findings were then translated to in-vivo 7T quantitative myelin-sensitive MRI, including T1 relaxometry (T1 map) and magnetization transfer saturation (MTsat). As indicated by the statistical moments of the SWM intensity profiles, the first 2 mm below the cortico-subcortical boundary were characterized by high structural complexity. We quantified SWM microstructural variation using a non-linear dimensionality reduction method and examined the relationship of the resulting microstructural gradients with indices of cortical geometry, as well as structural and functional connectivity. Our results showed correlations between SWM microstructural gradients, as well as curvature and cortico-cortical functional connectivity. Our study provides novel insights into the organization of SWM in the human brain and underscores the potential of SWM mapping to advance fundamental and applied neuroscience research.

APOE genotype confers context dependent neurovascular vulnerability in immune-vascularized human forebrain organoids
The APOE gene is a major genetic determinant of neurovascular and immune function, yet the mechanisms by which its isoforms modulate brain vulnerability to pathogenic stress remain incompletely understood. Here, we employ isogenic human iPSC-derived immune vascularized Forebrain Organoid-based Multicellular Assembled Cerebral Organoids (FORMA COs) to dissect isoform-specific responses to a clinically relevant viral challenge. We find that APOE2 and APOE4 FORMA-COs exhibit heightened viral RNA burden and distinct neuroinflammatory profiles compared to APOE3. Specifically, APOE4 promotes IL-1 and VEGFA induction, whereas APOE2 leads to elevated TNF{beta} and VEGFA protein accumulation, indicating divergent pathways of injury. Integrated transcriptomic analyses, combined with known and predicted APOE protein protein interaction networks, reveal genotype dependent enrichment of cytokine signaling, angiogenic remodeling, and immune dysregulation. In vivo validation using humanized mouse models corroborates APOE genotype specific vascular remodeling, microglial activation, and oligodendrocyte perturbation. These findings demonstrate that APOE genotype confers context-specific susceptibility to neuroimmune and vascular injury, providing insight into genetic risk mechanisms underlying infection-related and neurodegenerative brain disorders.

Linking Brain Entropy to Molecular and Cellular Architecture in Psychosis
Brain entropy reflects the complexity of intrinsic activity and has been associated with cognitive function and psychiatric disorders. However, its relationship with neurochemical and cellular architecture in the brain remains poorly understood. By integrating molecular imaging, and neuroimaging datasets, we provide converging evidence that the spatial distribution of diverse cell types, neurotransmitter systems, and mitochondrial phenotypes is systematically associated with brain entropy. We found significant differences in entropy correlations between normal controls and individuals with schizophrenia for the mu-opioid receptor and dopamine receptor (D1), and between normal controls and bipolar disorder for the norepinephrine transporter (NAT) and N-methyl-D-aspartate receptor (NMDA). No significant differences were observed between schizophrenia and bipolar disorder in the neurotransmitter domain. In terms of cellular and metabolic features, both the normal controls vs. schizophrenia and normal controls vs. bipolar disorder comparisons revealed widespread differences associated with most mitochondrial markers, as well as glial cells and inhibitory neurons. These findings suggest disruptions in energy metabolism, neuroinflammatory activity, and inhibitory neuronal regulation in the clinical groups. Furthermore, these results indicate that brain entropy is not randomly distributed but is systematically linked to specific neurochemical systems and cellular characteristics. This systems-level perspective offers valuable insights into how the complexity of brain activity emerges from the underlying molecular architecture and how it is altered in psychiatric disorders. Moreover, it provides a biological foundation for understanding brain entropy in the context of psychosis.

