bioRxiv Subject Collection: Neuroscience's Journal

Chemogenetic Manipulation of the Subthalamic Nucleus-Substantia Nigra Pars Reticulata Pathway Promotes Recovery in HemiParkinsonian Rat Models
Motor control through the basal ganglion is mediated primarily thought two pathways, the direct and indirect pathways. The indirect pathway functions in opposition to the direct pathway, balancing excitatory and inhibitory control over motor movement. In Parkinsons disease, the indirect pathway is thought to suppress movements through excessive excitation of inhibitory neurons within the globus pallidus internus and substantia nigra pars reticulata. In an attempt to restore this balance, we induced the expression of GAD65 in glutamatergic subthalamic neurons to enable the co-release of GABA. Previous studies indicated co-expression of GABA with glutamate reduces glutamate excitability and might restore balance to the network. Indeed, we observed a reduction in post-lesional amphetamine-induce rotations in 6OHDA lesioned rats co-transduced with GAD65 and excitatory DREADDs and activated by CNO. This study indicates rebalancing inhibitory and excitatory output from the subthalamic nucleus can have a positive effect on motor outcome.

Spatially Resolved Microglial Expression Around Aβ Plaques in Human Alzheimers Disease Tissue
Using microglia-enriched spatial transcriptomics on human Alzheimers disease tissue, we identify distinct gene expression changes across microglia located in direct contact with plaques, in periplaque regions, and in areas distant from plaques. We define a group of plaque contact only microglial (PCOM) genes whose expression increases exclusively in microglia directly contacting plaques. These genes show significant overlap with previously reported gene sets, suggesting that many of the well-characterised disease-associated microglia (DAM) and other AD-related gene-expression signatures are only upregulated when microglia contact plaques. We further identify distinct co-expression networks associated with disease-relevant covariates, including an immune module linked to APOE genotype and a synaptic-mitochondrial module negatively associated with Braak stage. Finally, we compare the human dataset to our previously published data from 18-month-old AppNL-F mice, generated using the same experimental paradigm and demonstrate cross-species concordance in gene expression particularly within plaque-contacting microglia.

Electrophysiological Characteristics of Epidural Spinal Signals in Preclinical Models of Spinal Cord Stimulation
Objectives: Epidural stimulation of the spinal cord evokes distinct electrophysiological responses that can be recorded epidurally. Here, we characterized evoked compound action potentials (ECAPs), doublets (secondary or tertiary ECAPs, likely of different physiological origin than primary ECAPs), evoked synaptic activity potentials (ESAPs), and electromyographic (EMG) signals in preclinical models. Our objective was to clarify the features and distinct physiological origins of these signals, in order to advance mechanistic studies and support clinical applications of spinal cord stimulation (SCS) therapy. Materials and Methods: Adult male Sprague-Dawley rats (300-440 g) were implanted with two epidural leads (caudal and rostral; each with eight electrodes) and received monopolar, biphasic stimulation (200 s pulse width) at 2 and 50 Hz, with current increased stepwise to motor threshold. Rhesus macaques (11.5 and 10.2 kg) were implanted with a single 12-electrode epidural lead and stimulated using either tripolar, triphasic pulses at 10 Hz (100 s) or tripolar, biphasic pulses at 3 Hz (80 s) up to 3xECAP threshold. Recordings were taken from non-stimulating electrodes. Results: ECAPs and EMG signals were recorded across multiple spinal segments in both rats (L1-T7) and macaques (L2-T11). Doublets presented as complex waveforms with multiple negative peaks, two in rats and three in macaques, likely representing distinct ECAPs at T11-T6 in a rat and L1-T11 in macaques. ESAPs, detectable in rats, showed anatomical specificity, over the L1/T13 vertebrae with peak responses at L1. Signal analysis included activation thresholds, amplitudes, latencies, and conduction velocities. Conclusions: This study outlines electrophysiological signals evoked by SCS in terms of their waveform, recruitment thresholds, and putative physiological origins. We propose that, to the extent these signals reflect different aspects of spinal processing and may serve as biomarkers of dysregulated nociceptive pathways, as well as indicators of SCS efficacy or potential side effects.

Deletion of the 5-HT3A receptor reduces behavioral persistence and enhances flexibility
The 5-HT3A receptor is the only ionotropic serotonin receptor and has been implicated in cognitive functions, yet its specific role remains unclear. To investigate the contribution of the 5-HT3A subtype, we trained wild-type (C57BL/6J) and 5-HT3A receptor knockout (Htr3a-/-) mice across a series of operant conditioning tasks and compared their behavioral performance. Following nose-poke training, both groups underwent a rule-switching task, extinction tests under fixed ratio (FR) and variable ratio (VR) reinforcement schedules, and a progressive ratio (PR) task to assess persistence. We found that 5-HT3A receptor knockout mice exhibited reduced responding during the extinction and PR tasks, suggesting diminished behavioral persistence. Notably, however, knockout mice acquired the new rule in the switching task significantly faster than wild-type controls, indicating enhanced cognitive flexibility. These findings suggest that the 5-HT3A receptor plays a role in regulating the balance between behavioral persistence and flexibility, normally biasing this balance toward persistence under normal physiological conditions. This mechanism may underlie the therapeutic effect of 5-HT3A receptor antagonists in treatment-resistant obsessive-compulsive disorder (OCD).

