bioRxiv Subject Collection: Neuroscience's Journal
 
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Tuesday, October 7th, 2025

    Time Event
    1:32a
    Rapidly Reconfigurable Dynamic Computing in Neural Networks with Fixed Synaptic Connectivity
    Learning and memory in the brain's neocortex have long been hypothesised to be primarily mediated by synaptic plasticity. Extensive research in artificial neural networks has shown that training networks by adjusting connection weights faces computational challenges, including large parameter spaces and the tendency of new learning to interfere with previous learning (catastrophic forgetting). We propose that the brain, which is resistant to these challenges, can also learn by modulating the excitability of each neuron in a network rather than changing synaptic strengths. We show here that learning a task-specific set of bias currents enables a feedforward or recurrent network with fixed and randomly assigned connections to perform well on and switch between dozens of tasks, including regression, classification, autonomous time series generation, a game and robotic control. Bias-only learning also provides a novel mechanistic explanation for representational drift. It directly links the noise robustness of neuronal representations on short and long time scales to the ability of neural circuits to preserve learned information while remaining adaptable. We postulate that subcortical structures, such as the basal ganglia or cerebellum, may provide similar bias inputs to the neocortex for rapid task learning and robustness against interference.
    1:32a
    Impacts of perinatal factors on white matter outcome at 8 to 10 years by diffusion tensor imaging
    Background: While perinatal factors are known to influence brain development, their long-term impact on white matter microstructure remains incompletely understood. Previous studies using tract-based spatial statistics (TBSS) have shown limited associations between neonatal measures and later white matter development. Methods: We investigated associations between perinatal factors (birth weight [BW], gestational age [GA], and head circumference [HC]) and white matter microstructure in 117 children aged 8-10 years from the UNC Early Brain Development Study cohort. Diffusion tensor imaging (DTI) data were analyzed using a fiber tract-based framework examining 54 major white matter tracts. Statistical analysis was performed using a functional analysis of fiber tract profiles. Results: GA and BW showed widespread significant associations with white matter microstructure (38 and 36 out of 54 tracts, respectively), while HC showed limited associations (3 out of 54 tracts). Post-hoc univariate analysis revealed stronger associations with axial diffusivity (AD) compared to radial diffusivity (RD) or fractional anisotropy (FA). AD associations with BW, GA, and HC were found in 30, 31, and 8 tracts, respectively. Conclusions: Using a fiber tract-based analysis approach, we demonstrated that GA and BW are strongly predictive of white matter organization at school age, while HC showed limited predictive power. The predominant associations with AD suggest these perinatal factors primarily influence axonal organization rather than myelination. These findings enhance our understanding of how early life factors impact long-term brain development.
    2:46a
    Sequential development of task representation from hippocampus to prefrontal cortex supports goal-directed spatial navigation
    Successful goal-directed navigation requires the coordination between the hippocampus and medial prefrontal cortex. However, it is not fully confirmed that the medial prefrontal cortex learns its spatial code from the hippocampus. To test this, we examined spatial representations of the intermediate hippocampus and medial prefrontal cortex while rats learned a spatial navigation task. Rats performed a goal-directed spatial navigation task in 2D VR to find an unmarked goal zone, and we discovered robust directional tuning of single neurons in both regions. Neural manifold analysis further confirmed population-level directional tuning in both regions, with manifolds having ring-like geometry. We found that this ring-like structure evolved after learning, in a way that the hippocampal-prefrontal manifolds converged to a shared geometry. Furthermore, this evolution of ring-like structure was preceded by the hippocampus at the trial level. It was further verified that the evolution of the ring-like structure is linked to phase locking to the hippocampal theta rhythm, particularly in the prefrontal manifolds. Our findings provide compelling evidence that spatial representations of the hippocampal-prefrontal network become aligned after learning, and also highlight the information flow from the hippocampus to the medial prefrontal cortex during this geometry synchronization.
    2:46a
    A Dual Inhibitory Network in the Thalamic Reticular Nucleus Delineated by Pallidal and Intra-Reticular Inhibition
    Long described as an inhibitory "guardian of the gateway," the thalamic reticular nucleus (TRN) shapes which thalamic signals reach the cortex during attention, arousal, and sensory processing. However, how the inhibitory wiring within TRN supports this flexible gating--from modality-specific tuning to global control--remains poorly defined. Using cell type-specific optogenetic input mapping and whole-cell patch-clamp recordings in mice, we dissect inhibitory connectivity in TRN from two major GABAergic sources: the TRN itself and the external globus pallidus (GPe). All recorded TRN neurons received inhibition from the GPe, whereas a subset also received intra-TRN inhibition. Intra-TRN inhibition arose predominantly from somatostatin-expressing onto parvalbumin-expressing TRN neurons (SOM[->]PV), revealing subtype-specific connectivity recruited by thalamic excitation to form a feedforward motif. These findings delineate a dual inhibitory architecture: local intra-TRN circuits provide spatially selective inhibition, whereas pallidal inputs deliver diffuse inhibition. These complementary mechanisms may support both modality-specific gating and global state-dependent control of thalamic output.
    2:46a
    HCN channel currents underlie distinct neurophysiology of mediodorsal thalamus subnuclei
    The mediodorsal thalamus (MD) is a hub coordinating cortical and subcortical brain regions to support execu-tive and social/emotional functioning. MD can be subdivided into medial (M), central (C), and lateral (L) based on synaptic coupling, molecular identity, and physiology. Recently, we identified differential intrinsic properties be-tween thalamocortical M and L neurons projecting to the medial prefrontal cortex (mPFC). L neurons projecting to mPFC showed increased hyperpolarization activated cyclic nucleotide gated (HCN) channel activity compared with M neurons, which caused L neurons to have lower cellular resistance and shorter time windows for integration of inputs. In addition to their role in synaptic integration, HCN channels are critical for thalamic rhythm generation. In this study, we used a combination of patch clamp electrophysiology and in situ hybridization to investigate how differences in HCN impact intrinsic oscillatory dynamics in M, C, and L neurons. We found that HCN current (Ih) differed across MD subnuclei with C > L >> M. Clustering neurons based on HCN properties was sufficient to classify subnuclei with >95% accuracy, highlighting the differences in HCN function between sub-nuclei. Greater HCN activity in MD neurons was associated with decreased input resistance, decreased action potential firing, and higher resonant frequency. These findings provide an ionic basis for differences in cellular resonance across MD subnuclei, with implications for thalamic rhythm generation and information processing.
    2:46a
    Evolution towards higher unitary conductance in mammals makes BK channels more efficient and precise
    The large conductance calcium-activated potassium channel, known as the BK channel, play an essential role in neuronal firing and is characterized by a very large ~250pS unitary conductance in mammals. However, this high unitary conductance is not consistent across all species with invertebrates demonstrating a much lower unitary conductance. We explored the calcium activation properties of BK channels of different unitary conductance in computational models and found that mammalian channels are more efficiently activated by calcium and produce a stronger potassium current compared to the channels of lower unitary conductance found in invertebrates. The lower unitary conductance channels display fierce competition for the available calcium, which results in low activation and weaker current. Due to these properties, mammalian BK channels are more suitable to repolarize sodium action potentials, which enables more precise spike timing, and may explain why evolution appears to have favored a trend towards very high unitary conductance in mammalian BK channels. This may be an essential component of the more advanced brain functions achieved by these species compared to invertebrates.
