bioRxiv Subject Collection: Neuroscience's Journal

Emergence of Pre-movement Beta Activity with Stable Sensorimotor Predictions to Facilitate Motor Adjustments
Daily, we adapt to perturbations to maintain efficient performance, especially when transitioning between environments with different features. Such an adaptative process relies on updating motor programs based on past errors, a process associated with beta oscillations (13-35 Hz). Yet, the spatio-temporal dynamics underlying the transition between different environments, and the updating of motor programs in response to specific environmental perturbations remain elusive. Here, we show for the first time that pre-movement beta activity in a cerebello-cortical network emerges as the features of a new environment and motor outcomes become more stable and predictable. Notably, the cerebellum and parietal cortex drive prefrontal activity near movement initiation to update these predictions. Using a single-trial approach, we reveal that pre-movement beta bursts predict the evolution of trial-by-trial motor adjustments within a stable environment. These findings demonstrate that pre-movement beta activity within cerebellar-cortical network encodes essential information for achieving efficient sensorimotor predictions following environmental changes.

Cerebral perfusion and metabolic response of astrocytes and neurons during locomotion
The hemodynamic response links neural oxidative metabolism changes to increased cerebral blood flow during brain activity. Although Roy and Sherrington introduced this concept over a century ago (1890), the exact cellular mechanisms remain unclear. This study demonstrates how local blood supply increases correlate with the metabolic response of individual brain cells during locomotion. Using Raman microspectroscopy, we observed an elevation in oxygen saturation levels (sO2) in cortical venules but not in arterioles, which were already near saturation. The increased sO2 in the venules was accompanied by vasodilation, indicating blood oversupply in the local brain area, a phenomenon known as functional hyperemia. We then analyzed the metabolic response of individual neurons and astrocytes to locomotion. In neurons, the levels of reduced cytochromes of c and b types [cyt c,b (Fe2+)] rapidly decreased at the onset of locomotion. This suggests an increase in the activity of the mitochondrial respiratory chain (electron transport chain, ETC) in response to heightened energy demands in these cells. In contrast, because astrocytes rely less on oxidative phosphorylation for their energy metabolism than neurons, we did not observe an initial decrease in reduced cytochromes in these cells. However, as locomotion continued, the cyt c,b (Fe2+) levels steadily increased in both cell types. In neurons, this led to a slow recovery from the initial drop, while in astrocytes, the increase exceeded baseline levels. Consequently, we observed an overload of electrons in the astrocytic ETC. The distinct responses of astrocytic and neuronal mitochondria to locomotion may reflect differences in the organization of the ETC in the two cell types. Furthermore, astrocytes may shift to glycolysis under increased neuronal activity. This difference also resulted in hydrogen peroxide (H202) production in astrocytic mitochondria but not neuronal mitochondria. Since H202 is a signaling molecule critical for cognitive function in the brain, we speculate that astrocytic mitochondria act as signaling hubs during exercise.

Auditory brainstem responses to speech-in-noise reflect selective attention, comprehension, and subjective listening effort
The auditory brainstem plays a crucial role in speech-in-noise listening, refining numerous acoustic features such as pitch and spatial location under continual descending influence from cortex. However, the difficulty of characterizing brainstem activity during continuous speech listening has obscured its functional role in ecologically valid contexts - not only the effects of selective attention on neural responses, but also their impact on comprehension and listening effort. Here, we evaluate the role of the brainstem on speech-in-noise perception and selective attention using a continuous, speech-based stimulus with embedded chirps (Cheech) that rapidly and effectively evokes auditory brainstem responses (ABRs) while participants listen to short story narratives. The Cheech-modified stories were presented alone or in the presence of another spatially separated talker, and neural responses were measured throughout by EEG. Both word-level detection performance and narrative-level comprehension were evaluated, as well as subjective reports of listening effort. ABR wave V was modulated by the presence of a competing talker, selective attention for the target versus masker, and the talker gender. Additionally, faster wave V peak latencies and larger amplitudes were associated with identification of the target words embedded within the stories, while faster latencies additionally related to better comprehension question accuracy and lower subjective listening effort. Collectively, our results provide clear evidence for the influence of brainstem encoding processes on individual speech-listening behaviors, including the ability to selectively attend to and comprehend target speech in the presence of a competing talker.

