bioRxiv Subject Collection: Neuroscience's Journal

Enkephalinergic Neurons Gate Sex-Specific Control of Voluntary Micturition
Barrington's nucleus (Bar) is a brainstem hub essential for lower urinary tract (LUT) function, yet the molecular identity and functional specialization of its neuronal subtypes remain poorly defined. Here, we construct a single-nucleus transcriptional atlas of Bar and identify an excitatory Penk-expressing population of (BarPenk) critical for LUT regulation. BarPenk neurons are active selectively during voiding, when the external urethral sphincter (EUS) relaxes, and their optogenetic activation elicits time-locked suppression of EUS activity. Chemogenetic activation of these neurons induces a sex-specific, aberrant pattern of micturition behavior, while targeted ablation impairs voluntary marking behavior in response to female cues. We observe multiple regions involved in visceromotor regulation and behavioral state control projecting to BarPenk neurons, supporting their role as integrators of internal state and environmental context to drive urinary output. These findings provide new insights into the brainstem circuits that shape reflexive and voluntary micturition, and highlight how discrete neuronal subtypes contribute to sexually dimorphic regulation of LUT function.

A hierarchy of time constants and reliable signal propagation in the marmoset cortex
A hierarchy of timescales in the cortex is functionally desirable for rapid information processing in sensory areas and slow time integration in association areas. Here, through an analysis of electrocorticography (ECoG) data, we identified a timescale hierarchy in the cortex of marmoset, a primate species commonly used in neuroscience. Constrained by the anatomical and electrophysiological data, we developed a multi-regional model of the marmoset cortex that captures the observed timescale hierarchy phenomenon. Furthermore, we used the model to investigate how the cortex reconciles information integration on distinct timescales in local areas with reliable signal propagation globally across regions. We found that a near-criticality state is optimal for both localized signal integration within areas and reliable signal propagation across areas in the multi-regional cortex. Our model also mechanically explains recent experimental observations that the structural and functional connectivities are less correlated in association areas than in sensory areas.

Cell type distribution of intrathecal antisense oligonucleotide activity in deep brain regions of non-human primates
Intrathecally administered RNase H1-active gapmer antisense oligonucleotides (ASOs) are promising therapeutics for brain diseases where lowering the expression of one target gene is expected to be therapeutically beneficial. Such ASOs are active, to varying degrees, across most or all cell types in the cortex and cerebellum of mouse and non-human primate (NHP), brain regions with substantial drug accumulation. Intrathecally delivered ASOs, however, exhibit a gradient of exposure across the brain, with more limited drug accumulation and weaker target engagement in deep brain regions of NHP. Here, we profiled the activity of a tool ASO against Malat1 in three deep brain regions of NHP: thalamus, caudate, and putamen. All neuronal subtypes exhibited knockdown similar to, or deeper than, the bulk tissue. Among non-neuronal cells, knockdown was deepest in microglia and weakest in endothelial stalk. Overall, we observed broad target engagement across all cell types detected, supporting the relevance of intrathecal ASOs to diseases with deep brain involvement.

Spatial distance and temporal attentional focus modulate voluntary action preparation and awareness
Peripersonal space (PPS)-the immediate space surrounding the body-modulates perception and motor control. However, its impact on how voluntary actions are initiated and subjectively experienced remains underexplored. Similarly, how directing attention to different phases of an action, such as intention formation versus execution, and anticipating outcomes of an action, modulates the neural readiness for movement, has yet to be fully examined. This study investigates whether spatial proximity, attentional focus, and anticipated action outcomes influence action preparation and action awareness, using a virtual reality adaptation of the Libet clock paradigm during EEG recordings. Neural results reveal that attentional focus and anticipated action outcomes modulate different phases of motor preparation, as indexed by the readiness potential (RP)-a gradual buildup of neural activity preceding voluntary movement. Focusing on decision timing (without subsequent action outcomes) enhances early RP amplitude and decreases the late RP slope, suggesting increased preparatory neural engagement during intention formation. In contrast, focusing on action execution leads to a steeper late RP slope, indicating later and faster motor activity buildup when attention is directed toward movement onset. Anticipating action outcomes increased late RP slope, which was accompanied by the temporal binding effect: when a tone followed the action, both decision and action estimates shifted toward it. Spatial proximity influences RP dynamics specifically in tasks when participants focused on their intention to act in the absence of an outcome. Behavioural results show that actions are perceived as occurring earlier when the clock is displayed near compared to far, indicating that PPS influences the temporal perception of action timing. Overall, these findings highlight the dynamic interplay among external spatial context and internal cognitive processes in shaping motor preparation and action awareness. Importantly, a temporal internal attentional focus on intention to act modulates early RP-traditionally considered an unconscious stage of neural readiness. These results contribute to a deeper understanding of how PPS and the locus of attention on specific action phases affect action preparation and awareness, with potential implications for future research on the sense of agency and voluntary action decision making.

Rapid FFR: A rapid method for obtaining Frequency Following Responses
Objectives: Frequency-Following Responses (FFRs) are typically recorded using stimuli of 40-250 ms in duration separated by silent intervals. Because robust FFRs require averaging across approximately 3000 stimulus repetitions, conventional acquisition is time-intensive. We introduce the Rapid FFR, a technique that minimises recording time by presenting the stimulus continuously (i.e., without interstimulus intervals) and by averaging across individual response cycles. This study aimed to: (a) compare Rapid and Conventional FFR performance under time matched conditions; (b) assess test-retest reliability of both methods, and (c) examine potential neural adaptation during extended Rapid FFR recordings. Design: All participants (37 in total) were young adults with clinically normal hearing. In Experiment 1, FFRs were elicited from 16 listeners using a 128 Hz sawtooth wave presented in two ways: (1) continuously over approximately 1 minute in each polarity for the Rapid FFR and (2) as discrete tone bursts (1500 trials per polarity) for the standard FFR. Signal-to-Noise ratios (SNRs), response amplitudes, and test-retest reliability were compared across techniques. In Experiment 2, the Rapid FFR was recorded continuously from 21 listeners for nearly nine minutes to assess potential adaptation over time. Results: The Rapid FFR produced significantly higher SNRs than the standard FFR, reflecting improved recording efficiency. Both techniques captured inter-individual differences reliably, with comparable frequency-domain response patterns across participants. In particular, measures derived from the Rapid FFR showed strong agreement with those from the standard FFR for lower harmonics (F0-H3). Higher harmonics (H4-H7) exhibited greater variability but remained consistent between techniques. In the prolonged recording condition, FFR amplitudes remained stable over time, with no significant decline across the nine-minute recording. This indicates that continuous stimulation did not result in measurable neural adaptation or response fatigue. Conclusions: The Rapid FFR offers a time-efficient alternative to standard protocols, preserving signal fidelity and reliability while enabling shorter acquisition times. These findings suggest that the Rapid FFR is well-suited for use in populations where long recordings are challenging (e.g., in infants and the clinic) and can facilitate more extensive experimental designs within a single session. The method holds promise for advancing both research and clinical applications of the FFR. Future studies should explore its use across a broader range of sounds (in particular, dynamically varying ones) and listener groups.