    10:45a
    LACK OF OXYGEN AND/OR GLUCOSE DIFFERENTIALLY POTENTIATES Aβ40EQ22- AND Aβ42-INDUCED CEREBRAL ENDOTHELIAL CELL DEATH, BARRIER DYFUNCTION AND ANGIOGENESIS IMPAIRMENT
    Background: Disrupted brain hemodynamics and cerebrovascular damage resulting in cerebral hypoperfusion occur early within Alzheimers Disease (AD) pathogenesis. Cerebral hypoperfusion is also an extremely common consequence of cardiovascular risk factors and diseases (CVRFs/CVDs), which usually manifest in midlife, when AD pathology initiates, and actively contribute to AD onset and progression. Previously our lab has demonstrated that the vasculotropic Dutch mutant, amyloid beta Q22, and amyloid beta 42 promote endothelial cells (ECs) apoptosis, barrier permeability, and angiogenic impairments. Prior research has indicated that hypoperfusion promotes analogous EC dysfunction. Amyloid beta deposition occurs within a hypoperfused environment in AD, but whether exposure of cerebral ECs to amyloid beta under hypoperfusion results in potentiated cerebral EC dysfunction through activation of common molecular mechanisms remained unknown. Methods: Human cerebral ECs were treated with Amyloid beta 40-Q22 or Amyloid beta 42, glucose deprivation (GD), or a combination of both, under normoxia or hypoxia conditions. Cell death mechanisms (apoptosis/necrosis), endothelial barrier dysfunction/permeability (TEER/barrier-regulating proteins/proinflammatory activation), and angiogenesis impairment (vessel branching/VEGF signaling) were evaluated. Results: Reduction of glucose and/or oxygen potentiates Amyloid-induced cerebral EC death, barrier instability, junction protein dysregulation, inflammatory activation, and angiogenesis/wound healing failure. In particular, hypoperfusion exacerbates Amyloid beta Q22-mediated cerebral EC apoptosis, TEER/ZO1 decreases, ICAM1, IL6, and IL8 upregulation, monocyte migration, and wound healing impairments. Differentially, when in combination with Amyloid beta 42, hypoperfusion more strongly potentiates cerebral EC necrosis as well as increases in MMP2, phosphorylated claudin-5, IFN gamma, and IL12p70 expression. Additionally, this study identified that GD exerts stronger effects on promoting increases in cerebral EC caspase-3 activation, apoptosis, and MMP2/ICAM1 expression, while hypoxia particularly increases necrosis, ZO1 expression, and pro-angiogenic protein expression. Conclusions: This study reveals specific and selective mechanisms through which hypoxia, low glucose and amyloidosis mutually operate to produce brain EC dysfunction and death, highlighting new potential molecular targets against vascular pathology in AD/CAA comorbid with hypoperfusion conditions.
    10:45a
    Multilayer control of KaiR1D-autoreceptor function by the auxiliary protein Neto
    Kainate-type glutamate receptors and their dedicated auxiliary protein Neto function at both pre- and postsynaptic sites to regulate the activity of synaptic networks. However, attributing specific synaptic functions to Neto and/or kainate receptors is challenging. Here we focus on Drosophila KaiR1D receptors, which modulate synaptic transmission at neuromuscular junction, and elucidate the role of Neto in the regulation of autoreceptor activities and neurotransmitter release. We show that Neto- limits the presynaptic accumulation and function of KaiR1D autoreceptors in vivo. Using outside-out patch recordings, we demonstrate that Neto- modulates the KaiR1D gating properties, slowing desensitization and attenuating the block by intracellular polyamines and extracellular toxins. Neto- also promotes the axonal distribution of KaiR1D, but this function is not critical for the KaiR1D-dependent regulation of synaptic transmission. Instead, Neto- increases the KaiR1D-mediated charge transfer leading to increased neurotransmitter release. Our data demonstrate that Neto- provides multiple layers of modulation to KaiR1D autoreceptors to ensure proper neurotransmitter release. These findings also suggest that coordinated regulation of receptor function and localization represents an ancestral strategy to safeguard synaptic stability.
    10:45a
    A parietal grid-like code rotates with cognitive maps but lags rapid behavioral transfer
    The neural grid code has been proposed to provide a mechanism for generalization and transfer of relational knowledge between situations enabling rapid adaptation of behavior in novel circumstances. However, to date, very little is known about the dynamics with which grid representations change at context transitions, or how such dynamics relate to downstream behavioral adaptation. Here we tested whether grid representations measured with fMRI rotate to match behavioral goals at context transitions and whether such rotations underlie knowledge transfer. Human participants performed a task that included unsignaled state changes at which the position of multiple target locations abruptly and synchronously rotated by the same degree. After state changes, participants were able to leverage the relative positions of the targets to rapidly infer locations, even novel ones, constituting a form of zero-shot transfer. We observed a cognitive grid-like code in the right posterior parietal cortex with a consistent phase angle that rotated with the relative positions of the targets. However, this rotation was too slow to account for rapid improvements in performance after a state change, and instead these improvements were more closely related to representations of the identity and location of spatial targets in the frontoparietal and orbitofrontal cortex, respectively. Our results highlight the ability of humans to rapidly transfer knowledge and demonstrate that a parietal grid-like code rotates into behaviorally relevant reference frames, but raise questions about the function of such rotations, pointing instead to alternate neural mechanisms for rapid knowledge transfer.
    10:45a
    Cerebral cortical structures linked to intelligence
    Understanding the neural basis of intelligence in humans remains an ongoing scientific pursuit. Early studies with small samples identified potential regions but lacked consistency across findings. Recent large-scale magnetic resonance imaging (MRI) datasets, using intelligence measures focused on verbal-numerical reasoning, now offer more robust opportunities for discovery. In this study (N=11,289), we showed the dorsolateral prefrontal cortex as exhibiting the strongest effect size and a significant causal relationship with intelligence, where larger surface area predicts higher intelligence as revealed by Mendelian randomization analyses. Additional regions, including the orbitofrontal and temporal cortices, also showed causal links to intelligence. These regions are critical for working memory, executive function, and language. Reverse causality analyses further indicated that higher intelligence contributes to increased total surface area and greater cortical thickness in the perisylvian language region. Our findings replicate prior evidence of a bidirectional relationship between total surface area and intelligence and further offer novel insights into regional cortical associations and causal effect. Collectively, these findings support a polyregional cortical configuration of intelligence, highlighting the dorsolateral prefrontal cortex, a key hub for cognitive ability.
    10:45a
    Typical development of the human fetal subplate: regional heterogeneity, growth, and asymmetry assessed by in vivo T2-weighted MRI
    The subplate (SP) is a transient fetal brain compartment supporting neuronal migration, axonal ingrowth, and early cortical activity, yet the dynamics of its regional development remain poorly understood in vivo. Using T2-weighted fetal MRI of 68 typically developing fetuses (22-32 weeks gestational age, GA), we developed a semi-automated pipeline to quantify regional SP morphology (thickness, surface area, and volume). SP characteristics scaled strongly with GA and residual brain volume and showed marked regional differences. After correcting for geometric confounds, regional variation of SP thickness persisted, with highest values in parietal and perisylvian regions, suggesting that SP thickness may serve as a sensitive marker of intrinsic developmental differences. Between late 2nd and early 3rd trimester, mean SP thickness increased by 39.2% with large variation across regions (11.0 SD), whereas surface area growth was more uniform (64.3%, 0.7 SD). Continuous growth trajectories clustered into distinct spatiotemporal profiles: early-developing regions (e.g., pericentral and medial occipital cortices) contrasted with later-developing regions (prefrontal, temporal, and parietal cortices). These patterns partially recapitulate primary-to-association, medial-to-lateral, and posterior-to-anterior maturational hierarchies, pointing to organized developmental program. SP development also showed region-specific hemispheric asymmetries, including leftward thickness and volume asymmetry in superior temporal and precentral gyri. Some asymmetries amplified, others attenuated or reversed with age, suggesting both transient states and potential precursors of postnatal lateralization. Together, these findings provide a framework for regional SP quantification and position SP morphology, particularly thickness, as a promising early biomarker that might link fetal SP changes to subsequent cortical development and neurodevelopmental outcomes.