Identifying brain-penetrant small molecule modulators of human microglia using a cellular model of synaptic pruning
Microglia dysregulation is implicated across a range of neurodevelopmental and neurodegenerative disorders, making their modulation a promising therapeutic target. Using PBMC-derived induced microglia-like cells (piMGLCs) in a scalable assay, we screened 489 CNS-penetrant compounds for modulation of microglial phagocytosis of human synaptosomes in a validated assay for microglia-mediated synaptic pruning. Compounds from the library that reduced phagocytosis by [≥]2 standard deviations across the library without cytotoxicity were validated in secondary screens, with 28 of them further confirmed to reduce phagocytosis by 50% or more. Image-based morphological measurements were calculated to measure the degree of ramified vs. amoeboid morphotype as an indicator of activation state. Additionally, transcriptomic profiling indicated divergent effects on cell signaling, metabolism, activation, and actin dynamics across confirmed compounds. In particular, multiple CNS-penetrant small molecules with prior FDA approval or demonstration of safety in vivo demonstrated modulatory effects on microglia. These potential disease-modifying agents represent high-priority candidates for repositioning studies in neurodevelopmental, neuroinflammatory, or neurodegenerative disorders.

Using deep generative models for simultaneous representational and predictive modeling of brain and behavior: A graded supervised-to-unsupervised modeling framework.
Research in cognitive neuroscience has increasingly used machine learning algorithms and multivariate pattern analysis (MVPA) to model brain-behavior relationships. These algorithms typically fall into two main types: unsupervised or supervised. In cognitive neuroscience, most studies assume that brain states map to behavior in a linear, one-to-one fashion. If such mapping exists, unsupervised and supervised approaches should lead to converging conclusions. Conclusions diverge, however, when the mapping is more complex. Unfortunately, the ground truth of brain-behavior relationships is rarely, if ever, known in advance, leading to the possibility of incorrect conclusions when scientists use a modeling approach guided by a single set of assumptions that may not be justified. In this paper, we introduce a possible solution to this dilemma. We combine unsupervised and discriminative supervised models with a model comparison strategy, and apply this approach on simulated data where the ground truth brain-behavior relationships are known. The combined modeling approach learns a latent space that models the distribution of simulated brain states (similar to unsupervised approaches). At the same time, the latent space contains information that can be used to predict behavior, thereby contributing to brain-behavior characterizations (similar to supervised approaches). We use four simulated datasets that vary in the linearity and homogeneity of the brain-behavior relationship to compare the modeling results for each simulated dataset along a continuum from fully unsupervised to fully supervised. More importantly, we examine what happens to the latent space as a consequence of incorrect assumptions that applied to a dataset during modeling. We further show how our framework can model diverse brain-behavior relationships in a way that fully unsupervised v. fully supervised approaches do not, by comparing the modeling results for each simulated dataset along a continuum from fully unsupervised to fully supervised.