CCR2 antagonism identifies blood-borne monocytes as a target for prevention of cognitive deficits after seizures
Seizure-associated cognitive co-morbidities can substantially reduce the quality of life in people with epilepsy. Neuroinflammation is an invariant feature of all chronic neurologic diseases, including epilepsy, and acute brain insults, including status epilepticus (SE). The generalized seizures of SE trigger a robust inflammatory response involving astrocytosis, erosion of the blood-brain barrier (BBB), activation of brain-resident microglia, and recruitment of blood-borne CCR2+ monocytes into the brain. We have shown that blocking monocyte recruitment into the brain via global Ccr2 knockout or systemic CCR2 antagonism with a small molecule alleviates multiple deleterious SE-induced pathologies, including BBB damage, microgliosis, neuronal damage, and monocyte brain invasion in the days following pilocarpine-induced SE. This study aimed to determine if fleeting CCR2 antagonism improves SE-associated cognitive impairments in the long term. Here, we show that the brief antagonism of CCR2 eliminates the profound deficit in working memory in the Y-maze and retention memory in the novel object recognition test but does not attenuate anxiety-like behavior in the open field arena. Microgliosis and astrocytosis were observed in brain sections from SE mice after the behavioral tests, and CA1 hippocampal astrocytosis mildly correlated with performance in the Y-maze. Notably, SE mice exposed to the vehicle showed robust neuronal loss in the cortex and CA1 region of the hippocampus, and mice treated with the CCR2 antagonist showed less neurodegeneration in both the cortex and hippocampus. Our results indicate that monocyte brain infiltration after SE opens a window for preventing cognitive co-morbidities and neurodegeneration with an orally available CCR2 antagonist.

Endotoxemia-induced inflammation in the absence of obesity decreases anxiety-like and impulsive behavior without affecting learning and memory
Obesity is associated with increased gut permeability, which contributes to a state of chronic low-grade inflammation. Obesity is also linked with altered neurocognitive functions, including impaired learning and memory. Whether these changes are secondary to neuroinflammation vs. other comorbidities associated with obesity is unknown. Here, we modeled the chronic low-grade inflammation that accompanies diet-induced obesity, but in the absence of obesity or consumption of an obesogenic diet. Male rats were implanted with intraperitoneal osmotic minipumps, continuously dispensing either saline (control) or lipopolysaccharide (LPS), an endotoxin produced in the gut that triggers inflammation when in circulation. Immunohistochemistry results revealed that LPS exposure led to neuroinflammation, with an increased number of Ionized Calcium-Binding Molecule 1 (Iba1+) cells in the amygdala and hippocampus in LPS rats vs. controls. Given that these brain regions are associated with impulse control, anxiety-like behavior, and learning and memory, we tested whether chronic LPS treatment impacted these behaviors. Interestingly, LPS exposure did not affect hippocampal-dependent memory in the Morris water maze, novel location recognition, or novel object in context memory tests, suggesting that neuroinflammation in the absence of obesity does not induce memory impairments. Further, chronic LPS significantly decreased anxiety-like behavior in the open field test and food impulsivity in an operant-based procedure. LPS animals also had significantly lower corticosterone and melatonin levels when compared to controls, which may contribute to these behavioral outcomes. These results suggest that the low-grade inflammation associated with obesity is not driving obesity-associated memory impairments but does reduce anxiety and food-motivated impulsive responses.

The semantics of dreams
Dreams are universal yet deeply personal experiences. While memory and personal concerns influence dream content, the impact of other individual, generalizable traits remains poorly understood. To address this gap, we built a multimodal dataset including dream and wakefulness reports, alongside demographic, psychometric, cognitive, and sleep-related measures in a large adult cohort. Natural language processing characterized the semantic features that quantitatively distinguish dream from wakefulness reports, with this distinction significantly modulated by individual-specific factors. Longitudinal and cross-sample analyses further demonstrated that major external events, such as the COVID-19 pandemic, affect dream content, leaving lasting traces. Overall, the findings highlight a dynamic interplay between stable individual traits and external events in shaping dream experiences, offering novel insights into the cognitive and emotional architecture of dreaming.

NaviGraph
Recent advances in neuroscience have enabled simultaneous collection of multimodal datasets, including behavioral tracking, physiological signals, and neuronal recordings. Yet most analysis tools process these streams independently, often requiring manual alignment and custom code. This fragmentation limits reproducibility and interpretability at the experiment level, particularly in models where cognitive impairments are subtle, and reflects a broader tendency to analyze behavior as isolated events rather than as a structured process. Topological methods, though successful in other domains, remain underused in behavioral neuroscience, leaving the architecture of decision-making largely unexplored. To address these, we developed NaviGraph (Navigation on the Graph), a flexible, open-source pipeline designed to integrate diverse data types into a unified graph-based framework suited for spatial decision-making studies. By modeling decision points as graph nodes and populating them with behavioral, neuronal, and physiological parameters, NaviGraph offers a holistic, multi-layered perspective on cognition, enabling computation of spatial and topological metrics. This approach shifts the focus from isolated modalities to comprehensive interpretation, making behavioral patterns more accessible and easier to validate across datastreams. We applied NaviGraph to a trial-based spatial memory task in a complex maze and uncovered nuanced sex- and genotype-specific differences. In a knock-in model of Apolipoprotein {epsilon}E (apoE4), the most prevalent genetic risk factor for Alzheimer's disease, females exhibited deficits detectable only through topological metrics, including inefficient navigation and increased visits to decision points, aligning with the heightened cognitive vulnerability observed in female apoE4 human carriers. Wildtype females, in contrast, displayed more direct recall navigation compared to males. To demonstrate NaviGraph's multimodal capabilities, we mapped neuronal activity from head-mounted miniaturized microscope calcium imaging in the retrosplenial cortex, an area extensively involved in path integration, alongside head orientation dynamics and behavioral trajectories onto the graph structure. This unified framework enabled visualization of decision-point-specific neuronal activity patterns, subpopulation dynamics linked to path familiarity, and physiological- behavioral alignment. With its modular architecture, NaviGraph supports diverse maze configurations and data types, providing a holistic, interpretable, and high-resolution tool for spatial navigation and cognitive research.