Longitudinal deep phenotyping in a mouse model of West syndrome reveals temporal dynamics of synapse remodeling, gliosis, and proteomic and lipidomic changes during seizure evolution
Neurodevelopmental disorders can have long-lasting effects, causing not only early pediatric symptoms but also a range of neurological issues throughout adulthood. West syndrome is a severe neurodevelopmental disorder marked by infantile spasms, an early symptom that typically subsides with age. However, many patients progress to other seizure forms, known as seizure evolution, which is closely linked to poor long-term outcomes. Despite its clinical significance, the neurobiological mechanisms behind seizure evolution in West syndrome remain poorly understood. Recent genetic studies have consistently identified the CYFIP2 p.Arg87Cys variant in West syndrome patients, and the Cyfip2+/R87C mouse model carrying this mutation has been shown to recapitulate key symptoms of the disorder, including infantile spasms. In this study, we aimed to gain deeper insight into seizure evolution by conducting longitudinal deep phenotyping of the Cyfip2+/R87C mouse model from the neonatal stage to seven months of age. We tracked seizure activity through behavioral and EEG recordings and employed multi-omic analyses, including tissue and single-cell level transcriptomics, ultrastructural analysis, proteomics, and lipidomics, to capture a comprehensive view of molecular and cellular changes. Our results showed that after an initial period of neonatal spasms, Cyfip2+/R87C mice entered a seizure-free phase, followed by spontaneous recurrent seizures in adulthood, ultimately leading to premature death. This progression was associated with synaptic remodeling, sequential activation of different glial cell types, lipid droplet accumulation in astrocytes, and significant proteomic and lipidomic changes in the brain. These findings suggest that seizure evolution in West syndrome involves complex, time-dependent interactions between neurons and glial cells, along with alterations in lipid metabolism. Our study highlights the potential of longitudinal multi-omic approaches to uncover underlying mechanisms of seizure evolution and suggests that targeting these changes could offer novel therapeutic strategies. Additionally, the dataset generated here may provide valuable insights for other epilepsy and neurodevelopmental disorder models.

Brain-wide cell-type-specific noradrenergic modulation of the transcriptome
Neuromodulatory systems such as the locus coeruleus-norepinephrine (LC-NE) system exert a widespread influence on brain function, yet the transcriptional consequences of such neuromodulatory perturbations remain largely unknown across the many unique cell types in the brain. In this study, we establish a generalizable framework to map brain-wide, cell-type-specific gene expression changes in mice following in vivo chemogenetic activation or inhibition of LC neurons. Single-nucleus RNA sequencing revealed that LC perturbation induces widespread but highly cell type- and region-specific transcriptional program changes, shaped by the distribution of adrenergic receptor subtypes. These findings support a model in which a shared global signal of neuromodulatory tone can produce discrete, context-dependent cellular outcomes through distinct molecular gating mechanisms of cell-type-specific adrenergic receptor subtype combinations. By establishing gene expression as a quantifiable metric of neuromodulatory control, this study lays the foundation for transcriptionally informed interventions capable of modulating brain functions with cellular precision.

Lrrns define a visual circuit underlying brightness and contrast perception
Brightness and contrast are fundamental features of vision, crucial for object detection, environmental navigation, and feeding. Here, we identify a brightness- and contrast-processing circuit in the zebrafish visual system and uncover the role of Leucine-rich repeat neuronal (Lrrn) cell adhesion molecules (CAMs) in regulating its assembly. Deep-projecting retinal ganglion cells (RGCs) serve as the first synaptic relay to the brain requiring Lrrn2 and Lrrn3a for precise axonal targeting and connectivity within the optic tectum. Genetic targeting of these CAMs leads to circuit disorganization and impairments in contrast sensitivity, leading to deficits in visually guided behaviors. Additionally, ultrastructural circuit reconstruction and functional imaging analysis revealed their critical role in luminance processing. These studies define a fundamental visual processing pathway and establish Lrrn CAMs as essential molecular drivers of its assembly.

An intracortical brain-computer interface for navigation in virtual reality in macaque monkeys
We present an innovative intracortical Brain-Computer Interface (BCI) to bridge the gap between laboratory settings and real-world applications. This BCI approach introduces three key advancements. First, we utilized neural signals from three macaque brain region- primary motor, dorsal and ventral premotor cortex- enabling precise and flexible decoding of real-time 3D sphere/avatar velocities. Second, we developed a realistic, immersive three-dimensional virtual reality setup with dynamic camera tracking, allowing continuous navigation and obstacle avoidance that closely mimic real-world scenarios. Finally, our BCI approach is optimized for use by paralyzed patients, featuring a brief training phase without overt movements and closed-loop operation without retraining of the decoder, relying on the neural plasticity of the user and the robust generalization of the decoder across tasks. Our BCI adapted to different environments, targets, and obstacles, illustrating its potential to significantly enhance the quality of life for paralyzed patients by enabling natural, reliable and flexible control in complex settings.