Collecting, detecting and handling non-wear intervals in longitudinal light exposure data
In field studies using wearable light loggers, participants often need to remove the devices, resulting in non-wear intervals of varying and unknown duration. Accurate detection of these intervals is an essential step in data pre-processing pipelines. However, the limited reporting on whether and how non-wear information is collected and detected has hindered the development of effective data pre-processing strategies and automated detection algorithms. Here, we deploy a multi-modal approach to collect non-wear time during a longitudinal light exposure campaign and systematically compare non-wear detection strategies. Healthy participants (n=26; mean age 28{+/-}5 years, 14F) wore a near-corneal plane light logger for one week and reported non-wear events in three ways: pressing an "event marker" button on the light logger, placing it in a black bag, and using an app-based Wear log. Wear log entries were checked twice a day to ensure high data quality and used as ground truth for non-wear interval detection. Participants showed high adherence to the protocol, with non-wear time constituting 5.4{+/-}3.8% (mean{+/-}SD) of total participation time. Considering button presses, our results indicated that extending time windows beyond one minute improved their detection at the start and end of non-wear intervals, achieving identification in >85.4% of cases. To detect non-wear intervals based on black bag use, we applied an algorithm detecting clusters of low illuminance to our data and compared its performance to detecting clusters of low activity. Performance was higher for illuminance (F1=0.76) than activity (F1=0.52). Transition states between wear and non-wear emerged as a major source of misclassification, and we suggest that combining illuminance and activity data could enhance detection accuracy. Lastly, we compared light exposure metrics averaged across the week derived from three datasets: the full dataset, a dataset filtered for non-wear based on self-reports, and a dataset filtered for non-wear using the low illuminance clusters detection algorithm. The differences in light exposure metrics across these datasets were minimal. Our results highlight that while non-wear detection may be less critical in high-compliance cohorts, systematically collecting and detecting non-wear intervals is both feasible and important for ensuring robust data pre-processing.

Foveal action for the control of extrafoveal vision
Microsaccades have been convincingly linked to extrafoveal covert attention shifts for more than two decades. However, the direction of causality between individual microsaccade generation and an alteration in both extrafoveal visual sensitivity and behavior remains debated: do microsaccades merely reflect, perhaps probabilistically, an altered extrafoveal sensitivity, or is the act of generating microsaccades sufficient to, on its own, modify such sensitivity? Using a novel exploitation of real-time retinal image stabilization, behavior, and neurophysiology in the superior colliculus, we show that exclusive experimental control over foveal oculomotor state is entirely sufficient to influence extrafoveal sensitivity. This happens for eccentricities as large as ~50 times those associated with microsaccades, and it also takes place in the absence of any differential attentional demands. Most importantly, such influence is mediated through well-known, classic pre- and post-saccadic visual processing changes. Thus, seemingly-innocuous subliminal eye movements do constitute an integral component of cognitive processes like attention.

Dissecting the functional heterogeneity of glutamatergic synapses with high-throughput optical physiology
Fluorescent reporters for glutamate release and postsynaptic Ca2+ signaling are essential tools for quantifying synapse functional heterogeneity across neurons and circuits. However, leveraging these probes for neuroscience requires scalable experimental frameworks. Here, we devised a high-throughput approach to efficiently collect and analyze hundreds of optical recordings of glutamate release activity at presynaptic boutons in cultured rat hippocampal neurons. Boutons exhibited remarkable functional heterogeneity and could be separated into multiple functional classes based on their iGluSnFR3 responses to single action potentials, paired stimuli, and synaptic parameters derived from mean-variance analysis. Finally, we developed a novel all-optical assay of pre- and postsynaptic glutamatergic synapse function. We deployed iGluSnFR3 with a red-shifted, postsynaptically-targeted Ca2+ sensor, enabling direct imaging and analysis of NMDA receptor-mediated synaptic transmission at large numbers of dendritic spines. This work enables direct observation of the flow of information at single synapses and should speed detailed investigations of synaptic functional heterogeneity.