    10:45a
    Non-overlapping social and food reward representations in the basolateral amygdala
    The ability to consider and appraise positively valenced stimuli in the environment, such as food and social interaction, to guide appropriate action is important for survival of most animals. Several studies have compared how food and social rewards are represented in different regions involved in reward processing and found either overlapping or distinct representations. In the basolateral amygdala (BLA) there seems to be opposing evidence for both shared and unique encoding of social and nonsocial stimuli. In our recent work, we found that the medial prefrontal cortex (mPFC), a region reciprocally connected to the BLA, has distinct social and food representations using a novel self-paced two-choice assay. Given that the BLA and mPFC play differing roles in reward processing, it is important to understand how these two nodes may differ in their encoding reward types within the same assay. To resolve how the BLA encodes social and food information, we recorded the activity of individual BLA neurons in female and male mice during a two-choice social-sucrose operant task. We found that BLA neurons robustly and distinctly respond to social and food reward. In contrast to the mPFC, BLA neurons did not show a bias towards social reward responsiveness and instead showed equal social/sucrose representation, in males, or a sucrose reward bias, in females. BLA neurons were sensitive to internal state - water deprivation increased the proportion of sucrose reward responsive neurons. Additionally, sucrose reward responsive BLA neurons were differentially sensitive to reward omissions, such that neurons that were excited by sucrose reward were more sensitive to reward omissions compared to those inhibited by reward. Together, these findings demonstrate distinct, heterogeneous response profiles within the BLA to social and food rewards, in a manner different from the mPFC.
    10:45a
    Sexual Dimorphism in c-Fos Networks Governing Aggression
    Circuit based studies of aggression often focus on the output of a small group of regions referred to as the core aggression circuit, yet a whole brain map of activity has yet to be produced. Using resident intruder assays in male and female Swiss Webster mice, we combined iDISCO+ cFos imaging with a weighted co-expression network analyses to identify mesoscale co-activation modules in aggressive (AGG) vs. non-aggressive (NON) animals. We performed a module preservation analysis between each phenotype within each sex followed by differential correlation to localize edge-level changes. Behaviorally, AGG mice spent more time attacking, while females showed greater social investigation. Network analyses revealed that NON networks often preserved density of AGG modules, but connectivity reorganized with aggression. In male AGGs there was large spread reorganization of numerous modules: a large sensorimotor subcortical blue module, a pallidal/hypothalamic/brainstem yellow module, and a brainstem-heavy green module. Surprisingly the brown module, enriched for classic social-behavior regions was moderately preserved in male NONs. In females, the turquoise module spanning somatosensory/interoceptive cortex and midbrain regions and the brown sensory cortex/amygdala module were the least preserved. These results indicate that aggression recruits distributed mesoscale communities via edge-specific gain, with males displaying broad strengthening along a cortex/basal ganglia/ hypothalamus/brainstem axis and females showing more targeted potentiation within sensory/arousal modules. This framework nominates candidate hubs and edges for causal manipulation.
    10:45a
    Astrocytes and neurons encode natural stimuli with partially shared but distinct composite receptive fields
    Astrocytes are increasingly recognized as active participants in sensory processing, but whether they show selective responses to stimulus features, analogous to neuronal receptive fields, is not yet established. To address this, we used two-photon calcium imaging in the auditory cortex of anesthetized mice during presentation of natural ultrasonic vocalizations. Our aim was to compare astrocytic responses with those of neighboring neurons and to determine whether astrocytes exhibit feature-selective receptive fields. Event detection showed that astrocytic calcium activity is highly heterogeneous, but only a minority of events were consistently stimulus-linked. To examine this stimulus-driven subset, we estimated receptive field features using maximum noise entropy modeling and compared them with those of concurrently recorded neurons. Despite qualitative similarities in receptive-field features, analysis of modulation spectra and principal angles showed that astrocytic and neuronal receptive fields overlap but occupy distinct regions of feature space. This indicates that astrocytes and neurons encode partially shared, but not identical, dimensions of the sensory stimulus. Our findings indicate that astrocytes encode diverse sensory features, providing an additional contribution to neuronal encoding. This suggests that astrocytic calcium activity is not simply a reflection of neuronal firing, but instead represents a distinct component of cortical sensory processing.
    10:45a
    Investigating the effect of channel pruning on functional near-infrared spectroscopy data collected from children aged 5-24 months
    Significance Infant functional near-infrared spectroscopy (fNIRS) data are particularly vulnerable to noise; participant behaviour can result in motion artefacts and reduced set-up times can cause poor optode coupling. Accurate channel pruning is therefore essential but approaches vary and often use adult-derived thresholds, risking unnecessary data loss. Aim This work systematically compared pruning approaches and parameter choices to evaluate their effects on data quality and retention in infant fNIRS. Approach Data from 5-24 month-old infants were collected across two cohorts, using two paradigms. Channel pruning was performed using the coefficient of variation (CV) and the Quality Testing of Near Infrared Scans (QT-NIRS) tool, varying key thresholds. Multilevel models assessed effects of pruning method, parameter choice, age, motion, and testing site on signal-to-noise ratio (SNR) and channels retained. Results QT-NIRS produced significantly higher SNR than CV pruning across nearly all age, task, and cohort combinations, when matched for data retention. Higher QT-NIRS thresholds improved quality but reduced retention. Motion prevalence strongly reduced both SNR and retention; testing site and age had smaller but notable effects. Conclusions QT-NIRS offers a better balance of data quality and retention than CV pruning. Lower QT-NIRS thresholds than adult defaults are recommended for infant data. These findings provide practical guidance for preprocessing pipelines in developmental fNIRS research.
    10:45a
    CORTICAL AUDITORY PROCESSING FROM CHILDHOOD TO ADULTHOOD: ASSOCIATIONS WITH SPEECH UNDERSTANDING
    The maturation of the auditory system is critical for the development of speech perception from childhood through early adulthood. However, the developmental trajectories and behavioral significance of cortical responses to speech sounds, particularly in relation to frequency specificity, remain poorly understood. Here, we presented low-frequency (/m/) and high-frequency (/s/) speech sounds to 60 typically developing individuals aged 5-24 years and recorded early cortical responses (P1 and N1) using electroencephalography. We also examined associations between these neural responses and speech understanding in quiet and in the presence of speech interferers. The developmental trajectories of P1 and N1 revealed distinct age- and stimulus-dependent patterns, including both linear and non-linear changes across development. These findings delineate frequency-specific maturational profiles within the cortical auditory system and identify potential neurophysiological markers of speech perception, providing a normative benchmark for assessing atypical auditory development.
    10:45a
    Evidence for age-related vulnerability in dopamine-glutamate projections to the lateral entorhinal cortex
    The lateral entorhinal cortex (LEC) is selectively vulnerable to age-related decline and is essential for novelty detection and episodic memory. While dopaminergic (DAergic) input is known to modulate LEC function, how aging impacts this circuitry remains unclear. Here, we used two viral labeling strategies to investigate projections from the ventral tegmental area (VTA) to the LEC. First, we employed an INTRSECT dual-recombinase approach in TH-Flp::VGLUT2-Cre mice to selectively label dopamine-only (DA-only) and dopamine-glutamate co-releasing (DA-GLU) neurons. Next, we used a DAT-Cre-driven ChR2-YFP strategy to broadly label all DA axons. We found that both DA-only and DA-GLU populations innervate the LEC. With age, we observed a selective reduction in tyrosine hydroxylase (TH) signal within DA axons in the LEC, despite preserved axonal structure as revealed by YFP labeling. VGLUT2 signal within DA-GLU terminals appeared less affected. In the VTA, TH+ neuron density declined with age, with distinct spatial patterns along the anterior-posterior axis. These findings reveal an age-related vulnerability of DAergic projections to the LEC and suggest a circuit-level mechanism may contribute to memory impairments in aging.