Single pulse electrical stimulation in white matter modulates iEEG visual responses in human early visual cortex
Electrical stimulation is increasingly used to modulate brain networks for clinical purposes. The basic unit of neurostimulation, a single electrical pulse, can travel through white matter to influence connected neuronal populations. However, the mechanisms by which it influences connected populations is not well understood: stimulation may excite, inhibit, or add noise to neuronal population activity. In this study, we investigated how single pulses modulate the neuronal processing of images in a well-controlled visual paradigm. In two human subjects implanted with iEEG electrodes for clinical purposes, single pulses were delivered to electrodes in white matter tracts connected to measurement electrodes in visual cortex. Images appeared on-screen at 0, 100, or 200 ms after each pulse. Using finite impulse response modeling, we decomposed the broadband and evoked potential responses into separate components induced by electrical stimulation and by visual processing. Single pulses induced transient broadband increases followed by suppression, but they did not modulate the visual broadband responses (i.e., stimulation response was additive to visual response). In contrast, single pulses elicited prominent brain stimulation evoked potentials and they modulated the visual evoked potentials. Specifically, visual evoked potentials were larger when stimulation occurred closer to visual onset. This indicates that a single electrical pulse can increase the strength or synchrony of visual inputs. Overall, these findings suggest that the effects of electrical stimulation in the visual system are two-fold: stimulation induces additive effects on broadband power, possibly by adding noise, and it interacts with synchronous visual inputs to amplify them.

Crossing effects in the tactile temporal order judgment task: A meta-analysis
The tactile temporal order judgment (TOJ) task is widely used in multisensory neuroscience. Participants judge which of two tactile stimuli, one on each hand, came first. A key finding is that TOJ performance declines when the arms are crossed, likely due to interactions between tactile, proprioceptive, and visual information. The TOJ crossing effect has been widely reported, but studies have employed various analysis methods, leaving open whether the choice of method influences the effect's magnitude. Moreover, some studies have reported modulations by the availability of visual information, response modality, or speeded response requirements. Through an exhaustive, systematic literature search, we identified 37 experiments that investigated the TOJ crossing effect. Meta-analysis estimated the effect size at approximately 1.4. The moderators did not significantly affect this estimate, though this is likely due to too few studies being available to obtain sufficient statistical power. The large effect size supports the TOJ task's use in other, e.g. developmental and clinical, research. However, the lack of statistically significant effect modulation by the moderators calls for caution when applying it for research questions beyond the crossing effect itself.

Separable global and local beta burst dynamics in motor cortex of primates
Sensorimotor beta band oscillations are known to modulate during normal movement control and abnormal beta modulation is linked to pathological bradykinesia. However, the functional differences between beta localized to one brain area versus beta synchronized across brain areas remains unclear. We monitored beta bursts in non-human primates, both neurotypical and stroke-impaired, during the performance of complex motor tasks. Across both groups of animals, we identified two distinct beta burst types: global bursts that tend to be synchronized across cortical and subcortical areas, and local bursts that tend to be confined to cortex. These two types exhibited distinct neural dynamics, with global bursts linked to reduced firing variability and overall slowed movements. In contrast, local bursts often occurred during the execution of complex behaviors, particularly during prehension. We found evidence for changes in the distribution of global and local bursts during recovery after stroke. In impaired animals early after stroke, global bursts predominated and were associated with reduced speed and impaired grasping. Notably, recovery of grasping was associated with a reduction in global bursts and an increase in local bursts, suggesting that local bursts may play an important role during prehension. Our findings reveal distinct roles of global and local beta bursts and indicate that the normalization of global and local burst timing tracks recovery of dexterity.