Cytoplasmic expression of the cell cycle regulator cyclin D1 in radial glial progenitor cells modulates brain cortex development
During nervous system development, the interplay between cell cycle regulation and neurogenesis is fundamental to achieve the correct timing for neuronal differentiation. However, the molecular players regulating this transition are poorly understood. Among these, the cell-cycle regulatory cyclins and their cyclin-dependent kinases (Cdks) play a pivotal role. In the present work we uncover an unknown function of cyclin D1 (Ccnd1) during cortex development which is independent of cell cycle regulation and that relies on its cytoplasmic localization and membrane association. We show that Ccnd1 is localized in the cytoplasm of the radial glial process (RGP) of neuron progenitors in different regions of the developing brain, including the cortex. Cytoplasmic Ccnd1 is enriched at the distal tip of the RGP, adjacent to the meningeal basement membrane, and overlaps with {beta}1-integrin at the plasma membrane. CCND1 knock-out animals show an abnormal cortical layering in which the distribution of Tbr2+ and Ctip2+ cells are affected without displaying proliferation defects. This is consistent with a cytoplasmic function of Ccnd1 as overexpression by in utero electroporation of a dominant negative Ccnd1, unable to activate Cdks, and targeted to the cytoplasmic membranes, reproduces some of these Tbr2 and Ctip2 defects. Finally, we provide evidence that cytoplasmic Ccnd1 affects neuron morphology and that it is required for the proper detachment of the RGP from the meningeal basement membrane by a mechanism involving the phosphorylation of the integrin effector protein paxillin. Hence, we propose that Ccnd1 has an important cytoplasmic function for cortical development independently of cell cycle regulation.

Significant StatementA key developmental step during nervous system formation is the transition from proliferating progenitors to postmitotic neurons. However, the molecular mechanisms regulating this process are not fully understood. Cyclin D1 (Ccnd1) is a canonical regulator of cell cycle in the cell nucleus. Surprisingly, we show that Ccnd1 is also located in the radial glial process of neuron progenitors and associated to the plasma membrane in different regions of the developing mouse brain. We uncover a novel function for this cytoplasmic Ccnd1 and show that it is required for proper cortical layering, independent of cell cycle regulation. Mechanistically, we provide evidence that this function is mediated by the integrin effector paxillin. We propose therefore that cytoplasmic Ccnd1 is important for cortex development independent of cell cycle regulation.

Spatiotemporal dynamics of EEG microstate networks over the first two years of life: A multi-cohort longitudinal study
The first two years of life are marked by rapid development of large-scale brain networks that support emerging cognition and behavior. Magnetic-resonance approaches have revealed much about largescale networks in sleep, but very little is known about functional network dynamics in awake, behaving infants during this period of substantial development. Microstates are brief instances of distinct spatial topographies of largescale neural activity measured with electroencephalography (EEG) that offer a novel approach to studying whole-brain network dynamics at sub-second scale in awake infants by capturing their temporally coherent brain activity. While emerging literature is leveraging microstate dynamics in adults to understand mature largescale network function, developmental trajectories during networks rapid construction in infancy remain uncharacterized. In this study, we leveraged longitudinal resting-state EEG data from 854 infants across two geoculturally diverse cohorts to explore largescale network development through EEG microstates over the first two years of life. We provide evidence for conserved emergence of various network configurations (microstate classes A-G) through infancy across cohorts using data-driven clustering analyses. We also demonstrate significant longitudinal changes in microstate dynamics during this period, characterized by more numerous and more rapid transitions between largescale configurations, especially over early infancy. While patterns of sensory microstate development were largely consistent between cohorts, higher-order cognitive microstates showed context-specific developmental trends. Together these results provide novel insights into how large-scale brain networks functionally develop and organize across the first two years of life.

The Restoration of Social Defects in Schizophrenic Mice by Plant Exposure
Schizophrenia is a serious psychotic disorder caused by both individuals' genetic background and their living environment. However, how cognitive and negative symptoms can be treated is still a challenge since most anti-psychotic drugs are only effective for positive symptoms. Previous epidemic studies have demonstrated that plant exposure could decrease the risk of schizophrenia and shorten the length of psychiatric hospital admissions for patients. However, it is still unknown whether plant exposure could improve cognition-related defects in schizophrenia, with no related animal studies. In the present study, we first induced a schizophrenia mice model by giving mice long-term (2 weeks) injections of the antagonist of the NMDA receptor: MK801. We then raised the animals in environments containing plants (4 weeks) including Epipremnum aureum and rosemary, and tested their locomotive, anxious and social behaviors. We found that plant exposure did not change the locomotion behaviors of wild-type animals, but significantly reduced the schizophrenia-related social and anxious behaviors in the schizophrenic animals. In addition, we tested the expression of c-Fos in animals exposed to plants after social behavioral testing. We found that the deficits in c-Fos expression in both the hippocampus and prefrontal cortex were partially rescued after plant exposure. These results indicate plant exposure will be a new tool to improve the clinical deficits of schizophrenia.