    10:45a
    Selective innervation of subpopulations of striatal neurons by distinct sets of neurons of the external globus pallidus
    The striatum, the primary input nucleus of the basal ganglia, contains diverse populations of projection neurons and interneurons, each with distinct roles in motor processing. The external globus pallidus contains distinct populations of inhibitory neurons that are highly interconnected with other regions of the basal ganglia. How pallidal neurons innervate different populations of striatal neurons is critical for our understanding of their role in motor processing. Here we use monosynaptic viral tracing in transgenic mice to quantitively define the organization of pallidostriatal connectivity. We show that FoxP2-expressing arkypallidal neurons provide the greatest input to the striatum, primarily targeting indirect pathway spiny projection neurons and cholinergic interneurons. In contrast, prototypic pallidal neurons, defined by Nkx2-1 expression, preferentially innervate parvalbumin- and somatostatin-expressing interneurons. These data reveal a structured and selective organization of pallidostriatal projections, suggesting that distinct classes of pallidal neurons modulate striatal circuits through complementary pathways. Mapping these connections is key to understanding how basal ganglia networks coordinate motor control.
    10:45a
    Measured and modelled transitions between self-paced walking and synchronization with rhythmic auditory cues
    Constraining gait rhythm with a metronome has been shown to influence gait pattern in many different ways. While rhythmic cues can improve several parameters in some clinical populations, they do alter the long-range autocorrelations naturally exhibited in series of stride durations. However, transitions between walking with and without a metronome (and vice versa) have not been measured; it is therefore unclear how people adapt to such a change in task. To address this gap, a total of 21 healthy volunteers were asked to walk overground under three conditions: one unconstrained control condition, followed by two conditions in which a metronome was activated during either the first or second half of the trial to test both transitions. The long-range autocorrelations were assessed over a sliding window on the stride series to measure their evolution. Our observations were reproduced with a computational model allowing us to relate sudden changes in movement parameters to the long-range autocorrelations, which are typically measured over longer timescales. The results showed a clear transition in both conditions involving a metronome, with long-range autocorrelations of the series of stride durations gradually reduced when the metronome was turned on and recovered when it was turned off. In these two conditions, the change in long-range autocorrelations could be reproduced in the model by an instantaneous switching of the control policy associated with the presence or not of the metronome, suggesting that long-range autocorrelations emerge from a flexible control strategy that rapidly regulates timing and amplitude parameters according to task requirements.
    1:34p
    Return of the GEDAI: Unsupervised EEG Denoising based on Leadfield Filtering
    Current electroencephalogram (EEG) denoising methods struggle to remove the complex physiological and environmental artifacts typical of real-world settings, which both hinders the isolation of true neural activity and limits the technology's translational potential. We present the Generalized Eigenvalue De-Artifacting Instrument (GEDAI), a novel algorithm for denoising highly contaminated EEG. GEDAI employs leadfield filtering to selectively remove noise and artifacts that diverge from a theoretically defined EEG forward model. This approach offers unique advantages over existing solutions, including 1) denoising of highly corrupt recordings without clean reference data, 2) single-step correction of artifactual epochs and bad channels, 3) unsupervised detection of brain and noise components based on the signal and noise subspace alignment index (SENSAI). In ground-truth simulations with synthetic and empirical EEG contaminated with realistic artifacts (EOG, EMG, noise), GEDAI globally outperformed leading denoising techniques based on principal component analysis (ASR) and independent component analysis (IClabel, MARA), revealing large effect sizes in challenging scenarios with simultaneous artifact mixtures, low signal-to-noise ratio (-9 dB), and high temporal contamination (up to 100%). Its superior denoising also enhanced neurobehavioral predictions, yielding highest accuracies in ERP classification and brain fingerprinting. GEDAIs autonomy, computational speed and noise-resilience could find future applications in 1) real-world medical, mobile and dry electrode EEG recordings 2) magnetoenecephalography (MEG) denoising (given the shared M/EEG forward model), and 3) real-time brain-computer interfaces (BCIs). The Matlab code for GEDAI is available as an open-source EEGLAB plugin at https://github.com/neurotuning/GEDAI-master
    5:47p
    Alzheimer's disease causes bone marrow myelopoiesis dysfunction
    Accumulating evidence suggests that both innate and adaptive immunity play crucial roles in combating Alzheimer's disease (AD). Specifically, enhancing the homing of monocyte-derived macrophages to the affected brain has been shown to reduce local inflammation, decrease proteinopathy, rescue neurons, and mitigate cognitive decline. However, the factors limiting their spontaneous recruitment remain unclear. Using multi-omics techniques, we identified impaired myelopoiesis and monocyte development in both mice and AD patients. While not the primary cause of the disease, this impairment is associated with disease progression. In the 5xFAD mouse model, monocyte differentiation was found to be disrupted due to a maladaptive bone marrow (BM) response, driven by type I interferon (IFN-I) signaling. A similar phenotype was found in circulating monocytes from AD patients compared to healthy controls. Blocking IFN-I with monoclonal antibodies or using chimeric AD mice with BM from mice lacking the IFN-I receptor (IFNAR1) alleviated myelopoiesis dysfunction, normalized monocyte phenotypes, and reduced cognitive impairment. These improvements in myeloid function were accompanied by an increased homing of monocyte-derived macrophages in the AD brain. Our results reveal an unexpected dysfunction in BM myelopoiesis in the context of neurodegeneration and support the emerging concept that neurodegenerative diseases are not solely brain-centric.
    6:18p
    Human brains construct individualized global rankings from identical few-shot local learning
    Ranking--a typical relational structure--helps people organize complex information and overcome cognitive load, yet in real-world settings it is often inferred from few-shot learning of partial comparisons. How the human brain makes relational inferences under such sparse conditions remains unknown. In a preregistered study combined with Magnetoencephalography (MEG) recordings, we show that even after identical few-shot local pair learning, individuals tend to construct distinct, stable global rankings that diverge from the actual ranking order. MEG recordings reveal that frontoparietal neural representations are reorganized to reflect each person's idiosyncratic ranking, distinct from innate ranking knowledge. These findings challenge the prevailing view that identical inputs yield shared outcomes across subjects and highlight the constructive and generative nature of human relational learning--human brains actively infer and impose structure under sparse data constraints.
    6:18p
    Linear and categorical coding units in the mouse gustatory cortex drive population dynamics and behavior in taste decision-making
    Cortical circuits produce time-varying patterns of population and single neuron activity that play a fundamental role in perceptual and behavioral processes. However, the functional contributions of individual neuron activity to population dynamics and behavior remain unclear. Here we addressed this issue focusing on the mouse gustatory cortex (GC) and using a taste mixture-based decision-making task, high-density electrophysiology, and computational modeling. GC population dynamics represented stimuli linearly during taste sampling and choices categorically before decisions. Single neurons were classified by their linear and categorical activity patterns, revealing subpopulations encoding sensory, perceptual, and decisional variables. To test their functional role, we built a recurrent neural network model of GC. Model perturbations showed linear and categorical neurons were essential for driving normal population dynamics and behavioral performance, whereas many units with other activity patterns could be silenced without consequence. These results have implications that extend beyond GC, and demonstrate the role of linear and categorical coding neurons in cortical dynamics and behavior during perceptual decision-making.
    6:18p
    Cnpy1 is a candidate endoplasmic reticulum chaperone of Vomeronasal type 2 GPCRs.