Increased vulnerability to noise exposure of low spontaneous rate type 1C spiral ganglion neuron synapses with inner hair cells (Pre-Print)
The inner hair cells (IHCs) in the inner ear form synapses with auditory nerve fibers (ANFs) that send sound signals to the brain. ANFs have been grouped by their level of spontaneous firing rates (SRs) into high-, medium-, and low-SR ANFs. Based on their molecular profiles evaluated by RNAseq experiments, ANFs have been divided into three groups (1A, 1B, and 1C) that likely correspond to high-, medium-, and low-SR ANFs, respectively. In guinea pigs, the synapses between IHCs and low-SR ANFs have been shown to be more vulnerable to noise exposure compared to other ANF subtypes, but not in a study performed in CBA/CaJ mice, questioning if these results can be generalized. Here, an LYPD1 reporter mouse model on a C57Bl/6J background with specifically labeled group 1C, low-SR ANFs was used to examine whether LYPD1 positive ANF synapses are more vulnerable to noise exposure. Six-week-old mice were exposed to an 8-16 kHz octave band noise presented at 100 dBA for 2 hours. One week later, cochlear tissue was harvested to quantify ANF synapses and compare the percentage of LYPD1 positive ANF synapses in noise-exposed and unexposed animals. Auditory brainstem response measurements were performed to assess hearing function after noise exposure. The number of all ANF synapses and the percentage of LYPD1-positive ANF synapses were reduced following noise exposure, concurrent with increased ABR thresholds and decreased ABR wave 1 amplitudes. The reduction in the percentage of LYPD1-positive ANF synapses specifically indicates greater vulnerability of LYPD1 positive ANF synapses to noise exposure compared to other ANFs in C57Bl/6J mice.

Glutamatergic Dysfunction of Astrocytes in Paraventricular Nucleus of Thalamus Contributes to Adult Anxiety Susceptibility in Adolescent Ethanol Exposed Mice
Repeated ethanol exposure during adolescence increases the risk for displaying anxiogenic phenotype in adulthood, but the underlying mechanisms are not fully understood. The paraventricular nucleus of thalamus (PVT) has been considered a hub brain area for controlling the anxiety network in the brain. Recent structural and functional investigations indicate that the PVT exhibits diverse neural signals aligned with early-life events, which are highly linked with anxiety-like behaviors. However, it remains unknown if repeated ethanol exposure during adolescence will affect the coordinated brain activities of the PVT in adulthood, and consequent behavioral adaptation. Here we show that adolescent repeated intermittent ethanol exposure (AIE) triggers anxiety-like behaviors and parallelly induces the glutamatergic adaptation in the PVT after four weeks withdrawal from the last ethanol exposure. The firing rates, along with the spatiotemporal calcium transients in the PVT neurons during behavior were increased in the AIE mice compared to those in the counterpart control mice. Importantly, with the chemogenetic inhibition of the PVT neurons, we found alleviated the anxiety-like behavior in the AIE mice. The increased neuronal activities in the PVT of AIE mice was, at least partly, via the reduction of GLT1 (an astrocyte dominant glutamate transporter, known as EAAT2, slc1a2). Our non-invasive magnetic resonance spectroscopy (MRS) measures also showed an increase in glutamate/GABA ratio in the thalamic area including the PVT of the GLT1 conditional knock-down mice, which exhibited the heightened anxiety-like behavior. In addition, while the selective knock-out of GLT1 in the astrocytes of PVT in the alcohol naive mice induces anxiogenic phenotypes, the selective upregulation of GLT1 in the PVT astrocytes of the mice that were treated with AIE paradigm alleviated the anxiety-like behaviors as well. These findings highlight the significant role of PVT astrocytic GLT1 in the anxiogenic phenotype in adulthood induced by withdrawal from adolescent repeated ethanol exposure, suggesting that GLT1 in the PVT could serve as a therapeutic target for alcohol use disorder and comorbid emotional disorders.

Analgesic actions of Intrathecal NaV 1.7 antisense in rats: loss of antagonist channel binding, message depletion, and neuraxial distribution of oligonucleotide
BackgroundGenome targeting strategies to address NaV 1.7 mediated signaling in nociceptive afferents produce highly selective and persistent analgesic outcomes. Here, we analyze the concentration-dependent effects of the reduction of primary afferent NaV 1.7 channel expression by intrathecal delivery of an antisense oligonucleotide on pain behaviors and the covariance of Scn9a knock-down on NaV 1.7 message expression and channel binding.

MethodsMale Sprague-Dawley rats were implanted with lumbar intrathecal catheters and dosed with different NaV 1.7 ASO concentrations (100 to 3000 g;10 L). Pain behavior assays were conducted 0-28 days after ASO injections. Brain, spinal cords (SC) and dorsal root ganglia (DRGs) were collected. Quantification of ASO knock-down was assessed through RT-qPCR. NaV 1.7 expression was assessed by binding of NaV 1.7 fluorescent labeled antagonist (ATTO488PTx-II). Distribution studies were performed using anti-ASO antibody staining in brain, SCs and DRGs.

ResultsNaV 1.7 message was detected in nerve, DRG and SC. Intrathecal ASO induced a concentration dependent gradient of knock down in DRGs (lumbar to cervical) of Scn9a mRNA and ATTO488PTx-II binding in small DRG neurons, and in spinal parenchyma, and a suppression of pain behaviors initiated by mechanical compression, inflammation and following intraplantar NaV1.7 agonist (OD1) or formalin. At 1000 {micro}g, there was a 47% reduction in phase 2 flinching, a 60% reduction in DRG mRNA and a 36% reduction in ATTO488PTx-II DRG binding in comparison with mismatch controls. Although marked changes were seen at the sensory ganglia level and spinal dorsal horn, no changes in NaV 1.7 binding or mRNA were detected in sciatic nerves. Reduction in DRG message displayed a rostrocaudal gradient that corresponded with ASO distribution.

ConclusionsThe study presents how NaV 1.7 ASOs reduce primary afferent channel binding through an effective knock-down on Scn9a mRNA, and channel binding leading to a covariate reduction in pain behavior.

Introductory notes before zebra finch song have unique timing properties while sharing acoustic properties with song
Preparatory neural activity precedes the initiation of simple movements and a key feature of this preparatory activity is its trial-by-trial correlation with features of the upcoming movement. Recent studies in the zebra finch, a songbird with a complex, naturally learned, movement sequence (song), have suggested that the repeats of short introductory notes (INs) at the start of each song bout, reflect motor preparation. However, whether IN properties correlate with upcoming song features remains poorly understood. Here, we addressed this question by recording and analyzing male zebra finch songs over a 3 year period. We found bout-to-bout correlations in the acoustic features of the last IN and the first song syllable. However, similar correlations were present between the first song syllable and the first IN and the first and second song syllable suggesting that INs are also part of the song sequence. Next, we found an age-related increase in the mean IN number before song and song tempo. If INs reflected preparation of song parameters, we expected age-related song changes to be predicted by IN-song correlations at a younger age. We did not find any such correlations. Finally, we compared INs to other repeated syllables within song and outside song bouts and found that the speeding up of intervals between successive INs is unique to INs. Overall our results showing similarities in the acoustic features of INs and song syllables suggest shared neural control of INs and song syllables, while differences in timing suggest different neural mechanisms controlling IN timing.