Elastase mediated white matter damage in cerebral small vessel disease: Microglia - neutrophils pas de deux
Cerebral small vessel disease (CSVD) leads to an extensive white matter damage associated with cognitive decline, yet the underlying damaging mechanisms remain incompletely understood. Here we established a positive correlation between plasma levels of serine proteinase elastase ELANE and periventricular white matter hyperintensity (PV-WMH) in a cohort of CSVD patients. In a CSVD murine model induced by bilateral carotid artery stenosis (BCAS), upregulated ELANE was detected both in microglia and peripheral blood neutrophils. Genetic ELANE deficiency significantly alleviated oligodendrocyte loss, thereby reducing white matter lesions (WMLs) as well as ameliorating sensorimotor and cognitive impairments in BCAS mice. In vitro studies demonstrated that ELANE triggered time-dependent and dose-dependent oligodendrocyte lineage cell death. Bone marrow transplantation showed that ELANE from microglia and peripheral blood both contributed to WML development and BCAS-induced neurological deficits. Mechanistically, ELANE, accumulated by oligodendrocytes, cleaved the phosphodiesterase domain of 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase). Pharmacological inhibition of ELANE with Sivelestat reduced oligodendrocyte loss and WMLs leading to the restoration of white matter integrity and neurological improvements in BCAS mice. In post-mortem brain specimens of CSVD patients ELANE accumulated within WMLs being predominantly localized in microglia (and hence defined as microglial ELANE) rather than in the brain-infiltrating neutrophils. We therefore posit microglial ELANE as an instigator of whiter matter injury in CSVD and suggest its potential therapeutic relevance.

APOE4 Increases Susceptibility to Amyloid, Accelerating Episodic Memory Decline
Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for sporadic Alzheimers disease (AD). Individuals with one copy of APOE4 exhibit greater amyloid-beta (A{beta}) deposition compared to noncarriers, an effect that is even more pronounced in APOE4 homozygotes. Interestingly, APOE4 carriers not only show more AD pathology but also experience more rapid cognitive decline, particularly in episodic memory. The underlying mechanisms driving this domain-specific vulnerability, however, remain unclear. In this study, we examined whether the accelerated decline in episodic memory among APOE4 carriers is due to increased A{beta} deposition or heightened susceptibility to A{beta}-related effects. Using data from the Alzheimers Disease Research Initiative, we modeled amyloid duration, the estimated number of years an individual has been amyloid-positive, and its impact on cognitive trajectories. Our findings reveal that APOE4 is associated with more rapid episodic memory decline as a function of amyloid duration. This decline was dose-dependent, with APOE4 homozygotes declining more rapidly than heterozygotes, and it was consistently observed across multiple episodic memory tasks and measures. Importantly, this pattern was not observed in other cognitive domains, such as processing speed, executive function, visuospatial skills, language, or crystallized intelligence. These results suggest that cognitive trajectories in AD differ by APOE genotype, with APOE4 conferring increased vulnerability to hippocampal dysfunction early in the disease course. Future research should investigate whether these cognitive differences stem from distinct pathological cascades in APOE4 carriers.

Neural differences in conflict monitoring and stimulus expectancy processes in experienced meditators are likely driven by enhanced attention
ObjectivesMindfulness meditation has been linked to enhanced attention and executive function, likely resulting from practice-related effects on neural activity patterns. In this study, we used an event-related potential (ERP) paradigm to examine brain responses related to conflict monitoring and attention in experienced mindfulness meditators to better understand key factors driving meditation-related effects.