    Mouse vomeronasal sensory neurons are continuously generated from stem cells and differentiate to express V1R or V2R G-protein coupled receptors (GPCRs), along with their respective Gi2 or Go G-protein subunits. We have previously reported that Go-type neurons exhibit elevated expression of endoplasmic reticulum (ER) chaperones and a distinctive hypertrophic, gyroid ER architecture. Here we identify full-length mouse Cnpy1 with its expression and localization exclusive to the ER of Go neurons. Cnpy1 deletion resulted in mice that were deficient in Go neuronal activation upon exposure to vomeronasal stimuli and a marked reduction in male-male aggressive behavior. In Cnpy1-/- mice, Go neuron develop normally till birth, but undergo selective, progressive apoptosis during postnatal development, despite normal trafficking of V2R GPCRs to dendritic tips. Immunoprecipitation and mass spectrometry revealed that Cnpy1 associates with V2R GPCRs and other ER chaperones. Together, these findings identify Cnpy1 as a component of an ER chaperone complex essential for Go neuron signaling and survival.
    7:32p
    The hallmark of colour in EEG signal
    Our perception of the world is inherently colourful, and colour provides well-documented benefits for vision: it helps us see things quicker and remember them better. We hypothesised that colour is not only central to perception but also a rich and decodable source of information in electroencephalography (EEG) signal recorded non-invasively from the scalp. Previous work has shown that brain activity carries colour information for uniform patches, but it remains unclear whether this extends to natural, complex images where colour is not explicitly cued. To investigate this, we analysed the THINGS EEG dataset, comprising 64-channel recordings from participants viewing 1,800 distinct objects (16,740 images) for 100 ms each, totalling over 82,000 trials. We established a perceptual colour ground truth through a psychophysical experiment in which participants viewed each image for 100 ms and selected perceived colours from a 13-option palette. An artificial neural network trained to predict these scene-level colour distributions directly from EEG signals showed that colour information was robustly decodable (average F-score of 0.5). We next modelled the interaction between colour and object perception in neuroimaging decoding. Images were segmented using the Segment Anything Model (SAM), each object was assigned a representative colour, and features were extracted from these colour-augmented images using CLIP vision encoders. We trained an EEG encoder, CUBE (ColoUr and oBjEct decoding), to align features in both object and colour spaces. Across EEG and MEG datasets in a 200-class recognition task, incorporating colour improved decoding accuracy by about 5%. Together, these findings demonstrate that EEG signal recorded during natural vision carries substantial colour information that interacts with object perception. Modelling this mutual interaction enhances neural decoding performance.
    7:32p
    Hippocampal Fos-expressing neurons stably encode boundaries in novel environments
    The hippocampus recruits place cell ensembles to represent novel environments, but how gene expression relates to this reorganization and its stabilization remains unclear. We imaged calcium transients and Fos-expression changes across ~30,000 CA1 neurons and found that neurons with higher Fos increases were more likely to be place cells in novel environments, rapidly cluster around environmental boundaries, and maintain stable boundary encoding across days, suggesting a role of Fos expression in place cell organization and stabilization
    8:47p
    Apathy as a Loss of Prior Precision on Action Outcomes
    Apathy is common in neurological disease, associated with poor prognosis and limited treatments. Current models posit that goal-directed actions are reduced because costs or effort outweigh the expected reward. We highlight an alternative account of apathy, based on the reduction in precision of prior beliefs about action outcomes. In this preregistered study, we test the hypothesis that precision is encoded in the GABAergic gain of prefrontal superficial pyramidal neurons. Fifty healthy adults undertook a goal-directed task during magnetoencephalography. Estimates of synaptic efficacy or gain were obtained by dynamic causal modelling of induced responses. There was strong evidence of a negative correlation between prior precision and apathy (Bayes Factor=12, p<0.01), and that prior precision was associated with gain in prefrontal and premotor neuronal populations (Posterior probability>0.99). The importance of prior precision and GABAergic gain for goal-directed actions opens new avenues to advance the understanding and treatment of apathy.
    9:20p
    Reduced SK channel control of mesolimbic dopamine neuron firing drives reward seeking adaptations in chronic pain
    Patients with chronic neuropathic pain typically experience affective symptoms that drive reduced quality of life and negatively impact pain management. Mesolimbic dopamine is necessary for reward valuation and learning, and the existence of a hypodopaminergic state has been proposed to underlie these affective symptoms of chronic pain. However, direct functional evidence for this hypodopaminergic state is lacking, and the mechanisms underlying its emergence over the acute to chronic pain transition are unknown. Here, we find a selective deficit in the ability of mesolimbic dopamine neurons to sustain burst firing, which is apparent uniquely at chronic timepoints following neuropathic injury. As a result, animals are unable to sustain effortful pursuit of rewards under conditions of high effort or time costs. Convergent biophysical modeling and experimental electrophysiology establish that in a spared nerve injury (SNI) model of chronic neuropathic pain, calcium-activated, small-conductance potassium (SK) channel function is impaired, resulting in lower peak firing and earlier entry into depolarization block of mesolimbic dopamine neurons. Critically, dopamine dependent reward learning, formation of cue-reward associations and locomotor activity remain intact, arguing against the interpretation of a generalized hypodopaminergic state. These results elucidate a circuit-level basis for selective motivational deficits emerging in chronic neuropathic pain.
    9:20p
    Smartphone behavior is suppressed during bursts of wake slow wave
    Real-world behavior unfolds as a continuous flow of actions over time. One possibility is that this continuous flow is enabled by a seamless stream of cortical activity. However, emerging evidence suggests that even during ongoing behaviors, cortical neural populations undergo brief periods of silence. This 'off-state' can be detected as wake slow waves in EEG, similar to the slow waves characterizing deep sleep. Here, we leveraged the spontaneously occurring fluctuations in smartphone touchscreen interactions in combination with EEG to investigate the dynamics of slow waves during behavior. We report that wake slow waves occur more frequently during a session of smartphone behavior than during a session of prolonged rest ($sim$1 h). We find that slow waves can occur in bursts - characterized by short consecutive intervals - interleaved with longer periods of absent slow waves. During smartphone use, the probability of bursts increased compared to rest, and the duration of burst-absent periods decreased. During the bursts, however, the likelihood of generating smartphone interactions was substantially diminished. Conversely, the periods of absent slow waves were more permissive to the behavioral output. We speculate that the dynamics of neural silencing are configured according to the overall behavioral state. This configuration, in turn, allows behavioral outputs to leverage the windows of opportunity that emerge between slow wave bursts. Our study, combining smartphone behavior with EEG, reveals how brief cortical silencing events punctuate the seemingly continuous flow of everyday actions.
    9:20p
    hpGRISZ: a high-performance fluorescent biosensor for in vivo imaging of synaptic zinc dynamics
    Despite the crucial role of synaptic Zn2+ in neurotransmission and neural processing, direct in vivo measurement of Zn2+ transients has remained challenging due to the limited responsiveness of existing fluorescent indicators. Here we report hpGRISZ (high-performance green indicator for synaptic Zn2+), an ultraresponsive turn-on green fluorescent biosensor engineered through iterative linker optimization, mutagenesis, and directed evolution. hpGRISZ exhibits exceptional brightness, thermostability, and a large fluorescence response (F/F0 {approx} 25) with micromolar affinity suitable for detecting extracellular synaptic Zn2+ release. We comprehensively characterized hpGRISZ in vitro, in mammalian cells, and in vivo. A membrane-anchored version of hpGRISZ traffics robustly to the cell surface under physiological conditions, where it retains strong responsiveness and supports wide-field, two-photon, and fiber photometry recordings in awake mice. These assays revealed synaptic Zn2+ dynamics across distinct brain regions and neuronal circuits. Together, our findings establish hpGRISZ as a powerful tool for dissecting zinc signaling in neural circuits and as a prototype for next-generation genetically encoded biosensors for in vivo imaging.