The NOX2-ROS-NLRP3 inflammasome axis in traumatic brain injury
BackgroundPhagocyte NADPH oxidase 2 (NOX2) is an enzyme complex responsible for reactive oxygen species (ROS) production. Chronic NOX2 activity sustains oxidative stress/damage and drives neuroinflammation following traumatic brain injury (TBI). NOX2 acts as a priming signal for NLRP3 inflammasome activation, which also plays a role in secondary injury after TBI. GSK2795039 is a small molecule brain penetrable drug that inhibits NOX2 in a NADPH competitive manner. Here, we investigated whether pharmacological inhibition of NOX2 using GSK2795039 can reduce secondary neuroinflammation after TBI, specifically via inhibition of downstream NLRP3 inflammasome activation, in both resident microglia and infiltrating myeloid cells in the injured brain.

MethodsImmortalised microglial (IMG) cells or primary microglia were pre-treated with GSK2795039 (NOX2 inhibitor) or MCC950 (NLRP3 inhibitor) and stimulated with lipopolysaccharide and nigericin to induce NOX2/ROS and NLRP3 inflammasome activation. The controlled cortical impact model, pharmacokinetic analyses, multi-dimensional flow cytometry, histology and neurobehavioral assessments were used to translate in vitro findings to an experimental TBI model in adult male C57BL6/J mice.

ResultsThe small molecule NOX2 inhibitor, GSK2795039, attenuated microglial NOX2 activity, thereby reducing ROS, nitrite and cytokine levels, as well as NLRP3 inflammasome components in pro-inflammatory microglia. TBI recruited NOX2/ROS/IL-1{beta}+ neutrophils and inflammatory monocytes into injured brain parenchyma with peak monocytic NOX2/ROS/IL-1{beta} production at 3 days post-injury (DPI), coincident with peak NOX2/ROS/IL-1{beta} expression in microglia. Systemic administration of GSK2795039 (100mg/kg; I.P.) starting 2 hours post-injury attenuated NOX2/IL-1{beta}+ microglial and infiltrating myeloid cell activation at 3 DPI. In addition, NOX2 inhibition reduced numbers of IL-1R+ T cells in the brain of TBI mice, indicating that myeloid-T cell crosstalk was altered by GSK2795039 treatment. Innate and adaptive neuroimmune changes were associated with improvements in motor function post-TBI. In the chronic phase through 28 DPI, pharmacological inhibition of NOX2 by GSK2795039 treatment resulted in modest improvements in neurobehavioral deficits and TBI neuropathology.

ConclusionsThese preclinical studies identify the NOX2-ROS-NLRP3 inflammasome axis along with myeloid-T cell crosstalk as effective targets for TBI neuroinflammation. Our translational studies indicate that NOX2 may be a promising therapeutic target for mitigating neuroinflammation in microglia, and peripheral immune cells, following experimental TBI in mice.

Dissociable Pupil and Oculomotor Markers of Attention Allocation and Distractor Suppression during listening
Emerging evidence suggests that ocular dynamics, pupil dilation, eye movements, and blinks, can serve as markers of task engagement. In this study, we examined whether these measures dissociate different perceptual states during an auditory attention task. Participants (Main and Control experiments; N = 34 and 27, both sexes) listened to tone sequences designated as Target, Distractor, and Probe, designed to isolate active attention from suppression of irrelevant input.

We focused on four physiological signals: pupil diameter (PD), pupil dilation rate (PDR), blink rate, and microsaccades (MS). Compared to a control condition, both Target and Probe intervals elicited sustained PD increases, blink suppression, and prolonged MS inhibition indicating extended attentional engagement. Interestingly, the Distractor interval also showed prolonged blink suppression and elevated PDR, suggesting active arousal to suppress irrelevant input. However, MS dynamics during Distractors were indistinguishable from control, implying that attention was not allocated to the distractors despite the heightened arousal. This dissociation supports the interpretation that MS is specifically modulated by attentional allocation, while PD and blinks also reflect general arousal or suppressive mechanisms.

Overall, these findings reveal that PD, MS, and blinking capture distinct aspects of cognitive control. Together, they offer a multidimensional framework for studying selective attention and distractor suppression in complex tasks.

Significance statementUnderstanding an individuals moment-to-moment state during demanding attention tasks is crucial for identifying perceptual challenges, explaining inter-individual variability, and diagnosing difficulties in special populations. Ocular measures, such as pupil size, blinks, and microsaccades, are gaining traction as objective, non-invasive indicators of perceptual and cognitive states. In this study, we demonstrate that, during a challenging auditory task requiring selective attention and active ignoring, different eye-related signals capture distinct aspects of listener state. Specifically, the dynamics observed during active attention differ systematically from those during active distractor suppression. These findings highlight the value of ocular metrics for assessment of cognitive performance and for disentangling the contributions of arousal and attention during complex tasks.

Error-driven changes in hippocampal representations accompany flexible re-learning
Flexible behavior requires both the learning of new associations, and the suppression of previous ones, but how neural circuits achieve this balance remains unclear. Here we show that continuous changes in hippocampal representations, known as drift, may facilitate this process. We used voluntary head-fixation and calcium imaging to record from CA1 in rats during an odor-guided navigation task that required frequent re-learning. We found systematic representational changes over the course of the multi-hour sessions that were increased following errors. A simple neural network model revealed that such error-driven drift can enable flexible re-learning by allowing new associations to form from new neural patterns. A consequence of this is that previous associations are maintained in latent synaptic weights. These findings reconcile the apparent tension between representational drift and stable memory storage, demonstrating how dynamic neural codes could support both flexible behavior and lasting memories.

Reorganization of spinal neural connectivity following recovery after thoracic spinal cord injury: insights from computational modelling
Rats exhibit significant recovery of locomotor function following incomplete spinal cord injuries, albeit with altered gait expression and reduced speed and stepping frequency. These changes likely result from and give insight into the reorganization within spared and injured spinal circuitry. Previously, we developed computational models of the mouse spinal locomotor circuitry controlling speed-dependent gait expression (Danner et al. 2017; Zhang et al. 2022). Here, we adapted these models to the rat and used the adapted model to explore potential circuit-level changes underlying altered gait expression observed after recovery from two different thoracic spinal cord injuries (lateral hemisection and contusion) that have roughly comparable levels of locomotor recovery (Danner et al., 2023). The model reproduced experimentally observed gait expression before injury and after recovery from lateral hemisection and contusion, and suggests two distinct, injury-specific mechanisms of recovery. First, recovery after lateral hemisection required substantial functional restoration of damaged descending drive and long propriospinal connections, suggesting compensatory plasticity through formation of detour pathways. Second, recovery after a moderate midline contusion predominantly relied on reorganization of spared sublesional networks and altered control of supralesional cervical circuits, compensating for weakened propriospinal and descending pathways. These observations suggest that symmetrical (contusion) and asymmetrical (lateral hemisection) injuries induce distinct types of plasticity in different regions of the spinal cord, indicating that effective therapeutic strategies may benefit from targeting specific circuits according to injury symmetry.