MethodsWe measured electroencephalography-derived N2 and P3 ERPs reflecting conflict monitoring and attention processes from 35 meditators and 29 non-meditators across both an easy and a hard Go/Nogo task (50% Nogo and 25% Nogo stimuli, respectively).

ResultsMeditators displayed distinct neural activity patterns compared to non-meditators, with enhanced N2 responses in fronto-midline electrodes following hard Nogo trials (pFDR = 0.011, np2 = 0.111). The fronto-midline N2 ERP was also larger following Nogo trials than Go trials, in the harder task condition, and was related to correct responses. Meditators also exhibited a more frontally distributed P3 ERP in the easy task compared to the hard task, while non-meditators showed a more frontally distributed P3 ERP in the hard task (pFDR = 0.015, np2 = 0.079).

ConclusionsMindfulness meditation was associated with distinct topographical patterns of neural activity in the attention task, without corresponding increases in global neural activity amplitudes. These meditation-related effects appear to be driven by attention-specific mechanisms, despite the examined neural activity being associated with conflict monitoring and stimulus expectancy. Our findings suggest that the cognitive benefits of meditation may only emerge in tasks that actively engage targeted cognitive processes, such as sustained attention.

Attention field as a cognitive-behavioral marker for demarcating internet- but not smoking-addiction from reward
Attentional effect (AE), attention profile (AP), and attention field (AF) have been studied extensively, however, their roles in addiction and demarcating addiction from rewards remain unclear. Using a modified Posner-paradigm with two types of pre-rewarded-cues (addiction-related and addiction-unrelated) and four groups (smoking-dependents, internet-dependents, and respective HCs), we found that both AEs and APs were independent of either cue type or group, while AFs were interactively modulated by the two. AFs of addiction-related cues were narrower than those of addiction-unrelated cues for internet-dependents, but not for either smoking-dependents or HCs; AFs of internet-dependents (not smoking-dependents) were narrower than those of HCs for addiction-related cues, but not for addiction-unrelated cues. Significantly, internet-dependents reduced AFs can be simulated by the divisive-normalization computation, both of which closely tracked their addictive severities. Our findings identify a cognitive-behavioral marker for demarcating internet-addiction from rewarding, arguing against the notion that internet-addiction, or, more generally, non-substance-addiction, is ill-posed.

A single Citrobacter rodentium infection in Pink1 knockout and wild type mice leads to regional blood-brain-barrier perturbation and glial activation without dopamine neuron axon terminal loss
A growing body of research supports the hypothesis of links between immune system activation and the development of Parkinson's disease (PD). A recent study revealed that repeated gastrointestinal infection with Citrobacter rodentium can lead to PD-like motor dysfunction in Pink1 knockout (KO) mice and immune cell entry in the brain. With the objective of better understanding the mechanisms leading to immune attack of the brain in this model, we evaluated the hypothesis that such mild infections are sufficient to increase blood brain barrier (BBB) permeability and cause brain inflammation. Pink1 wild-type (WT) and KO mice were infected with Citrobacter rodentium and at day 13 and 26 post infection, we conducted gadolinium-enhanced magnetic resonance imaging (MRI) to identify signs of BBB permeability changes. Quantification of MRI results provided evidence of increased blood-brain barrier permeability in both WT and Pink1 KO mice at 26 days after the infection in the striatum, dentate gyrus, somatosensory cortex, and thalamus. This was not accompanied by any change in global expression of tight-junction proteins or in markers of the integrity of the dopamine (DA) system in the striatum at both time points. However, chronic microglial activation was detected at day 26 post infection, accompanied by an elevation of the inflammatory mediators eotaxin, IFNgamma, CXCL9, IL-17 and MIP-2 in the striatum, accompanied by an elevation of IL-17 and CXCL1 in the serum of Pink1 KO mice. Neutrophil infiltration in the brain of infected mice was also noted at day 26 post infection, as revealed by immune cell profiling by flow cytometry. Finally, a bulk RNA-seq transcriptome analysis revealed that gene sets related to synaptic function were particularly influenced by the infection and that inflammation-related genes were upregulated by the infection in the Pink1 KO mice. Our results support the hypothesis that even after mild gastro-intestinal infection, increased BBB permeability could contribute to perturbations of brain homeostasis including altered expression of synaptic genes, increased microglial activation and the establishment of a chronic state of brain inflammation. Such perturbations could potentially act as a first hit for subsequent induction of PD pathology in the context of aging in genetically susceptible individuals.