    9:20p
    VTA GABA Cell Bipotential Induction of iLTP or iLTD Synaptic Plasticity is Input Selective, where iLTD is Uniquely Eliminated by Cocaine.
    The ventral tegmental area (VTA) is a key reward circuit hub, implicated in drug seeking and addictive behaviors. The VTA contains dopaminergic and GABAergic neurons that both play roles in reward prediction, aversion, motivated reward behavior, etc. Synaptic plasticity, including VTA excitatory and inhibitory long-term potentiation (LTP/iLTP) and long-term depression (LTD/iLTD), are fundamentally involved in processing reward learning and memory, which is maladaptively altered by abused drugs mediating dependence induction. This report extends our prior research of the understudied VTA GABA cells and the rationale for their bipotential plasticity (iLTP or iLTD) capacity by optogenetic circuit level examination of their unique GABAergic inputs. In addition, we examine potential cocaine impact on both plasticity forms. Optogenetic activation of either lateral hypothalamus or rostromedial tegmental nucleus induced iLTP in VTA GABA cells, while optogenetic activation of local VTA GABAergic inputs induced iLTD. This suggests expression of bipotential plasticity is input specific, and highlights implications for each type of plasticity on reward signaling. Drug of abuse cocaine eliminated iLTD while sparing iLTP, suggesting selective impairment of local GABA signaling to VTA GABA cells by cocaine versus projection GABA signaling. This emphasizes potential differential VTA GABA cell plasticity in reward processing and the need to further examine cocaine impact on inhibitory signaling in addition to known impact on the dopaminergic system. By elucidating the circuit-dependence of plasticity type in VTA GABA cells and drug-induced impact, our research could potentially identify additional targets for therapeutic intervention of drug dependence via the GABAergic system.
    10:32p
    Temperature and pH-dependent Potassium Currents of Muscles of the Stomatogastric Nervous System of the Crab, Cancer borealis
    Marine crustaceans, such as the crab Cancer borealis, experience large fluctuations in temperature and pH, yet their stomatogastric neuromuscular system must remain functional to support feeding. We examined 16 of the ~40 pairs of stomach muscles and found that warming consistently hyperpolarized muscle fibers (~10 mV per 10 {degrees}C) and reduced excitatory junctional potentials and currents. Voltage-clamp analysis in the gastric muscle 5b (gm5b) revealed a temperature-activated conductance with a reversal potential near the potassium reversal potential, consistent with a potassium current, and insensitive to tetraethylammonium. Quantitative RT-PCR identified expression of two putative two-pore domain potassium (K2P) channels in these muscles. Muscle responses were also strongly influenced by extracellular pH. We observed an optimal operating window between pH 6.7-8.8; outside this range, responses diminished and abnormal activity, including spontaneous firing, appeared. Voltage-clamp recordings confirmed pH modulation of the same potassium conductance. Together, these results demonstrate that muscle excitability in Cancer borealis is shaped by temperature- and pH-sensitive currents, presumably carried by K2P channels. Functionally, these channels provide a plausible mechanism for stabilizing neuromuscular output despite environmental perturbations. As temperature increases, the pyloric and gastric rhythms accelerate, increasing synaptic drive to muscles. Activation of K2P channels counterbalances this input by reducing excitability, thereby preventing over-contraction and extending its dynamic range. This work highlights a muscle-intrinsic contribution to the well-known robustness of the stomatogastric system and identifies K2P channels as key players in adapting motor performance to changing environments.
    11:46p
    The role of disulfide bonds in the GluN1 subunit in the early trafficking and functional properties of GluN1/GluN2 and GluN1/GluN3 NMDA receptors
    N-methyl-D-aspartate receptors (NMDARs) are ionotropic glutamate receptors essential for excitatory neurotransmission. Previous studies proposed the existence of four disulfide bonds in the GluN1 subunit; however, their role in NMDAR trafficking remains unclear. Our study first confirmed the existence of four disulfide bonds in the GluN1 subunit using biochemistry in human embryonic kidney 293T (HEK293T) cells. Disrupting the individual disulfide bonds by serine replacements produced the following surface expression trend for GluN1/GluN2A, GluN1/GluN2B, and GluN1/GluN3A receptors: wild-type (WT) > GluN1-C744S-C798S > GluN1-C79S-C308S > GluN1-C420S-C454S > GluN1-C436S-C455S subunits. Electrophysiology revealed altered functional properties of NMDARs with disrupted disulfide bonds, specifically an increased probability of opening (Po) at the GluN1-C744S-C798S/GluN2 receptors. Synchronized release from the endoplasmic reticulum confirmed that disruption of disulfide bonds impaired early trafficking of NMDARs in HEK293T cells and primary hippocampal neurons prepared from Wistar rats of both sexes (embryonic day 18). The pathogenic GluN1-C744Y variant, associated with neurodevelopmental disorder and seizures, caused reduced surface expression and increased Po at GluN1/GluN2 receptors, consistent with findings for the GluN1-C744S-C798S subunit. The FDA-approved memantine inhibited GluN1-C744Y/GluN2 receptors more potently and with distinct kinetics compared to WT GluN1/GluN2 receptors. We also observed enhanced NMDA-induced excitotoxicity in hippocampal neurons expressing the GluN1-C744Y subunit, which memantine reduced more effectively compared to the WT GluN1 subunit. Lastly, we demonstrated that the presence of the hGluN1-1a-C744Y subunit counteracted the effect of the hGluN3A subunit on decreasing dendritic spine maturation, consistent with the reduced surface delivery of the NMDARs carrying this variant.
    11:46p
    Robust Decoding of Speech Acoustics from EEG: Going Beyond the Amplitude Envelope
    During speech perception, properties of the acoustic stimulus can be reconstructed from the listener's brain using methods such as electroencephalography (EEG). Most studies employ the amplitude envelope as a target for decoding; however, speech acoustics can be characterised on multiple dimensions, including as spectral descriptors. The current study assesses how robustly an extended acoustic feature set can be decoded from EEG under varying levels of intelligibility and acoustic clarity. Analysis was conducted using EEG from 38 young adults who heard intelligible and non-intelligible speech that was either unprocessed or spectrally degraded using vocoding. We extracted a set of acoustic features which, alongside the envelope, characterised instantaneous properties of the speech spectrum (e.g., spectral slope) or spectral change over time (e.g., spectral flux). We establish the robustness of feature decoding by employing multiple model architectures and, in the case of linear decoders, by standardising decoding accuracy (Pearson's r) using randomly permuted surrogate data. Linear models yielded the highest r relative to non-linear models. However, the separate decoder architectures produced a similar pattern of results across features and experimental conditions. After converting r values to Z-scores scaled by random data, we observed substantive differences in the noise floor between features. Decoding accuracy significantly varies by spectral degradation and speech intelligibility for some features, but such differences are reduced in the most robustly decoded features. This suggests acoustic feature reconstruction is primarily driven by generalised auditory processing. Our results demonstrate that linear decoders perform comparably to non-linear decoders in capturing the EEG response to speech acoustic properties beyond the amplitude envelope, with the reconstructive accuracy of some features also associated with understanding and spectral clarity. This sheds light on how sound properties are differentially represented by the brain and shows potential for clinical applications moving forward.
    11:46p
    A Na+-selective High-salt Taste Receptor Mediates State-Dependent Sodium Aversion
    Animals balance sodium intake by seeking low concentrations to meet physiological needs while avoiding toxic excess. However, how internal state selectively regulates high-sodium aversion remains unknown. Here, we identify the first Na+-selective high-salt taste receptor and demonstrate its essential role in internal-state-dependent sodium avoidance. In Drosophila, the ionotropic receptor IR11a, together with co-receptor IR25a, functions in bitter gustatory receptor neurons (GRNs) to mediate aversion to high Na+. Loss of IR11a abolishes neuronal and behavioral responses to Na+ and Li+, while sparing detection of K+, Ca2+, and bitter compounds. Heterologous expression confirms that IR11a and IR25a form a Na+-selective channel. Notably, sodium deprivation or satiety specifically modulates Na+ sensitivity in IR11a+ GRNs--without altering responses to K+ or bitter stimuli--and this modulation requires the IR11a/IR25a complex. These findings reveal a dedicated, state-dependent Na+-sensing pathway embedded within aversive taste cells, providing a peripheral mechanism for adaptive sodium consumption based on physiological need.