Development of noninvasive imaging to measure spontaneous pain in mice
Objectively measuring pain in laboratory animals is essential for pain research and analgesic development. Despite the development of various behavioral tests to measure evoked pain in animal models, measuring spontaneous pain remains challenging. To address this unmet need, we developed a novel imaging approach to detect spontaneous nociception in animal pain models. To do this, we generated a Bacterial Artificial Chromosomes transgenic mouse that expresses Redquorin under the murine synapsin 1 promoter. Redquorin is a fusion protein consisting of chimera and a 2x tandem dimer Tomato Aequorin (tdTA), which emits long wavelength bioluminescence from activated neurons in the presence of coelenterazine. This luminescence can penetrate tissues and form a projected image on the body surface that can be detected with a spectrum In Vivo Imaging System, thus creating a Nociceptive Neuronal Activity Imaging mouse. We used the tdTA mice to image bioluminescence in the spinal regions as a surrogate of spontaneous pain induced by capsaicin, the HIV-1 envelope glycoprotein gp120, and spinal nerve ligation. Results show that Redquorin-emitted bioluminescence is a sensitive optical surrogate to measure spontaneous pain. This approach offers a new method to measure spontaneous pain in animal models for basic and translational research.

Purkinje Cell spike patterns do not correlate with nuclei cell spike patterns in mouse models for cerebellar disease
Cerebellar dysfunction causes various movement disorders, including ataxia, dystonia, and tremor. Previous work demonstrated that spike patterns in cerebellar nuclei neurons were distinct between different movement disorder mouse models. However, often these changes arise from neural dysfunction in the cerebellar cortex, through misfiring, miswiring, or degenerating Purkinje cells. Even though Purkinje cells form the sole output from the cerebellar cortex, their information is relayed to other regions of the motor network via cerebellar nuclei cells. Purkinje cells make GABAergic synapses onto cerebellar nuclei cells, and it is often assumed that changes in Purkinje cell spike patterns result in inverse changes in nuclei cell spike patterns. Here, we test this hypothesis by answering the question of whether a reliable relationship between Purkinje cell and nuclei cell spike patterns exists. Single-cell, in vivo electrophysiology recordings of both cell types from six mouse models for cerebellar movement disorders were analyzed according to parameters relating to spike rate and irregularity. We investigated whether Purkinje cell spike patterns correlated with nuclei cell spike patterns. We found that some parameters for firing irregularity were positively correlated between Purkinje and nuclei cells but no - and particularly no inverse - relationship was observed between Purkinje and nuclei cell spike rate. Overall, this study begins to illuminate that the relationship between Purkinje cells and nuclei cell spike activity in a disease state is more complex and unpredictable. The data suggest Purkinje cell spike activity changes cannot accurately predict nuclei cell changes, which ultimately drive cerebellar disease states. Our findings underscore the importance of studying cerebellar nuclei cell function in cerebellar disease, as lack of changes in Purkinje cell firing patterns can mask disease-causing firing patterns in these cerebellar output cells.

Accelerating Neuron Reconstruction with PATHFINDER
Comprehensive mapping of neural connections is essential for understanding brain function. Existing automated methods for connectome reconstruction from high-resolution images of brain tissue introduce errors that require extensive and time-consuming manual correction, a critical bottleneck in the field. To address this, we developed PATHFINDER, an AI system that segments volumetric image data, identifies potential ways to assemble neuron fragments, and evaluates the plausibility of resulting shapes to reconstruct complete neurons. Using a dataset of all axons in an IBEAM-mSEM volume of mouse cortex, we show that PATHFINDER reduces the error rate in axon reconstruction by an order of magnitude over previous state of the art, leading to an improvement in proofreading throughput of up to 84x relative to prior estimates in the context of a whole mouse brain. By drastically reducing the manual e"ort required for analysis, this advance unlocks the potential for both large-scale connectome mapping and routine investigation of smaller volumes.

Anti-amyloid antibody equilibrium binding to Aβ aggregates from human Alzheimer disease brain
ImportanceAnti-amyloid immunotherapy is used to treat Alzheimer disease (AD) with moderate benefits and potentially serious side effects due to amyloid related imaging abnormality with effusions/edema (ARIA-E). Different anti-amyloid antibodies have different in vitro binding characteristics to different synthetic A{beta} aggregates, leading to the assumption that they bind different species in the human brain. Lecanemab is hypothesized to bind "protofibrils," but these are not well-characterized in human brain. It is also unknown how binding differences correlate with ARIA-E rates. The APOE {varepsilon}4 allele increases ARIA-E risk, but how it affects antibody binding characteristics is unknown.

ObjectivesTo determine whether anti-amyloid antibodies bind different species of human brain A{beta} and whether these binding properties to human brain A{beta} explains ARIA-E rates.

DesignCross-sectional study of 18 postmortem human brains.

SettingSingle tertiary care hospital.

ParticipantsDeceased patients with AD and cerebral amyloid angiopathy (CAA).

Main Outcomes and MeasuresEquilibrium binding constants (KD) and total A{beta} binding (Bmax) of recombinant aducanumab, lecanemab, and donanemab equivalents to human brain soluble and insoluble amyloid plaque-enriched and CAA-enriched A{beta} aggregates.

ResultsLecanemab did not bind with greater affinity to the soluble fraction of A{beta} compared to aducanumab. All three antibodies were bound essentially identical quantities of A{beta} across the 18 cases and fractions (Pearsons r 0.84 - 0.97). Antibody preference for plaque vs CAA A{beta} did not differ in soluble fractions but differed slightly in insoluble extracts. The APOE {varepsilon}4 allele led to a more soluble antibody-accessible A{beta} pool in a dose-dependent manner for all three antibodies.

Conclusions and RelevanceThe lecanemab binding target in human brain is unlikely to be distinctly "protofibrillar" compared to other antibodies. Differences in antibody preference for plaque vs CAA A{beta} are unlikely to fully explain differences in ARIA-E rates. The APOE {varepsilon}4 allele may plausibly increase ARIA-E risk by making antibody-accessible A{beta} more soluble. These results have implications for improving the safety and efficacy of current and future anti-amyloid antibody therapies.

Intercellular communication in the brain via dendritic nanotubular network
Recent studies have identified intercellular networks for material exchange by bridge-like nanotubular structures, yet their existence in neurons remains unexplored within the brain. Here, we identified long, thin dendritic filopodia that establish direct dendrite-to-dendrite contacts, forming dendritic nanotubes (DNTs) in mammalian brains. Using super-resolution microscopy, we characterized their unique molecular composition and dynamics in dissociated neurons, enabling Ca2+ propagation over distances. Utilizing imaging and machine-learning-based analysis, we confirmed the in situ presence of DNTs connecting dendrites to other dendrites whose anatomical features are distinguished from synaptic dendritic spines. DNTs mediate the active transport of small molecules or human amyloid-beta (A{beta}), implicating the role of DNT network in AD pathology. Notably, DNT levels increased prior to the onset of amyloid plaque deposits in the mPFC of APP/PS1 mice. Computational simulations predicted the progression of amyloidosis, providing insight into the mechanisms underlying neurodegeneration through these DNTs. This study unveils a previously unrecognized nanotubular network, highlighting another dimension of neuronal connectivity beyond synapses.