Convergent motifs of early olfactory processing are recapitulated by layer-wise efficient coding
The architecture of early olfactory processing is a striking example of convergent evolution. Typically, a panel of broadly tuned receptors is selectively expressed in sensory neurons (each neuron expressing only one receptor), and each glomerulus receives projections from just one neuron type. Taken together, these three motifs--broad receptors, selective expression, and glomerular convergence--constitute "canonical olfaction," since a number of model organisms including mice and flies exhibit these features. The emergence of this distinctive architecture across evolutionary lineages suggests that it may be optimized for information processing, an idea known as efficient coding. In this work, we show that by maximizing mutual information one layer at a time, efficient coding recovers several features of canonical olfactory processing under realistic biophysical assumptions. We also explore the settings in which noncanonical olfaction may be advantageous. Along the way, we make several predictions relating olfactory circuits to features of receptor families and the olfactory environment.

Anatomical and Neurochemical Profiles of GABAergic Projection Neurons in the Mouse Inferior Colliculus
The inferior colliculus (IC) is a critical hub for the integration of auditory signals in the midbrain. Although both glutamatergic and GABAergic neurons in the IC project to the medial geniculate body (MGB), the detailed neurocircuitry and neurochemical properties of GABAergic projection neurons remain poorly understood. In this study, glutamate decarboxylase 67 (GAD67)-Cre mice and the viral vector were utilized to selectively visualize the axonal projections of GABAergic neurons in the IC. These neurons project predominantly to the medial division of MGB (MGv) and contralateral IC and minorly to the ventral nucleus of the trapezoid body. Importantly, GABAergic projections from both lemniscal and non-lemniscal regions of the IC primarily targeted the lemniscal division of the MGB, whereas those projections from the external cortex of the IC, which is part of the non-lemniscal pathway, additionally extended into non-lemniscal MGB subregions. Using a retrograde tracer, a substantial proportion of GABAergic projection neurons targeting the MGB and contralateral IC were positive for several neurochemical markers, implying that some GABAergic neurons send axon collaterals to both targets. Notably, GABAergic neurons constituted 10% of the total neuronal population in the IC, whereas GABAergic neurons accounted for approximately 20% of IC neurons projecting to the MGB or contralateral IC. Our results suggest that GABAergic projection neurons are more involved in the IC to MGB pathway than would be expected based on their proportion in the IC and may exert widespread influence on auditory processing via direct inhibition of the MGv and indirect modulation through suppression of the contralateral IC.

Evaluating Place Cell Detection Methods in Ratsand Humans: Implications for Cross-Species Spatial Coding
Place cells, first identified in the rat hippocampus as neurons that fire selectively at specific locations, are central to investigations of the neural underpinnings of spatial navigation. With recent work with human patients, identifying and characterizing place cells across species has become increasingly important for understanding the extent to which decades of rodent research generalize to humans and uncovering principles of spatial cognition. One challenge, however, is that detection methods differ: rodent studies often rely on spatial information (SI), whereas human studies employ analysis of variance (ANOVA) - based approaches. These methodological differences may affect the identified place cell population, which complicates how their properties are interpreted and cross-species comparisons. To address this, we systematically applied multiple detection pipelines to human and rat datasets, supported by simulations that vary place-field properties. Our analyses and simulations demonstrate that spatial information and ANOVA-based approaches are responsive to distinct place field properties: spatial information primarily reflects the contrast between peak and average firing rates, while ANOVA emphasizes consistency across trials. Across species, rodent place cells revealed a broad spectrum of spatial tuning, including strongly tuned neurons with high spatial information (SI) and high ANOVA values. In contrast, human place cells lacked this strongly tuned population and exhibited a narrower distribution of tuning scores, concentrated at the lower end of both spatial tuning metrics. Despite these differences, both species had an overlapping population of neurons with weaker yet consistent spatial tuning, which may support important functional roles such as generalization and mixed selectivity. Together, our study provides a roadmap showing how spatial tuning metrics shape place cell detection and interpretation, while underscoring the functional importance of weaker-tuned neurons in cross-species comparisons.

Cortical control of a forelimb prosthesis in mice
Robotic upper-limb prostheses aim to restore the autonomy of paralyzed patients and amputees. So far, advances in this field have relied on monkey pre-clinical and human clinical research. Here, we report on the direct brain control by mice of a miniature mouse forelimb prosthesis. We show that mice implanted with a cortical, microelectrode-based brain-machine interface can learn to control the prosthesis via neuronal operant conditioning, and solve a water collection task in a 2-dimensional and up to a 3-dimensional space. As they learned this task, the mice shaped increasingly consistent prosthesis movements that led to rewards, thanks to coordinated patterns of neuronal activity across the several control dimensions. Beyond the demonstration of unexpected cognitive and motor control abilities in mice, we anticipate that this preclinical model of upper-limb prosthesis control will be a tool to address several of the most pressing issues in BMI-controlled prosthetics.

Learning neural dynamics through instructive signals
Rapid learning is essential for robust behavior, allowing animals to quickly adapt to changing environments and task conditions. However, traditional Hebbian plasticity rules lack the power to induce the rapid, flexible changes in neural dynamics needed for such learning. Here we propose a network model with a rapid, heterosynaptic plasticity rule inspired by circuit motifs in hippocampus, cerebellum, and mushroom body, which relies on interactions between pre-synaptic activity and an "instructive signal" such as dopamine. We show that this rule can quickly produce highly flexible nonlinear dynamics using sparse, low-dimensional instructive signals while also admitting precise mathematical interpretation inspired by the well-known support vector machine. Using adaptive control theory, we additionally derive an online rule allowing such networks to learn using instructive signals guided by real-time feedback. Thus, heterosynaptic instruction-mediated plasticity is a powerful, biologically plausible and analytically tractable mechanism for the rapid learning of flexible dynamics, shedding light on the neural basis of complex adaptive behavior.