    11:46p
    Rapid phonetic learning of Mandarin tones in adults: Daily behavioral improvement and brain activity changes
    Although adults learn foreign languages more slowly than children, behavioral improvements can still emerge rapidly with training. Previous phonetic learning studies have mostly focused on pre- and post-training comparisons, leaving daily learning trajectories largely unexplored. Here, in Finnish speakers naive to tone languages, we tracked day-to-day changes in Mandarin tone perception during a short training program (1 h/day for 4 days), complemented by pre- and post-training behavioral and event-related potential (ERP) measures. Each learning session comprised exposure to Mandarin tones in continuous and isolated speech with cues, change detection and identification with feedback, and a listen-and-repeat exercise. To assess the role of co-presence, participants learned either in pairs (n = 22) or individually (n = 20). We found that discrimination and categorization speed, as well as discrimination accuracy, improved from pre- to posttest, with performance also increasing across daily training sessions. Paired learners showed higher sensitivity (d') to tone changes on the first day than individual learners, consistent with co-presence-driven attentional facilitation. At the neural level, P3a amplitude to tone changes during passive listening increased after training, reflecting enhanced automatic orienting to novel sounds at whole group level. These findings demonstrate that short-term training induces rapid behavioral gains and selective neural plasticity in adult phonetic learning, with early co-presence effects and transfer to novel speech sounds.
    11:46p
    TI-Toolbox: An Open-Source Software for Temporal Interference Stimulation Research
    Background: Temporal interference stimulation is a novel non-invasive brain stimulation approach that promises selective targeting of deep brain structures while minimizing off-target cortical stimulation. Despite a growing interest in TI applications, there is a need for integrated computational tools that seamlessly connect neuroimaging data preprocessing through montage optimization, field simulation, and analysis within a unified framework designed for translational and clinical research. Methods: We developed TI-Toolbox, an open-source software platform that integrates established neuroimaging tools (dcm2niix, SimNIBS, FreeSurfer) with specialized algorithms for temporal interference research. The platform provides end-to-end workflows encompassing structural MRI preprocessing, volume conduction modeling, montage optimization, electric field simulation, and region-of-interest analysis. Both graphical user interface and command-line interface implementations ensure accessibility across user expertise levels. The platform employs containerized deployment via Docker to ensure reproducibility and cross-platform compatibility. Results: TI-Toolbox successfully automates the complete TI research pipeline, from DICOM conversion through final field analysis. The platform demonstrates robust performance across operating systems and provides standardized workflows that enhance reproducibility. Furthermore, our case studies support the validity of our HD-EEG mapping approach for montage standardization and the need for individualized modeling for exposure assessment. Conclusions: TI-Toolbox addresses critical infrastructure gaps in temporal interference research by providing researchers with a unified, validated platform that reduces technical barriers and accelerates translational research in non-invasive deep brain stimulation.
    11:46p
    Transcriptomic and network analyses of an alcohol-induced peripheral neuropathy model identify putative role for histone demethylase Jmjd1c
    Background Alcohol-induced peripheral neuropathy (AIPN) is a painful and prevalent condition associated with chronic alcohol use, yet its molecular underpinnings remain poorly understood. Because the analgesic effects of ethanol may reinforce alcohol consumption, elucidating the mechanisms driving AIPN is essential. This study aimed to identify ethanol-regulated gene expression patterns in the nervous system of a mouse model of AIPN. Methods Male (n = 10) and female (n = 12) C57BL/6J mice were administered either an ethanol-containing Lieber-DeCarli liquid diet at 5% or an isocaloric control diet for four weeks. Ethanol consumption was recorded daily for the experimental group. After the drinking protocol, spinal cord and dorsal root ganglia tissues were collected for RNA sequencing. Results Ethanol-regulated genes were identified for each sex-tissue group using DESeq2, and results were compared to known rodent neuropathic pain gene signatures. Weighted gene co-expression network analysis (WGCNA) identified modules of co-expressed genes associated with ethanol administration. Hub genes with high intramodular connectivity were identified for ethanol-correlated modules. Of the 14 identified hub genes, 10 have been previously implicated in pain or neuropathy, including Jmjd1c, Phf8, and Gas6, which emerged as particularly strong candidates for involvement in AIPN pathophysiology. Conclusions These findings provide novel insights into the gene networks underlying AIPN and nominate specific genes for future functional studies.
    11:46p
    Repetitive Trans-spinal magnetic stimulation Promotes Repair in Inflammatory Spinal Cord Injury Through Sex-Dependent Immune Modulation
    Spinal cord injuries (SCI), whether traumatic or inflammatory such as transverse myelitis (TM), are characterized by severe neuroinflammation, demyelination, and long-term disabilities. Current treatments remain limited, highlighting the need for novel non invasive therapeutic approaches. Repetitive magnetic stimulation (RMS) has emerged as a promising strategy, but its mechanisms and efficacy in inflammatory contexts remain poorly described. Here, we investigated the effects of RMS applied as trans spinal RMS (rTSMS) in a mouse model of focal spinal cord demyelination induced by lysophosphatidylcholine (LPC). When applied one day after LPC injection, rTSMS reduced inflammation, demyelination, and fibroglial scar formation, while promoting early locomotor recovery in both sexes. In contrast, when treatment was initiated three days after LPC injection, corresponding to the peak of motor deficits, rTSMS conferred tissue protection and functional benefits only in female mice. RNA sequencing analyses revealed sex dependent immune modulation: in females, rTSMS primarily regulated adaptive T cell related pathways, whereas in males, it mainly targeted innate immune responses such as neutrophil activity and phagocytosis. Complementary in vitro experiments using microglial and macrophage cultures further demonstrated that RMS modulates transcriptomic responses differently depending on cell type and inflammatory state. Specifically, RMS attenuated IL1 induced pro-inflammatory signaling in macrophages and completely abolished these effects in microglia. Altogether, our findings establish rTSMS as a non invasive therapy capable of reducing neuroinflammation and demyelination in inflammatory SCI, with pronounced sex dependent effects. By uncovering distinct immune pathways engaged in male and female mice, this study provides mechanistic insights into rTSMS action and opens perspectives for its translational use in neuroinflammatory diseases.
    11:46p
    Compositional Recombination Relies on a Distributed Cortico-Cerebellar Network
    Human cognition depends on the ability to flexibly recombine existing knowledge in new ways. Although this capacity for compositionality has traditionally been attributed to cortical networks, its broader neural basis remains unclear. Here, we combined dimensionality reduction of task-based fMRI with recurrent neural network modelling to dissociate two processes underlying compositional cognition: the recruitment of specialised components; and the more general process of recombination. Across 87 participants performing a well-established compositional task, component processes were supported by domain-selective cortical and anterior cerebellar regions, whereas recombination engaged a distributed cortico-cerebellar network that was low-dimensional, highly integrated, and generalised across contexts. Similar functional signatures were also observed in recurrent neural networks trained to perform multiple cognitive tasks, suggesting that low-dimensional recombination is a general solution for flexible compositional cognition. Our findings revise existing models of compositional cognition by highlighting cortico-cerebellar interactions as a mechanism for flexible, integrative task generalisation.