Reactivation of reward representations associated with the reinforcement of behavior
Reward-related representations are found distributed throughout many human subcortical and neocortical regions that support different neural processes. These representations get reinstated for different but related tasks. There is rising evidence that representations reactivate during learning to reinforce prior rewarding choices. However, there remains a critical lack of understanding for whether and how reactivations in humans can facilitate behavioral reinforcement. To investigate this, we recorded from the temporal lobe and prefrontal cortex with intracranial electrocorticography while human subjects learnt two-choice decisions across two different scenes. Crucially, subjects were able to straightforwardly reactivate knowledge gained in a prior scene to make decisions in the current scene, but only when the reward contingencies stayed the same between the two scenes. Using a Bayesian learner, we inferred reward expectation from choice behavior, and measured representations of these reward expectations in electrocorticography data. We found that the representations of reward expectation in the medial temporal lobe and orbitofrontal cortex were reactivated, only when the subjects could straightforwardly transfer knowledge between the two scenes. In the anterior temporal lobe, the reactivation of value representations increased as learning increased, suggesting an area of plasticity during learning. This work presents a novel framework for measuring the reinforcement, or reactivation, of representations from human electrophysiology during the reinforcement of behavior.

Cell-specific delivery of GJB2 restores auditory function in mouse models of DFNB1 deafness and mediates appropriate expression in NHP cochlea
Mutations in the GJB2 gene cause the most common form of human hereditary hearing loss, known as DFNB1. GJB2 is expressed in two cell groups of the cochlea--epithelial cells of the organ of Corti and fibrocytes of the inner sulcus and lateral wall--but not by sensory hair cells or neurons. Attempts to treat mouse models of DFNB1 with AAV vectors mediating nonspecific Gjb2 expression have not substantially restored function, perhaps because inappropriate expression in hair cells and neurons could compromise their electrical activity. Here, we used genomic chromatin accessibility profiling to identify candidate gene regulatory elements (GREs) that could drive cell-type-specific expression of Gjb2 in the cochlea. HA-tagged GJB2, delivered to a conditional knockout model in an AAV vector with GRE control of expression, was localized to the appropriate cell types, prevented the cochlear degeneration observed in untreated knockout mice, and partially rescued hearing sensitivity. In a Gjb2 partial knockdown mouse model, such exogenous GJB2 prevented degeneration and completely restored hearing sensitivity. We tested control of expression by these GREs in nonhuman primate cochleas and found that vector-delivered human GJB2.HA was located in the appropriate cell types and caused little or no reduction in hearing sensitivity. Together, these findings suggest that GRE-mediated expression of GJB2 could prevent hearing loss in DFNB1 patients.