Distinct contributions and sensorimotor encoding of PV and FoxP2 neurons in the external globus pallidus during perceptual decision-making
The external globus pallidus (GPe), a central nucleus of the basal ganglia (BG), comprises diverse cell types, including PV and FoxP2 neurons. While previous studies have delineated their distinct roles in movement regulation and sensory processing, their contributions to perceptual decision-making remain unclear. Here we investigated the sensorimotor functions of PV and FoxP2 neurons in mice performing a Go/No-Go visual task. Optogenetic activation of either population impaired task performance, whereas only inhibition of PV, but not FoxP2 neurons, disrupted behavior. Electrophysiological recordings revealed that PV and FoxP2 neurons exhibited distinct encoding of visual stimuli, licking movement, and trial outcomes. Moreover, inhibiting GPe PV neurons altered stimulus and outcome selectivity, as well as task-related activity, in the substantia nigra pars reticulata, a major output nucleus of the BG. These findings reveal that GPe PV and FoxP2 neurons uniquely regulate the flow of sensorimotor information within the BG during perceptual decision-making.

Representational geometry of emotional empathy in the ventromedial prefrontal cortex and in the mid-posterior insula.
Facial expressions provide rapid and informative cues about others' emotional and mental states, playing a critical role in social interactions. However, whether distinct emotional expressions reflect discrete neural processes or arise from varying combinations of underlying affective dimensions such as arousal and valence remains a subject of investigation. Crucially, these accounts need not be mutually exclusive: different brain regions may encode emotional expressions along both categorical and dimensional axes to varying degrees. To test this hypothesis, we probed different brain systems involved in emotion recognition - the ventral attentional network and the cortical limbic system centered on the ventromedial prefrontal cortex (vmPFC) - to investigate the extent to which these networks and their subregions encode emotional facial expressions in terms of (1) perceived arousal, (2) arousal+valence, or (3) six discrete emotion categories (anger, disgust, fear, happiness, pain, sadness). To this aim, we modelled the fMRI signal from perceiving movies of facial emotional expressions with ratings for either arousal, arousal+valence or emotion category using representational similarity analysis (RSA) - a method that aims at assessing which ratings model better represents how the perception of facial expressions is reflected by the fMRI parameter estimates across all the voxels within a brain region. This analysis showed that regions in the vmPFC network, including the subgenual cingulate and the medial OFC, are sensitive to ratings for distinct emotion category and for arousal+valence - significantly more so for the former - while they fail to show sensitivity for arousal ratings alone. In the ventral attentional network, the mid-posterior insula showed a similar profile, while the most posterior and ventral insular show evidence of encoding arousal+valence, but not for emotion category or arousal alone. Our findings support the idea that the vmPFC and the mid-posterior insula play a role in encoding emotion-specific and valence representations beyond general arousal processing. These results contribute to understanding how integrative brain regions support emotional empathy and social cognition.

Identification of bacterial signals that modulate enteric sensory neurons to influence behavior in C. elegans
The bacterial microbiome influences many aspects of animal health and disease. Some bacteria have beneficial functions, for example providing nutrients, whereas others act as pathogens. These bacteria are sensed by host cells to induce adaptive changes in physiology and behavior. While immune and intestinal cells detect bacterial signals through well-characterized mechanisms, recent studies indicate that neurons can also directly sense bacterial signals. However, the bacterial sensory mechanisms in neurons are less well understood. In the nematode Caenorhabditis elegans, the enteric sensory neuron NSM innervates the pharyngeal lumen and is directly activated by bacterial food ingestion; in turn, NSM releases serotonin to induce feeding-related behaviors. However, the molecular identities of the bacterial signals that activate NSM are unknown. To identify these signals, we systematically probed bacterial macromolecules from nutritive bacteria using biochemical approaches and GC-MS identification. We find that polysaccharides from gram-positive and gram-negative bacteria are sufficient to activate NSM. We further identify peptidoglycan from gram-positive bacteria as a specific component capable of activating NSM. NSM responses to polysaccharides require the acid-sensing ion channels DEL-3 and DEL-7, which localize to its sensory dendrite in the pharyngeal lumen. Ingestion of bacterial polysaccharides enhances feeding rates and reduces locomotion, matching the known effects of NSM on behavior. We also examine bacterial signals from pathogenic bacteria that can infect and kill C. elegans. This approach identifies prodigiosin, a metabolite from pathogenic Serratia marcescens, as a bacterial cue that prevents NSM activation by nutritive bacterial signals. This study identifies molecular signals that underlie neuronal recognition of nutritive bacteria in the alimentary canal and competing signals from a pathogenic bacterial strain that mask this form of recognition.