    11:46p
    Direct encoding of new visual concepts in early visual cortex
    Neocortical memories are assumed to rely on slow systems consolidation through hippocampal offline reactivation. However, recent studies show rapid neocortical integration of new memories for information associated with prior knowledge. Testing the limits of rapid neocortical learning, we tracked memory formation across 24h with functional and diffusion-weighted MRI in subjects acquiring either conceptual or detailed knowledge of novel objects from identical visual stimulation. Concept learning-induced rapid, 24h-stable changes in strength and pattern of functional early visual cortex responses. These were co-localized with microstructural changes, correlated positively with categorization performance and negatively with context recognition. Detailed item-context learning elicited analogous changes in posterior parietal areas. Results show that the neocortex can rapidly learn without prior knowledge and that concept learning can occur in early sensory regions that process corresponding visual features. Thus, we substantiate the possibility of direct or parallel neocortical encoding without offline abstraction from individual episodes.
    11:46p
    Single-nucleus transcriptional and chromatin accessibility profiling of mouse hypothalamic LepRb neurons reveals cell type-specific cis-regulatory elements linked to human obesity
    Leptin receptor-expressing hypothalamic neurons (LepRHypo) are key regulators of energy balance, yet a comprehensive, cell type-resolved, chromatin accessibility map of these neurons is lacking. We profiled ~20,000 LepRHypo nuclei using single-nucleus multiome (snRNA-seq/snATAC-seq), identifying 39 transcriptionally and epigenetically distinct clusters, including AgRP (two subtypes), Pomc (two subtypes), Foxb1, Irx5/3 (three subtypes), Nts, PNOC (two subtypes), Kiss1/Pdyn (KNDy, two subtypes), Ghrh, Tcf7l2, and Sf1/Nr5a1 (three subtypes) populations. We also identified three Glp1r-expressing clusters with the highest Lepr enrichment, each marked by distinct molecular signatures. Cluster-specific open chromatin regions (OCRs) delineated putative cis-regulatory elements unique to each LepRHypo subtype. Mouse cell-type specific OCRs conserved in the human genome were identified; a subset were proximal to genes with high Human Genetic Evidence (HuGE) scores for obesity-related traits, overlapped obesity-associated GWAS loci, and/or coincided with eQTLs, including variants with the potential to influence human energy balance. Together, these data provide cell type-specific cis-regulatory atlas of LepRHypo neuronal subtypes, including Glp1r/Lepr-enriched populations, and highlight evolutionarily conserved, subtype-specific regulatory elements, associated candidate genes, and putative functional variants that may modulate LepRHypo subtype function and influence energy homeostasis and obesity susceptibility in humans.
    11:46p
    Impact of serotonin transporter deficiency on parvalbumin- and neuropeptide Y-producing interneurons of the basolateral amygdala
    Hyperactivity of the basolateral amygdaloid nuclear complex (BLA) is a hallmark of anxiety-related disorders in humans. Excitation of BLA projection neurons (PN) is fine-tuned by inhibitory interneurons (INs). Monoaminergic afferents to the BLA modulate PN and IN activity. In the present study, BLA-INs immunoreactive(ir) for parvalbumin (PV) or neuropeptide Y (NPY) and their interrelations with serotonergic and catecholaminergic afferents were analyzed in wildtype (WT) and serotonin transporter knockout (5-HTT KO) mice, a model for anxiety- and stress-related disorders. In WT mice, PV- and NPY-ir INs fall into morphological subgroups which possess perisomatic appositions by serotonergic and tyrosine hydroxylase-ir afferents. Dual immunolabeling shows no colocalization of PV and NPY. NPY/somatostatin(SOM) dual labeling documents colocalization of the peptides in some neurons, and single labeling for NPY or SOM in others. These features appear largely preserved in 5-HTT KO mice. However, quantification of PV- and NPY-ir neurons documents a reduction in number and density of NPY-ir neurons throughout the rostrocaudal extent of the amygdala in 5-HTT KO mice. PV-ir neurons remain unchanged. Quantitative PCR shows increased expression of Npy receptor 2, Som receptor 4, and corticotropin releasing factor receptor 1 in the BLA of 5-HTT KO mice. mRNA for the three peptides is unchanged, indicating that it may be NPY propeptide translation which is reduced in 5-HTT KO mice. Taken together, the results document an effect of life-long serotonin imbalance on the BLA NPY-system, which may contribute to previously observed morphological alterations in BLA PNs and increased anxiety-like behavior in 5-HTT KO mice.
    11:46p
    Neuromodulation of zebrafish primary motoneuron firing is shaped by developmental changes in the M-current
    Movements during development are refined through the ongoing maturation of the spinal circuits that mediate them. In many vertebrates, including zebrafish, this maturation process involves neuromodulators such as acetylcholine, serotonin, and dopamine; however, the targets of this neuromodulation remain largely unknown. Recent work has revealed distinct developmental dynamics of the non-inactivating subthreshold potassium current, the M-current, in primary motoneurons of larval zebrafish. Considering that neuromodulators play a role in the maturation of locomotor control in larval zebrafish, we asked whether neuromodulators might target the M-current in primary motoneurons during development. Our patch-clamp experiments in primary motoneurons of zebrafish aged 3 to 5 days post-fertilization (dpf) reveal distinct modulation of the M-current by serotonin and acetylcholine that is age-dependent. Our data demonstrates an inhibitory influence of serotonin signaling via 5HT1A receptors that promotes repetitive firing in primary motoneurons specifically at 3 dpf. We also show that acetylcholine, likely via M2/M4 receptors, enhances the M-current and limits repetitive firing in primary motoneurons but does so only after 3 dpf. Modulation of the M-current in primary motoneurons was not observed across all neuromodulators as dopamine had no effect at any age. Considering that the M-current transiently peaks at 3 dpf and is reduced at 4 and 5 dpf, our findings suggest that the developmental changes in this current can shape how neuromodulators modulate firing properties of primary motoneurons.
    11:46p
    Deveolopment of patient-derived neuroprogenitor cells (hNPCs), neurons, and astrocytes to explore the etiology of Guam Parkinsonism-dementia complex (PDC)
    Parkinsonism-Dementia Complex (PDC) is one phenotype of a disappearing neurodegenerative disease (Guam ALS-PDC) that shows clinical and neuropathological relationships with amyotrophic lateral sclerosis (ALS), atypical parkinsonism and Alzheimer disease. ALS-PDC has been linked with exposure to environmental factors (notably cycad plant neurotoxins), but evidence from human and animal studies is inconclusive. Patient-derived induced pluripotent stem cells (iPSCs) provide a powerful in vitro system to explore the underlying cause of PDC. iPSC lines were derived from lymphocytes of a PDC-affected Guamanian Chamorro female patient and an age- and gender-matched healthy Chamorro resident of PDC-unaffected Saipan using non-integrating episomal plasmids. iPSCs derived from both patients expressed pluripotency markers (Oct4, SSEA-4, TRA-1-60, Sox2) prior to the generation of neuroprogenitor cells (hNPCs), neurons and astrocytes. An embryoid body protocol was used to derive hNPCs from both iPSC lines while a differentiation media was used to generate neurons from hNPCs. hNPCs derived from both iPSC lines displayed established neuroprogenitor markers (nestin, Sox2), while the differentiated hNPCs exhibited both neuronal (beta-tubulin III, Map2, doublecortin) and synaptic (synaptophysin, PSD-95) markers. Expression of these protein markers in hNPCs and neurons by dot blotting was also observed for both lines. Astrocyte progenitor cells and mature astrocytes with appropriate markers were also developed from the hNPCs of both lines using commercial kits. Development of these patient-derived iPSCs provides a human model for evaluating the role of environmental (e.g., cycad toxins) and genetic factors in ALS-PDC and possibly other related neurodegenerative diseases.

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