Atypical Visual Selective Attention in Children with Dyslexia: Evidence from N2pc and PD
Efficient visual attention is fundamental to the development of reading abilities. Previous studies have identified visual attention impairments in individuals with dyslexia, particularly in visual attention span and sluggish attention shifting. However, findings regarding basic visual selective attention remain controversial. To address this issue, the present study provides event-related potential (ERP) evidence to verify whether children with developmental dyslexia (DD) suffered from deficits in visual selective attention. A pop-out visual search task was used to examine visual attentional patterns to a lateral target in 66 children (33 children with DD and 33 typically developing (TD) children) using electroencephalography. Compared to TD children, children with DD showed a larger and prolonged P1 component, as well as a larger target-evoked N2pc component. The larger P1 amplitude was associated with lower reading fluency while the larger N2pc amplitude was associated with poor reading comprehension performance. Interestingly, the target-elicited N2pc was followed by positivity (PD component) in TD children but not in children with DD; however, the N2pc amplitude was correlated with the PD amplitude in children with DD. Children with DD show immature early attentional processing and may have an imbalance in the regulation of visual selective attention between attentional selection and suppression. Our findings provide ERP evidence for interpreting the underlying neural mechanism of visual selective attention in children with DD and may offer a new perspective for exploring the mechanism of visual attention deficits in dyslexia.

Research HighlightsO_LIIn a pop-out visual search task, children with dyslexia exhibited a larger N2pc and an absent PD component.
C_LIO_LIThe absence of the PD component in children with dyslexia may be associated with their larger N2pc amplitudes.
C_LIO_LIN2pc amplitude is associated with reading ability in children with dyslexia.
C_LIO_LIChildren with dyslexia need to allocate more resources towards the target but also struggle to disengage from the attended location.
C_LI

RiboTag-based RNA-Seq uncovers oligodendroglial lineage-specific inflammation in autoimmune encephalomyelitis
Oligodendroglial lineage cells (OLCs) are critical for neuronal support functions, including myelination and remyelination. Emerging evidence reveals their active roles in neuroinflammation, particularly in conditions like Multiple Sclerosis (MS). This study explores the inflammatory translatome of OLCs during the early onset of experimental autoimmune encephalomyelitis (EAE), an established MS model. Using RiboTag-based RNA sequencing in genetically modified Olig2-Cre RiboTag mice, we identified 1,556 upregulated and 683 downregulated genes in EAE OLCs. Enrichment analysis indicated heightened immune-related pathways, such as cytokine signaling, interferon responses, and antigen presentation, while downregulated genes were linked to neuronal development and myelination. Notably, OLCs expressed cytokines/chemokines, and their receptor, highlighting their active involvement in neuroinflammatory signaling. Functional studies demonstrated that interferon-gamma (IFN-{gamma}) signaling in OLCs exacerbates EAE pathology by enhancing antigen presentation and chemokine production, whereas interferon-beta (IFN-{beta}) signaling showed minimal impact. These findings provide novel insights into the inflammatory role of OLCs in EAE and suggest therapeutic potential in targeting OLC-mediated neuroinflammation for MS and related disorders.

Assessment of Contralateral Efferent Effects in Human Via ECochG
Efferent projections from the brainstem to the inner ear are well-described anatomically and physiologically but their precise function remains debated. The medial olivocochlear (MOC) system and its reflex, the MOCR, have been particularly well studied. In animals, anatomical and physiological data are fine-grained and extensive and suggest an important role for the MOCR in anti-masking e.g. to improve the detection of tones in background noise. Extensive behavioral studies in human support this role, but direct linking of behavioral paradigms to the MOCR is challenging because of the difficulty in obtaining appropriate human neural measures. We developed a new approach in which mass potentials were recorded near the cochlea of normal hearing and awake human volunteers to increase the signal-to-noise (SNR) ratio, and examined whether broadband noise to the contralateral ear elicited MOCR anti-masking effects as reported in animals. Probing the mass potential to the onset of brief tones at 4 and 6 kHz, convincing anti-masking or suppressive effects consistent with the MOCR were not detected. We then changed the recording technique to examine the neural phase-locked contribution to the mass potential in response to long, low-frequency tones, and found that contralateral sound suppressed neural responses in a systematic and progressive manner. We followed up with psychophysical experiments in which we found that contralateral noise elevated detection threshold for tones up to 4 kHz. Our study provides a new way to study efferent effects in the human peripheral auditory system and shows that contralateral efferent effects are biased towards low frequencies.