Somatostatin released by single O-LM interneurons slowly inhibits intrinsic neuronal excitability in a paracrine and autocrine manner
Somatostatin (SST) is a neuropeptide known to inhibit both neuronal excitability and excitatory synaptic transmission in principal neurons. While SST is expressed in some GABAergic interneurons such as Oriens-Lacunosum Moleculare (O-LM) cells, the precise conditions governing SST release remain poorly defined. We show here that, in the presence of GABAA receptor antagonist, single O-LM interneurons of CA1 are able to inhibit pyramidal neuron excitability when O-LM cells fire at frequencies above 20 Hz. This inhibition is suppressed by the SST receptor antagonist cyclo-SST and is absent when the O-LM interneuron is located more than 150 micormeters from the pyramidal cell. Likewise, a single O-LM cell was also able to inhibit the intrinsic excitability of another O-LM cell, provided the two cells are in proximity. Exogeneous application of SST transiently inhibits excitatory synaptic transmission and intrinsic excitability in O-LM interneurons through SST1 and SST2, respectively. Notably, this transient inhibition became sustained when clathrin-dependent endocytosis of SST receptors was blocked. Blocking of SST receptors reduced NMDA receptor-mediated responses, prevented induction of both synaptic and intrinsic potentiation in pyramidal neurons and reduced the coherence of theta oscillations. These findings reveal that SST released by O-LM interneurons constitutes an additional inhibitory mechanism, modulating both synaptic excitation and intrinsic excitability beyond the transient inhibition mediated by GABA release.

Adolescent stress impairs parvalbumin interneurons and their associated perineuronal nets: protective effects of microglia-modulating minocycline treatment
Adolescence is a critical period of brain maturation during which exposure to stress can lead to long-lasting behavioral and neurobiological alterations linked to increased vulnerability to psychiatric disorders. Here, we investigated whether minocycline, a tetracycline antibiotic that modulates microglial activity, could prevent or attenuate the long-term effects of adolescent stress on behavior, parvalbumin (PV)-expressing (+) interneurons (PVIs), perineuronal nets (PNNs), and microglia in adulthood. Male mice were exposed to a 10-day footshock stress protocol during adolescence (postnatal days 31-40) and treated with minocycline (30 mg/kg; i.p.) either during or after stress exposure. Behavioral assessments in adulthood revealed that adolescent stress impaired sociability, social memory, and object recognition memory, which were attenuated by minocycline treatment during or after adolescent stress exposure. Stress also reduced the number of PV+, PNN+, and PV+/PNN+ cells in the prefrontal cortex (PFC) and ventral hippocampus (vHip). These effects were prevented by minocycline administration at both time points. No significant long-lasting changes were observed in microglial number, density, or spatial distribution in either region. However, minocycline treatment modulated microglial morphology in a region- and timing-dependent manner, with increased microglial area observed in the PFC and subtle alterations in circularity in the vHip. These findings suggest that adolescent stress induces enduring impairments in PVIs and behavior, possibly through transient microglial intervention and PNN degradation. Minocycline treatment during or after stress was effective in preventing these changes, supporting its potential as a therapeutic strategy to mitigate the long-term consequences of adolescent stress and to reduce vulnerability to stress-related psychiatric disorders.

Parallel Belief States account for Learning and Updating of Attentional Priorities in Multidimensional Environments
Inferring the behavioral relevance of visual features is difficult in multidimensional environments as many features could be important. One solution could involve tracking the experience with multiple features and using attentional control to decide which subset of features to explore and chose. Here, we characterize this attentional control process with a model of parallel belief states and test it with a task requiring the learning and updating of attention to features with varying selection histories and motivational costs. We found that exploring and exploiting features was accounted for by a model that tracks the latent beliefs about the relevance of multiple features in parallel. These parallel belief states accounted for the fast learning of feature-based attention, for perseverative selection history effects for features that were previously relevant, and for enhanced learning performance when the motivational costs of making errors increased. Taken together, these results quantify how multiple parallel belief states guide exploration and exploitation of feature-based attention during learning. We suggest parallel belief states represent attentional priorities that are read out by a competitive attentional control process to explore and exploit those visual objects in multidimensional environments that are believed to be relevant.

Tool and hand adaptation and localization in immersive virtual reality
The human brain readily adapts movements to achieve motor goals. Most visuomotor adaptation studies use planar reaching with a cursor, where misaligned feedback leads to compensatory adjustments, reach aftereffects, and shifts in perceived hand location. Whether these effects extend to more natural settings and tool use remains unclear. In the Hand Experiment, we showed that in immersive virtual reality (VR), adaptation to 30{degrees} and 60{degrees} visuomotor rotations produced robust reach aftereffects and the expected shifts in hand localization. In the Pen Experiment, we extended this paradigm to a familiar hand-held tool, assessing localization of both the tool tip and the hand. Adaptation with the pen induced comparable or greater recalibration effects than with the hand-cursor, including shifts in both perceived tool and hand position. These findings demonstrate that visuomotor adaptation in immersive VR generalizes beyond cursor-based tasks, revealing how the sensorimotor system recalibrates internal representations of both the body and tools in realistic 3D environments.

Successful transfer of myoelectric skill from virtual interface to prosthesis control
Objective. Prosthesis control can be seen as a new skill to be learned. To enhance learning, both internal and augmented feedback are exploited. The latter represents external feedback sources that can be designed to enhance learning, e.g. biofeedback. Previous research has shown that augmented feedback protocols can be designed to induce retention by adhering to the guidance hypothesis, but it is not clear yet if that also results in transfer of those skills to prosthesis control. In this study, we test if a training paradigm optimised for retention allows for the transfer of myoelectric skill to prosthesis control. Approach. Twelve limb-intact participants learned a novel myoelectric skill during five one-hour training sessions. To induce retention of the novel myoelectric skill, we used a delayed feedback paradigm. Prosthesis transfer was tested through pre-and post-tests with a prosthesis. Prosthesis control tests included a grasp matching task, the modified box and blocks test, and an object manipulation task, requiring five grasps in total ('power', 'tripod', 'pointer', 'lateral grip', and 'hand open'). Main results. We found that prosthesis control improved significantly following five days of training. Importantly, the prosthesis control metrics were significantly related to the retention metrics during training, but not to the prosthesis performance during the pre-test. Significance. This study shows that transfer of novel, abstract myoelectric control from a computer interface to prosthetic control is possible if the training paradigm is designed to induce retention. These results highlight the importance of approaching myoelectric and prosthetic skills from a skill acquisition standpoint, and open up new avenues for the design of prosthetic training protocols.