Brain Multi-Omic Subtypes of Neuroticism Reveal Molecular Signatures linked to Alzheimer's Disease
ImportanceMolecular mechanisms linking neuroticism with Alzheimers disease traits are unknown.

ObjectiveTo identify molecular subtypes of neuroticism and examine their association with ADRD traits.

DesignThree ongoing cohort studies were used; Religious Orders Study (ROS), Rush Memory and Aging Project (MAP) and Minority Aging Research Study (MARS), that began enrollment in 1994, 1997, and 2004, respectively.

SettingOlder priests, nuns, and brothers from across the U.S. (ROS), older adults (MAP) and older African-American adults (MARS) from across the greater Chicago metropolitan area.

Participants1,028 decedents with multi-omic data from the dorsolateral prefrontal cortex (DLPFC), the anterior cingulate cortex (AC), and the posterior cingulate gyrus (PCG).

Exposure(s)Eight layers of omics (DNA methylation and histone acetylation from DLPFC; RNA seq from AC, DLPFC, and PCG, single-nucleus RNA, TMT proteomics and metabolomics from DLPFC) and Neuroticism using the 12-item version from the NEO Five-Factor Inventory.

Main outcome(s) and measure(s)Person-specific multi-omic molecular pseudotime representing molecular progression from low to high phenotypic expression of neuroticism, and three multi-omic brain molecular subtypes of neuroticism which represent distinct omic pathways from no/low neuroticism to high neuroticism that differ by their omic constituents.

Participants are exclusively assigned to the subtype which aligns mostly with their multi-omic profile.

ResultsThe top drivers of subtype differentiation were transcriptomic alterations across three brain regions (DLPFC, AC, PCG) which extensively and differentially characterized the subtypes. The subtypes were also differentially associated with AD pathology, temporal lobe atrophy, and AD dementia, with subtype N1 showing the strongest associations.

Conclusions and RelevanceNeuroticism may be driven by three distinct molecular subtypes, with subtype N1 driving ADRD-related associations, N2 showing some ADRD associations, and N3 being completely independent of these outcomes. Our data provide novel insights into the biology of individual differences in predispositions of neuroticism and its associations with ADRD traits.

Key pointsO_ST_ABSQuestionC_ST_ABSWhat are the brain multi-omics molecular signatures linking neuroticism with Alzheimers diseases and related dementias (AD/ADRDs)?

FindingsWe identified three distinct brain multi-omic molecular subtypes reflecting different molecular pathways underlying neuroticism. Top omic features of the subtypes were extensively and differentially characterized by transcriptomic alterations across three brain regions - dorsolateral prefrontal cortex, anterior cingulate cortex, and posterior cingulate gyrus. Subtype N1 was strongly associated with AD pathology, AD dementia, and temporal lobe atrophy.

MeaningThe association we typically observe between phenotypic neuroticism and ADRD clinical traits might be largely driven by a molecular pathway underlying this trait.

The Human Insula Encodes Somatotopic Representation of Motor Execution with an Effector-Specific Connectomic Map to Primary Motor Cortex
Understanding motor representation in the human brain requires mapping beyond the primary motor cortex, into the distributed networks that coordinate complex movements. The insular cortex, a multifunctional hub buried within the Sylvian fissure, has been implicated in motor control through clinical observations and neuroimaging. Yet its precise relation to movement processing remains one of the least understood aspects of motor neurophysiology. To address this gap, we quantified electrophysiological changes from implanted depth electrodes in patients performing simple movement tasks combined with single-pulse electrical stimulation (SPES) to map functional connectivity. The movement data reveal distinct somatotopic representation bilaterally, as well as inter-effector regions that are active for different movement types. Hand representation is centered along the ventral aspect of the middle and posterior short gyri bilaterally, while tongue/mouth tuned sites cluster in the dorsal posterior short gyrus and the dorsal long gyri. Insular activity temporally follows the primary motor cortex (M1) and precedes movement onset. SPES revealed somatotopically-specific connectivity between corresponding sites in M1 and insula (hand-to-hand, tongue-to-tongue) and between bilateral insulae. These observations establish that somatotopy is a conserved property of distributed motor control incorporating the insula, with direct implications for basic and clinical neuroscience.

Chimpanzee and human ApoE isoforms differ in the stimulation of neurite differentiation consistent with structural predictions with relevance to brain development and aging
BackgroundAmong anthropoids, humans uniquely possess ApoE isoforms that modulate Alzheimers disease (AD) risk and brain aging. While chimpanzee and human ApoE4 share R112 and R158, chimps do not exhibit advanced AD. A key difference is T61 in chimps versus R61 in humans, structurally resembling ApoE3.

ObjectiveWe examined how astrocyte-derived ApoE isoforms impact neuronal morphology and used structural modeling to explore functional divergence.

MethodsNeonatal rat hippocampal neurons were cultured with astrocyte-conditioned media (ACM) from mice expressing human ApoE3, ApoE4, or chimpanzee ApoE. Neuronal outgrowth was quantified after 72 hours.

ResultsChimpanzee ACM increased neurite number by 30% over human ApoE isoforms. However, chimpanzee ACM resembled ApoE4 functionally, producing 40% shorter neurites and spines. Structural modeling supported greater similarity to ApoE4.

ConclusionsChimpanzee ApoE is structurally and functionally more similar to ApoE4 than ApoE3, revealing evolutionary distinctions relevant to AD risk and neurodevelopment.

Two senses, one rhythm: Pre- and post-stimulus neural states predict perceived audio-visual synchrony
How does the brain integrate or segregate multiple sensory inputs? In our study, we used magnetoencephalography to comprehensively investigate local and network dynamics before and after the presentation of sequences of beeps and flashes that are sometimes perceived as synchronous or asynchronous. Frequency-tagging and spectral analysis revealed that under identical physical conditions, subjective perceptual fusion of multisensory signals elicits stronger evoked sensory responses in both visual and auditory cortices. Crucially, perceptual fusion is preceded by locally reduced pre-stimulus alpha activity, as well as enhanced functional connectivity between auditory and visual cortices within the pre-stimulus gamma activity. We also show that pre-stimulus neuronal states in the occipital cortex predict post-stimulus sensory responses to auditory sequences in the temporal cortex, but not the opposite. The current findings provide evidence that the perceptual fusion of multisensory events relate to a complex interplay between local and inter-sensory neuronal states before and after stimulus presentation.

Significance StatementHow does the brain blend information from multiple sensory systems into one holistic perception? We developed a novel frequency-tagging paradigm in Magnetoencephalography (MEG) to robustly estimate the sensory responses to a series of flashes and beeps in early sensory areas, and to demonstrate how these responses are shaped by ongoing fluctuations in local, and long-range network activity. By combining the steady-state method with spectral, and functional connectivity analysis of ongoing oscillations in source space, the current study provides novel insights into the relationship between internal brain states and the way we perceive multisensory events.