Cognitive Load Impairs Professional Scepticism in Decision-Making: The Mitigating Role of Default Nudges
Cognitive overload may compromise critical competencies essential for effective auditing, including fraud detection and risk assessment. Auditors, tasked with processing extensive information under time constraints, may experience difficulties in maintaining professional scepticism, a fundamental mechanism that supports these core evaluative functions. Default nudges or pre-selected options, subtly shape choices with the premise of easing cognitive load and ultimately enhancing audit performance. This study examined how cognitive load and default nudges shape decision-making-based professional scepticism. In three online experiments, we investigated how default nudges influence professional scepticism under varying cognitive loads among auditors. Experiment 1 validated a cognitive load manipulation (minimal, low, medium, high) using reaction time and accuracy, selecting low and high load conditions for further study. Experiment 2 confirmed load-dependent reaction time increases, with audit task accuracy remaining stable. Experiment 3a tested the effect of default nudge on professional scepticism under varying levels of cognitive load, revealing that nudging accelerated responses and improved audit accuracy, but only under cognitive load. Experiment 3b explored default-setting-response alignment, showing that nudging toward considering an accounting item as "non-aggressive" (e.g., not indicative of fraud), the less sceptical and most common case, enhanced accuracy, whereas nudging toward considering the item "aggressive", reduced it. These findings highlight how cognitive load disrupts scepticism and suggest that strategically placed nudges can enhance audit decision-making based professional scepticism under pressure. Insights from this study have direct implications for high-stakes professions, where optimized decision environments could support critical judgment under cognitive strain.

Modulation of cofilin 1 phosphorylation induces juvenile-like plasticity in the adult mouse visual cortex.
Cofilin 1 is an actin-depolymerizing protein that plays a fundamental role in actin dynamics, particularly within dendritic spines, where it has been implicated in both structural and functional plasticity. We recently demonstrated (by differential proteomics, western blot and immunohistochemistry) that the expression of cofilin 1 and its inactive phosphorylated form are dynamically regulated in the mouse visual cortex during postnatal development and by visual experience, with expression levels correlating with periods of heightened plasticity. In this study, we investigated the role of cofilin 1 in structural and visual plasticity in adult mice through pharmacological modulation of its activity. Specifically, we administered a synthetic peptide inhibitor of cofilin 1 activity in vivo (PCOF). Following monocular deprivation, adult mice received either the PCOF peptide or a control peptide. Structural plasticity was assessed by quantifying dendritic spine density using Golgi-like staining, while visual plasticity was evaluated by measuring visual acuity through the optomotor response test. Our results show that, in adult mice treated with the PCOF peptide - but not in controls - monocular deprivation led to a significant reduction in dendritic spine density in the contralateral visual cortex, as well as a decrease in visual acuity of the previously deprived eye. These findings indicate that cofilin 1 activity is crucial for the regulation of experience-dependent plasticity in the adult mouse visual cortex.

Systems biology analysis of vasodynamics in mouse cerebral arterioles during resting state and functional hyperemia
Cerebral hemodynamics is tightly regulated by arteriolar vasodynamics. In this study, a systems biology approach was employed to investigate how the interplay between passive, myogenic, neurogenic, and astrocytic responses shapes arteriolar vasodynamics in small rodents. A model of neurovascular coupling is proposed in which neurons inhibit and dampen the myogenic response to promote vasodilation during activation, and facilitate the myogenic response to promote rapid vasoconstriction immediately post-activation. In this model, inhibition of the myogenic response is mediated by the hyperpolarization of smooth muscle and endothelial cells. Dampening and facilitation of the response are mediated by neuronal production of nitric oxide and release of neuropeptide Y, respectively. We also introduce a model for gliovascular coupling, in which astrocytes periodically inhibit the myogenic response upon detecting an increase in myogenic activity through interactions between their endfeet and arterioles. Our study revealed that in the resting state, the interplay between the delayed myogenic response and passive distension, acting as negative and positive feedbacks respectively, generates undamped oscillations in vessel diameter, known as vasomotion. In the active state, these oscillations are disrupted by the neurogenic and astrocytic responses. The biophysical model of arteriolar vasodynamics presented in this study lays the foundation for quantitative analysis of cerebral hemodynamics for cerebrovascular health diagnostics and hemodynamic neuroimaging.