Perceptual Support for Temporal Normalization Across Hundreds of Milliseconds
Perception across time is limited: phenomena like masking and temporal crowding reveal perceptual interference between sequential stimuli, even when separated by hundreds of milliseconds. However the underlying causes of these suppressive temporal interactions remain unclear. A potential explanatory mechanism is temporal normalization, a form of divisive suppression proposed to operate across time in the visual cortex, but largely untested behaviorally. Here in three experiments we tested a key perceptual prediction of temporal normalization: contrast-dependent suppression between sequential stimuli. By independently manipulating the contrasts of two sequential gratings presented 250 ms apart, we found that perceptual sensitivity to a target's orientation decreased when a high- vs. low-contrast non-target appeared either before or after it. Reduced sensitivity arose from both decreased orientation precision and increased "swapping" errors. The results provide perceptual support for a temporal normalization computation operating across hundreds of milliseconds, offering a theoretical framework for perceptual limits across time.

Alterations in steady-state synchronisation between Acute and Chronic Tinnitus suggests reduction in both tinnitus and central gain.
The mechanism of tinnitus remains unclear as the generation and persistence of tinnitus is not widely understood. The acute tinnitus population serves as an ideal group for investigating the mechanisms behind the origin and persistence of tinnitus, from its initial onset to its subsequent chronification. One of the neural markers for measuring tinnitus such as neural synchrony or central gain is the Auditory Steady State Response (ASSR). The experiment was carried out on 39 participants with acute tinnitus (18 followed back six months post baseline), 30 with chronic tinnitus, and 27 controls. The results reveal that both cross sectionally and longitudinally, there were no significant differences in absolute amplitudes of ASSR across intensities and the slope of ASSR growth function between the groups. However, Controls tend to have an overall increase in ASSR amplitude when compared to Acute and Chronic Tinnitus which can be attributed to changes in neural synchronisation, attentional modulation, tinnitus-related distress, and diminished GABAergic inhibition coinciding with the presence of tinnitus. As there were no changes in the ASSR amplitude between Acute and Chronic Tinnitus or between Acute and Post Acute Tinnitus despite variations in distress and tinnitus loudness, we infer that auditory sensitivity/neural sensitvity is independent of the tinnitus.

An Evaluation of the Efficacy of Single-Echo and Multi-Echo fMRI Denoising Strategies
Resting-state functional magnetic resonance imaging (rsfMRI) is commonly used to study brain-wide patterns of inter-regional functional coupling (FC). However, the resulting signals are vulnerable to multiple sources of noise, such as those related to non-neuronal physiological fluctuations and head motion, which can alter FC estimates and influence their associations with behavioral outcomes. The best strategy for acquiring and processing rsfMRI data to mitigate noise remains an open question. In this study of 358 healthy individuals, we compared the denoising efficacy of 60 multi-echo (ME) and 30 single-echo (SE) rsfMRI preprocessing pipelines across six distinct measures of data quality. We also evaluated how each pipeline influences the effect sizes of FC-based predictive models of personality and cognitive measures estimated via cross-validated kernel ridge regression. We found that ME pipelines generally showed superior denoising efficacy to SE pipelines, but that no single pipeline was associated with both superior denoising efficacy and behavioural prediction. Using a heuristic scheme to rank pipelines across benchmark evaluations, we found that an ME acquisition combined with Automatic Removal of Motion Artifacts Independent Component Analysis (ICA-AROMA) and Regressor Interpolation at Progressive Time Delays (RIPTiDe) offered a reasonable compromise between denoising efficacy and brain-behavior predictions for both ME and SE data. In general, ME pipelines ranked more highly than SE pipelines. These findings support the use of ME acquisitions in future work but suggest that no single denoising pipeline should be considered optimal for all purposes.

The Influence of Force Field Perturbations on Symmetric and Asymmetric Bimanual Reaching
Bimanual symmetric and asymmetric reaching movements require the motor system to coordinate the two limbs under varying spatial and physical demands. While prior research has shown a strong tendency for temporal synchronization between the hands, little is known about how bimanual reaching is organized when each limb is subjected to distinct types of force fields, such as viscous or elastic loads. This study systematically investigated how matched (viscous/viscous, elastic/elastic) and mismatched (e.g., viscous/no load, elastic/no load, viscous/elastic) load conditions influence key timing and kinematic parameters during bimanual reaching tasks across different spatial configurations and force magnitudes. Results show that kinematic measures for each arm, including peak velocity, peak acceleration, and peak deceleration, exhibit significant differences across both matched and mismatched load conditions, reflecting clear adaptations in limb behavior. In contrast, temporal aspects of movement-specifically the timepoints of peak velocity, peak acceleration, peak deceleration, and movement end time-remain coupled under matched loads but become decoupled under mismatched loads, with each limb operating more independently regardless of the spatial configuration of the task. Together, these findings clarify how the motor system balances the need for coordinated bimanual performance with the flexibility required to adapt to varying load conditions. This study extends prior work by demonstrating that not all bimanual reaches are temporally synchronized; instead, task-specific factors such as load type and symmetry critically shape how the limbs coordinate, revealing the motor system's capacity for flexible, context-dependent control.