Disturbed engram network caused by NPTXs downregulation underlies aging-related memory deficits
Engram cells storing specific memories are allocated to separate neuronal ensembles, which preferentially recruit either excitatory or inhibitory inputs to drive precise memory expression. However, how these formed neuronal ensembles maintain their stability, and whether the disturbed stability contributes to aging-related memory deficits remain elusive. Here, we show that neuronal pentraxin1 (NPTX1) facilitates Kv7.2-mediated inhibition of Fos+ensemble hyperexcitability, thereby restricting its response to excitatory inputs from medial entorhinal cortex (MEC) and promoting memory expression in the fear context. Meanwhile, NPTX2 facilitates the perisomatic inhibition of the Npas4+ ensemble by parvalbumin+ (PV+) interneurons, thus preventing fear memory overgeneralization. Pharmacological activation of Kv7.2 or chemogenetic activation of PV+ interneurons repaired memory deficits caused by engram specific NPTXs depletion. Contextual fear memory precision and NPTXs expression in dentate gyrus (DG) engram cells are decreased in aged mice. Overexpression of NPTX1 in Fos+ensemble or AMPAR binding domain of NPTX2 in Npas4+ ensemble rescued memory imprecision. These findings elucidate that the coordination of NPTXs prevents engram ensembles from becoming hyperactive and provide a causal link between engram network destabilization and aging-associated memory deficits.

Seizure Circuit Activity in the Theilers Murine Encephalomyelitis Virus Model of Infection-induced Epilepsy Using Transient Recombination in Active Populations.
Epilepsy affects one in twenty-six individuals. A major cause of epilepsy worldwide is viral encephalitis. Central nervous system infections can provoke seizures in the short term and increase the risk of spontaneous, recurrent seizures post-infection. However, the neural mechanisms underlying seizures during acute infection are unknown. These neuronal changes can be studied in C57BL6/J mice infected with Theilers murine encephalomyelitis virus (TMEV). TMEV-infected mice experience seizures 3-8 days post-injection (DPI), clear the virus by DPI 14, and may develop chronic, acquired temporal lobe epilepsy. TMEV may incite seizures during the acute infection period through inflammation, reactive gliosis, and cell death in hippocampal area CA1. Here, we explore the neuronal circuits underlying acute seizures in TMEV-injected mice using c-Fos driven TRAP (targeted recombination in active populations). TRAP mice (c-Fos- CreERT2 x CAG-tdTomato) were injected with PBS or TMEV and gently handled on DPI 5 to induce seizures. 4-OHT was administered to mice either 1.5 or 3 hr after seizures to tag the active cells expressing c-Fos with tdTomato. After 1 week, the mice were sacrificed and whole mouse brains were sectioned and immunostained for tdTomato expression. Percent area of fluorescence was quantified, and comparisons were made between TMEV-injected mice and PBS controls, sites ipsilateral vs contralateral to TMEV injection site, and between sexes. TdTomato expression was elevated in the TMEV-injected mice in the ipsilateral and contralateral hippocampus, thalamus, lateral septal nucleus, basal ganglia, triangular septal nucleus, fornix, and corpus callosum. Critically, the expression pattern suggests that seizures induced on DPI 5 arise from the hilus, dentate gyrus, and CA3 hippocampal subregions. Generalized seizures during acute TMEV infection may have propagated to the contralateral hemisphere via CA3 and the hippocampal commissure. TRAP has not been previously utilized in the TMEV mouse model and these experiments address crucial questions regarding seizure spread during TMEV infection.

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Shared Hierarchical Representations Explain Temporal Correspondence Between Brain Activity and Deep Neural Networks
The visual cortex and artificial neural networks both process images hierarchically, progressing from low-level features to high-level semantic representations. We investigated the temporal correspondence between activations from multiple convolutional and transformer-based neural network models (AlexNet, MoCo, ResNet-50, VGG-19, and ViT) and human EEG responses recorded during visual perception tasks. Leveraging two EEG datasets of images presented at different durations, we assessed whether this correspondence reflects general architectural principles or model-specific computations. Our analysis revealed a robust mapping: early EEG components correlated with activations from initial network layers and low-level visual features, whereas later components aligned with deeper layers and semantic content. Moreover, for images presented during longer times, the extent of correspondence correlated with the semantic contribution to the EEG response. These findings highlight a consistent temporal alignment between biological and artificial vision, suggesting that this correspondence is primarily driven by the hierarchical transformation of visual to semantic representations rather than by idiosyncratic computational features of individual network architectures.

Brain State Convergence and Divergence as Resting State FMRI Biomarkers: A Large-Scale Study of Continuous, Overlapping, Time-resolved States Differentiates Four Psychiatric Disorders
AO_SCPLOWBSTRACTC_SCPLOWIdentifying biomarkers- objective, quantifiable biologically-based measures to complement traditional clinical assessments- is critical for studying the links between brain and disorders. Recent advances in neuroimaging have shifted biomarker discovery from traditional univariate brain mapping techniques, which analyze individual brain regions separately, to multivariate predictive models that consider complex patterns across multiple regions, with dynamic functional network connectivity (dFNC) emerging as a key approach offering a dynamic view of the temporal coupling between different brain networks. Here, we introduce an innovative approach to estimate dynamic double functional independent primitives (ddFIP) by first applying a spatially constrained independent component analysis (ICA) to derive intrinsic connectivity networks (ICNs), followed by a second ICA applied to dFNC matrices. This procedure provides a set of "states" that reflect dynamic connectivity patterns. To characterize these states, we propose several dynamic measures: (1) amplitude convergence, which quantifies the extent to which multiple states contribute similarly to the connectivity profile at a given time (indicating more uniform state contributions); (2) amplitude divergence, quantifying the tendency for states to contribute at varying levels which does not assume dominance but rather reflects a spread of amplitudes across states; as well as (3) dynamic state density which shows the number of strongly occupied states, reflecting the brains preference for spending time in a smaller or larger set of dominant states. We apply this approach to uncover ddFIP-based biomarkers from seven resting-state functional magnetic resonance imaging (rs-fMRI) clinical datasets, which include four neuropsychiatric disorders--schizophrenia (SCZ), autism spectrum disorder (ASD), major depressive disorder (MDD), and bipolar disorder (BPD)- comprising a total of 5,805 participants. Our results revealed disorder-specific patterns in dynamic connectivity measures. SCZ exhibited widespread disruptions with high variability and increased divergence, suggesting a tendency for states to contribute at varying levels rather than uniformly. ASD, in contrast, showed significantly reduced divergence and increased convergence, indicating more uniform contributions across states and atypical stability in dynamic connectivity. BPD demonstrated heightened variability, particularly in mood regulation networks, while MDD displayed moderate disruptions, especially in self-referential processing networks. Notably, ASDs increased state convergence reflects a pattern where state weights are more similar, was sharply distinct from SCZs increased divergence, as indicated by state occupancy measures. In sum, our findings highlight the potential of continuous dFNC as a FNC-based biomarker to capture disorder-specific connectivity signatures. Moreover, by analyzing both the convergence and divergence of dynamic states, we capture a detailed view of connectivity, reflecting the brains adaptability and resilience within each disorder.