The cellular associates of late life changes in white matter microstructure
The microstructural architecture of white matter supporting information flow across local circuits and large-scale networks changes throughout the lifespan. However, the genetic and cellular factors underlying age-related variations in white matter microstructure have yet to be established. Here, we examined the genetic associates of individual differences in diffusion-based measures of white matter in a population-based cohort (N=29,862) from the UK Biobank. Estimates of heritability from Genome-Wide Association Study (GWAS) data revealed that genetic factors are linked to population variability in 96.1% of 432 tract microstructural measures. The presence of shared genetic influences was observed to be greater within, relative to between, broad tract classes (commissural, association, projection, and complex cerebellar). Age associations with microstructural changes were estimated across diffusivity measures, with association class tracts showing the greatest vulnerability to age-related decline in older adults. Analyses of imputed cellular associates of age-related changes in white matter revealed a preferential relationship with cell gene markers of oligodendrocytes and other glial cell types, with sparse relationships observed for inhibitory and excitatory cells. These data indicate that white matter tract microstructure is shaped by genetic factors and suggest a role for glial cell-related transcripts in late-life changes in the structural wiring properties of the human brain.

Natural language processing captures memory content associated with shared neural patterns at encoding
People can experience the same event yet form distinct memories shaped by individual interpretations. Prior research shows that multivariate activity patterns in the Default Mode Network (DMN) are correlated across individuals during shared experiences, suggesting a role in representing high-level event features. However, it remains unclear whether these shared neural patterns reflect similarity in subsequent memory content. Here, we examined whether memory similarity correlates with intersubject spatial patterns in the DMN. Using topic modeling, we transformed verbal recall into vectors of latent topics to quantify memory similarity across participants. Twenty-four individuals watched and recounted two cartoon movies during fMRI scanning. We found that greater similarity in recalled content was associated with stronger shared activation patterns at encoding, particularly in the posterior medial cortex. These findings highlight the utility of natural language processing tools in linking memory representations to brain activity and underscore the DMN's role in encoding and interpreting complex event features.

Fetal network controllability co-develops with synaptic density and synchronizes with maternal network controllability during pregnancy
White matter undergoes rapid changes during the fetal period that are foundational for later cognition. However, how these changes contribute to the brain's capacity for dynamic state transitions-its controllability-remains largely unknown. Here, we apply network control theory (NCT) to investigate the developmental trajectory of controllability from the second trimester through the first postnatal month. We analyzed structural connectivity data from 217 fetuses, 448 term infants, and 194 preterm infants as part of the developing Human Connectome Project. We identified a robust, nonlinear U-shaped developmental curve of whole-brain controllability across the perinatal period, with a minimum at approximately 35 gestational weeks. Preterm birth disrupted these trajectories, leading to greater controllability and earlier minimums compared to age-matched fetuses. We used positron emission tomography in seven pregnant rhesus macaques to quantify changes in fetal synaptic density. Increased synaptic density in non-human primates (NHPs) co-occurred with periods of reduced controllability in humans, suggesting that changes in controllability may be driven by synaptogenesis. Finally, using longitudinal scans of a pregnant woman, we mapped the trajectory of changes in maternal controllability during pregnancy. This trajectory exhibited a U-shaped pattern that inversely correlated with the fetal trajectory and reached a maximum around 36 weeks. Together, fetal controllability follows a nonlinear trajectory that co-develops with synaptic density in NHPs and synchronizes with maternal changes in controllability during pregnancy.

Human neuronal firing is modulated by the frequency of local field potential oscillations
Neural oscillations play a critical role in shaping neuronal firing patterns. While phase-locked neuronal firing ("phase tuning") has been extensively studied in animal models and human invasive recordings, much less is known about whether neurons show preferential firing at specific oscillatory frequencies, termed frequency tuning. Here, we employ human intracranial recordings across several brain regions including hippocampus, entorhinal cortex, anterior and posterior cingulate cortex, and orbitofrontal cortex to test the hypothesis that neurons exhibit frequency-specific firing. We analyzed 357 single units recorded simultaneously with local field potentials in 19 neurosurgical patients during awake resting. We estimated the instantaneous frequency of the LFP using adaptive spectral decomposition and assessed frequency tuning of each neuron while controlling for changes in firing rate unrelated to frequency changes. We found 27% neurons exhibited increased or decreased firing within specific frequencies, most commonly within the low-theta range (<10 Hz). Neurons exhibiting frequency tuning were distinct from those displaying phase tuning, and both types of tuning were observed across multiple brain regions with no anatomical preference. Together, our results demonstrate that the instantaneous frequency of neural oscillations modulates neuronal firing which may serve as an additional mechanism for information processing in the human brain, opening new avenues for frequency-targeted neural stimulation.

Novel object-place configurations increase excitability of layer 5 lateral entorhinal cortex engram cells
Associative recognition memory is essential for our everyday lives, allowing us to form cognitive representations of and remember relationships between things we encounter and their environments, such as where we left our keys or parked the car. Evidence suggests that these associations are represented in the lateral entorhinal and medial prefrontal cortices. However, the identity of neurons in which these associations are formed, the cellular mechanisms supporting them and how representations of object-associations react to changes in the environment are not understood. Here we use transgenic mice to label associative recognition memory engrams in mice, finding that memory recall reactivates engram cells in multiple cortical regions, but that engram cell reactivation only correlates with behavioural performance in the dorsolateral entorhinal cortex, where reactivation was highest in layer 5/6. Chemogenetic inhibition of engram cells in lateral entorhinal cortex impaired memory retrieval. Electrophysiology from ex vivo slices following memory recall demonstrated that engram cells in lateral entorhinal cortex layer 5, but not other cortices or layers, showed increased excitability only when the engram-specific objects had been reconfigured. These data collectively identify neurons in deep layers of lateral entorhinal cortex as probable loci of object-place associations and propose a mechanism by which new information is incorporated into pre-existing neural representations.

A transformation from vision to imagery in the human brain
Extensive work has shown that the visual cortex is reactivated during mental imagery, and that models trained on visual data can predict imagery activity and decode imagined stimuli. These findings may explain why imagery can feel and function like vision, but give little insight into how the brain activity patterns that encode seen and mental images differ. While one popular theory (''weak vision'') suggests that imagery differs from vision only in strength, recent work points to more complex differences. To clarify the relationship between visual and imagery activity in the human brain, we introduce the concept of an imagery transformation - a mapping from visual to imagery activity patterns evoked by the same stimulus. Importantly, this approach can describe a variety of possible scenarios, from simple rescaling to the selective removal or reorientation of activity dimensions. Using two 7T fMRI datasets, we estimated imagery transformations across different visual areas and found they accurately predict imagery activity. We show that imagery transformations are indeed more complex than simple weakening: in early visual cortex, they halve the number of active dimensions and reorient them, such that reconstructions of visual activity in terms of imagery dimensions explain only 25 - 50% of the variance. Nonetheless, these reoriented dimensions still coarsely encode the features encoded by the principal dimensions of visual activity. These findings help to explain the ''same but different'' relationship between mental imagery and vision: imagery activity patterns are transformations of visual activity patterns that approximate them, but encode fewer features and occupy a distinct subspace within the overall space of brain activations.

Developing a model of temporomandibular disorder in the common marmoset using nerve growth factor
Developing an animal model that more closely represents the human multidimensional pain experience is an important step towards addressing the current chronic pain crisis. The common marmoset has potential as this model species given its biological, neurological and phylogenetic similarity to humans. Here, we developed a model of myofascial temporomandibular disorder (TMD) in the marmoset by injecting nerve growth factor (NGF) into the superficial masseter. Following injection, animals showed reduced mechanical withdrawal thresholds at 5 g and 10 g doses of NGF and changes in circadian rhythm and feeding initiation following injection of 10 g of NGF. Animals did not show evidence of jaw dysfunction, masticatory alterations, or grimace during novel behavioural assays. The model is transient, with pain resolution occurring approximately 7 days after onset, which allows for repeated testing on the same animal. This same NGF-TMD model has been previously validated in rodents and humans and presents an opportunity for forward and reverse translation to examine mechanisms, develop relevant pain assessment tools, and ultimately test novel treatments for TMD and other musculoskeletal pain conditions.

Astrocytic lysosome deficits reduce alpha-synuclein degradation and induce spread of pathology
Parkinson's Disease (PD) is a neurodegenerative disorder caused by the loss of dopaminergic neurons in the substantia nigra due to Lewy body aggregates, primarily composed of misfolded alpha-synuclein (Syn). While PD progression is thought to be driven by a prion-like spread of Syn aggregates between neurons, the role of astrocytes remains unclear. Observations of Syn pathology in PD patient astrocytes suggest their potential involvement in processing aggregates. To investigate this, we studied astrocytes' interactions with Syn pre-formed fibrils (PFFs) and their effects in astrocyte-neuron co-cultures on the spread of seed-competent Syn. Primary astrocytes quickly internalized and degraded Syn PFFs. However, degradation was significantly hindered by lysosome-compromising agents like chloroquine, Leupeptin, or CA-074. Adding astrocytes to neuron cultures reduced endogenous Syn aggregation, indicating their role in mitigating Syn pathology. When lysosome efficiency in astrocytes was compromised, their anti-seeding effect diminished. Moreover, lysosome-compromised astrocytes preloaded with Syn PFFs enhanced Syn pathology in neurons, whereas unimpaired astrocytes did not. These findings suggest astrocytes can modulate and contribute to Syn pathology spread, playing a significant role in PD pathogenesis.

Children with Autism Show Impaired Oculomotor Entrainment to Predictable Stimuli
Individuals with Autism Spectrum Disorder (ASD) show altered synchronization with external events, which may underlie the rigidity and reduced adaptability that characterize the condition. We previously demonstrated that electroencephalography (EEG) recorded from children with ASD reveals impaired neuronal entrainment to predictable visual sequences. Whether similar effects are reflected in other physiological signals remains unclear. Here, we investigated whether eye movement and pupil dilation responses exhibit comparable entrainment differences in ASD. Microsaccades (MS) and pupil diameter were recorded from 31 children with ASD (6-9 years) and 21 age- and IQ-matched typically developing (TD) controls during a task in which four equally spaced visual cues preceded an auditory target. We analyzed modulation of MS release time (MS RT) and pupil response time (pupil RT), along with trial-by-trial variability, as indices of ocular entrainment. Both groups exhibited periodic oculomotor responses to the cues, including phasic MS inhibition and repeated pupil constrictions. In TD children, MS RT and pupil RT increased across cues while their variability decreased, consistent with progressive temporal alignment. These effects were significantly reduced in the ASD group. Oculomotor entrainment measures correlated with EEG inter-trial phase coherence (ITPC) in TD but not ASD children. They also correlated with behavioral response times in both groups, and moderately correlated with autism severity scores. Children with ASD thus showed diminished oculomotor modulation and greater variability in response to predictable stimuli, paralleling earlier EEG findings. These results suggest convergence across physiological systems in indexing impaired processing of predictability in ASD and highlight the promise of multimodal approaches.