Enhanced anti-nociception by novel dual antagonists for 5HT2aR and mGluR5 in preclinical models of pain
Significant research has focused on developing anti-nociceptive pain treatments by targeting specific molecular candidates. The serotonin 2a receptor (5-HT2aR) and metabotropic glutamate receptor 5 (mGluR5) are recognized as key mediators in neuropathic pain. However, the combined effects of simultaneous inhibition of these targets remain unexplored. This current study investigated the therapeutic potential of concurrently antagonizing 5-HT2aR and mGluR5. Using spinal nerve ligation (SNL) and formalin-induced pain models in male Sprague-Dawley rats, we demonstrated that the simultaneous administration of both antagonists significantly enhanced anti-allodynic and anti-nociceptive effects, resulting in increased allodynia thresholds and reduced pain-related behaviors. This dual antagonism provided pain relief comparable to that of gabapentin and morphine. Furthermore, novel small molecules designed to simultaneously antagonize 5-HT2aR and mGluR5 exerted anti-nociceptive effects by suppressing excitatory postsynaptic responses and inhibiting the phosphorylation of ERK and AKT signaling molecules. Notably, the dual antagonist maintained anti-allodynic efficacy with repeated administration, unlike morphine, which exhibited clear tolerance development with daily use. Moreover, when administered intravenously, the dual antagonist demonstrated a low potential for abuse. These findings indicate that the simultaneous antagonism of 5-HT2aR and mGluR5 represents a promising pharmacological target for the management of chronic pain. This approach may offer enhanced analgesic outcomes while reducing the risk of undesirable side effects, such as tolerance and the potential for abuse.

SPONTANEOUS VISUAL IMAGERY DURING EXTENDED MUSIC LISTENING IS ASSOCIATED WITH RELIABLE ALPHA SUPPRESSION
Music is widely recognised as being able to evoke images in the minds eye. However, the neural basis of visual imagery experiences during music listening remains poorly understood. Here, we combined probe-caught experience sampling methodology with 32-channel electroencephalography (EEG) recordings in order to investigate the neuro-oscillatory correlates of music-evoked visual imagery and examine how spontaneously generated imagery compares to more deliberately generated forms. Thirty participants listened with closed eyes to four blocks of music, differing in their familiarity and relaxation potential and spanning a range of genres. In response to probes sent throughout listening, participants indicated whether or not they had been experiencing visual imagery and, if they had, whether the experienced visual imagery had been spontaneous or deliberate. Cluster permutation analyses on the time-frequency decomposed EEG data revealed alpha power suppression during visual imagery that was more reliable during spontaneous than deliberate imagery. Further, while theta and delta bands did not discriminate the presence or absence of the visual imagery experience or its intentionality subtypes, we observed that gamma power suppression in fronto-central areas was present during visual imagery experiences. Our results extend prior findings of a role of posterior alpha suppression in visual imagery to show its reliability in music-evoked spontaneous imagery specifically. We consider plausible interpretations of the presence and absence of other oscillatory signatures in relation to the listening conditions used in the current study.

HighlightsO_LIProbe-caught method shown to be effective in capturing moments of music-evoked visual imagery
C_LIO_LIEvidence for a high prevalence of spontaneous music-evoked imagery
C_LIO_LISpontaneous music-evoked visual imagery shown to be associated with posterior alpha suppression
C_LI

The Modulation of the Blood-Brain Barrier by Focused Ultrasound Stimulates Oligodendrogenesis
ObjectiveThe current study aims to fill a gap in knowledge on the effects of focused ultrasound (FUS)-mediated blood-brain-barrier (BBB) modulation on the proliferation and development of oligodendrocyte progenitor cells (OPCs). Researchers established that FUS combined with intravenous microbubbles can modulate the BBB in a controlled, reversible, localized, and non-invasive manner to facilitate the delivery of intravenous therapeutics to the brain. Over a decade ago, we discovered that, even without intravenous therapeutics, FUS-BBB modulation stimulates elements of brain repair, including hippocampal neurogenesis.

MethodsIn adult mice, FUS-BBB modulation was targeted unilaterally to the hippocampus and proliferation of OPCs was quantified at 1, 4, 7, and 10 days post-FUS. Mature oligodendrocytes were quantified at 30 days post-FUS. OPC proliferation was assessed at 7 days post-FUS, and mature oligodendrocytes at 30 days.

ResultsThe proliferation of hippocampal OPCs was increased by 6.8-fold and 2.3-fold between 1 and 4 days post-sonication, respectively, resulting in a 5.3-fold increase in mature oligodendrocytes one month later. To test the robustness of oligodendrogenesis following FUS-BBB modulation, the striatum was targeted as a second brain region with an independent experimental design. In line with hippocampal results, striatal FUS-BBB modulation promoted the generation of OPCs by 3.9-fold during the first week, leading to a 5.2-fold increase in oligodendrogenesis 30 days post-treatment.

InterpretationWe conclude that FUS-BBB modulation in the hippocampus and striatum promotes oligodendrogenesis by stimulating the proliferation of OPCs and being permissive to their maturation.

HighlightsO_LIBeyond the potential for the delivery of therapeutics to the brain, the modulation of the BBB by FUS can stimulate regenerative effects, including oligodendrogenesis.
C_LIO_LIFUS-BBB modulation induced a significant proliferation of OPCs which resulted in increases in oligodendrogenesis of 5.3-fold in the hippocampus and 6.7-fold in the striatum
C_LI

Mechanisms of Output Gating for visual working memory
Working memory tasks often require comparing remembered visual arrays to test displays, yet little is known about how people edit the contents of working memory at test. Across three experiments, we used contralateral delay activity (CDA) as a neural index of working memory load to examine how memory representations are selectively accessed at test. In Experiment 1, when a single test item was probed, CDA amplitudes increased with larger set sizes, indicating that untested items were still actively maintained, suggesting minimal editing based on spatial location. To test whether this was due to spatial grouping, Experiment 2 presented memory items sequentially in different temporal frames but identical spatial locations. The continued maintenance of all items at test suggested that simple spatial grouping could not explain the lack of editing effect seen in Experiment 1. In Experiment 3, however, when items belonged to distinct mnemonic categories, CDA amplitudes at test were reduced, consistent with selective editing based on category relevance. These findings suggest that working memory editing during retrieval is guided by categorical structure rather than spatial position. Supporting this, analysis of the P3 old-new effect revealed that decision speed and strength were influenced by the number of items maintained at test. Together, our results show that while people do not edit their working memory load based on spatial cues, they edit their working memory based on categorical relevance, allowing for more efficient retrieval of task-relevant information.