Dentate gyrus and CA3 activity mediate light-tone second-order conditioning expression in mice
Second-order conditioning (SOC) enables animals to form complex predictions about their environment, even in the absence of direct experience. While the neural mechanisms underlying first-order conditioning (FOC) are well characterized, the circuits supporting SOC expression remain poorly understood. To address this gap, we investigated the brain regions and cell types involved in SOC recall in mice and tackled the technical challenges of quantifying brain-wide neural activity. We employed a light/tone SOC paradigm in TRAP2:Ai14 mice, which allowed us to tag neurons active during SOC recall via tdTomato expression. Applying generalized linear models, we identified that the activity in the dentate gyrus (DG) and CA3 regions of the dorsal hippocampus significantly associated with SOC-related behavioral responses. To test their functional relevance, we used chemogenetic inhibition of CaMKII+ neurons in these regions, which confirmed a causal role for DG/CA3 circuits in SOC recall. Together, our results highlight the dorsal hippocampus as a critical substrate for retrieving indirectly learned associations.

Behavioral expression of decision confidence engages disentangled confidence coding in the orbitofrontal cortex
Task engagement is thought to recruit subsets of neurons encoding task-relevant variables, but it remains unclear whether it also reorganizes the geometry of population codes and how such reorganization supports behavior. Here we show that, in the orbitofrontal cortex (OFC), task engagement aligns population activity along a confidence axis, thereby enabling the behavioral use of decision confidence. We recorded OFC activity while rats performed two variants of the same perceptual decision-making task that differed only in reward-timing uncertainty, which altered the utility of post-decision confidence for guiding reward waiting. OFC neurons exhibited more linear responses to confidence when confidence was more strongly expressed in behavior. Although the proportion of OFC neurons encoding confidence was similar across strategies, strategy-dependent alignment of population activity to confidence emerged under variable long delays, and this alignment predicted confidence-based waiting behavior. These findings suggest that OFC population codes flexibly adapt to the behavioral relevance of task variables, linking cognitive strategy to the geometry of neural representation.

Efficient incorporation of dendrites into a large-scale cortical model reveals their surprising role in sharpening optogenetic responses
Single-photon optogenetics enables chronic wide-field stimulation of cortex, facilitating large-scale manipulation of neural code to study cortical processing and advance neuroprosthetics. However, access to neural codes organized at fine spatial scales is compromised by the horizontal spread of stimulation-evoked cortical activity. Overcoming this limitation requires a quantitative understanding of the mechanisms contributing to spread, which include light scattering, dendritic activation, and synaptic transmission. We addressed this with morphology-aware simulations of optogenetic stimulation in a functionally-detailed network model of primary visual cortex. We find that synaptic transmission extends activation by 37-50 % beyond the illuminated area, while, paradoxically, neuronal morphology sharpens activation, as apical dendrites sample from the superficial cortex, which is less affected by light dispersion. This unexpected sharpening enhances the fidelity of stimulation with spatially distributed patterns. Our study offers guidance for optogenetic interventions targeting topographically organized neural codes and provides a computational testbed to interpret such experiments.

Spatially resolved transcriptomics identifies intercellular signaling post-ischemic stroke that controls neural stem cell proliferation
Stroke is the second leading cause of death and disability worldwide. Ischemic stroke mobilizes adult neural stem cells (NSCs) out of the quiescent state. The multifaceted responses of endogenous NSCs to ischemic stroke involve proliferation, migration, and differentiation. Hence one strategy which could be leveraged for recovery after ischemic stroke is the intrinsic mechanism of endogenous NSC mobilization. However, the survival rate of recruited endogenous NSCs is low. Moreover, the intercellular signals that activate NSCs after ischemic stroke are poorly understood. We hypothesized that after stroke, cells located in the cerebral lesion send signals to the NSC niche to initiate the regenerative response. To test this hypothesis, we used CellChat to computationally infer the cell-cell communication between the ischemic infarct region and ventricular-subventricular zone (V-SVZ) NSC niche from spatial gene expression profiles. We identified ligand-receptor pairs and signaling pathways involved in the signal transduction events at 2, 10, and 21 days after stroke. Out of several candidate genes of interest we identified, here we reported the regulatory function of galectin-9 on the proliferation of NSCs. Our present work portrays galectin-9 as a checkpoint signaling molecule that guards the responses of NSCs under physiological conditions and potentially during the recovery phase post-ischemic stroke. We suggest that TIM-3 mediates the inhibitory effect of galectin-9 on NSC proliferation and propose a working hypothesis that the stroke-induced proinflammatory factors stimulate the Toll-like receptor 4 (TLR4) on ependymal cells and result in the increased secretion of galectin-9, which in turn modulates neighboring NSCs. Our study paves the way for potential therapeutic approaches which leverage the TLR4 and galectin-9/TIM3 signaling pathways.

Cortical Representation of Pitch Perception in Mice
Pitch perception arises from temporal and spectral cues in sound. We hypothesized that mice rely on temporal cues because they have wide auditory filters, resembling humans with hearing loss or cochlear implants. Using computational modeling, behavioral assays, and widefield calcium imaging, we found that the structure of periodotopy in auditory cortex predicts how well mice recognize temporal pitch cues, establishing mice as a robust model for temporal pitch perception.