bioRxiv Subject Collection: Neuroscience's Journal
 
[Most Recent Entries] [Calendar View]

Tuesday, May 6th, 2025

    Time Event
    10:32a
    Nociceptin Orphanin F/Q Pathways are Dysregulated by Stress and Modulate Reward Learning and Motivation Across Species
    Nociceptin orphanin F/Q has been implicated in stress-related depressive phenotypes. Specifically, exposure to chronic stressors upregulates nociceptin receptors (NOPR), whereas NOPR antagonism has anti-depressant/anti-anhedonic effects. The mechanisms underlying these effects remain, however, unclear. Here, we investigated the role of NOPR in depressive phenotypes alongside potentially prohedonic effects of NOPR antagonism across species. In Study 1, we evaluated whether exposure to early-life adversity (ELA) upregulated ventral tegmental area (VTA) and striatal prepronociceptin (Pnoc) gene expression in adult mice. In Study 2, we tested whether chronic social defeat altered Pnoc gene expression in reward-related regions. To establish whether direct NOPR modulation is implicated in reward-related behaviors, in Study 3, we assessed whether NOPR antagonism alters reward learning in rats. Finally, in Study 4, we tested whether NOPR antagonism boosts motivation among depressed humans. ELA induced anhedonic behavior and increased Pnoc expression in the VTA; in females (but not males), ELA increased Pnoc expression in the dorsal striatum (Study 1). Furthermore, chronic stress reduced Pnoc-expressing cells in the VTA, dorsal striatum and prefrontal cortex and susceptible rats showed reduced VTA NOPR gene (Oprl1)-expressing cells (Study 2). In a behavioral assay, a single 30-mg dose of a NOPR antagonist (BTRX-246040) boosted reward learning in rats (Study 3). Finally, in depressed humans, relative to placebo, 8-week treatment with BTRX-246040 increased incentive motivation (Study 4). Collectively, our findings indicate that chronic stressors alter Pnoc and mRNA levels of Pnoc-expressing cells in a sex-selective and region-specific manner impacting reward structures, and that NOPR antagonism shows anti-anhedonic properties.
    10:32a
    Age-specific regulation of sociability by hypothalamic Agrp neurons
    Social isolation enhances sociability, suggesting that social behavior is maintained through a homeostatic mechanism. Further, mammalian social needs shift dramatically from infancy through adolescence into adulthood, raising the question of whether the neural mechanisms governing this homeostatic regulation evolve across developmental stages. Here, we show that agouti-related peptide (Agrp) neurons, which regulate hunger in adults, are activated by social isolation from weaning through adolescence but not in adulthood. Importantly, the activity of these neurons is critical for social behavior during adolescence: inhibiting Agrp neurons reduced isolation-induced sociability in juveniles but not in adults, and Agrp neuron activation promoted sociability only in young mice. After isolation, reunion with siblings or other conspecifics, but not unfamiliar adult males, rapidly decreased neuronal activity in juveniles, an effect requiring intact olfaction. These findings identify Agrp neurons as a key component of the circuitry governing age-specific social homeostasis.
    10:32a
    Dynamics of auditory word form encoding in human speech cortex
    When we hear continuous speech, we perceive it as a series of discrete words, despite the lack of clear boundaries in the acoustic signal. The superior temporal gyrus (STG) encodes phonetic elements like consonants and vowels, but how it extracts whole words as perceptual units remains unclear. Using high-density cortical recordings, we investigated how the brain represents auditory word forms - integrating acoustic-phonetic, prosodic, and lexical features - while participants listened to spoken narratives. Our results show that STG neural populations exhibit a distinctive reset in activity at word boundaries, marked by a brief, sharp drop in cortical activity. Between these resets, the STG consistently encodes distinct acoustic-phonetic, prosodic, and lexical information, supporting the integration of phonological features into coherent word forms. Notably, this process tracks the relative elapsed time within each word, independent of its absolute duration, providing a flexible temporal scaffolding for encoding variable word lengths. We observed similar word form dynamics in the deeper layers of a self-supervised artificial speech network, suggesting a potential convergence with computational models. Additionally, in a bistable word perception task, STG responses were aligned with participants' perceived word boundaries on a trial-by-trial basis, further emphasizing the role of dynamic encoding in word recognition. Together, these findings support a new dynamical model of auditory word forms, highlighting their importance as perceptual units for accessing linguistic meaning.
    10:32a
    Distinct roles of neuronal phenotypes during neurofeedback adaptation
    Learning adaptation allows the brain to refine motor patterns in response to changing environments rapidly. While population-level neural dynamics and single-neuron activity in motor learning have been widely studied, the contributions of individual neuron types remain poorly understood. Here, we employed a brain-machine interface (BMI) task with perturbations of varying difficulty to investigate single-neuron dynamics underlying neurofeedback adaptation in two rhesus macaques. Cortical neurons were classified based on waveform shape into narrow waveform (NW) and broad waveform (BW) categories, representing putative inhibitory interneurons and excitatory pyramidal neurons, respectively. Compared to BW neurons, NW neurons were more active and more strongly involved in the learning process. Moreover, task difficulty modulated neural responsiveness and coordination within both neuron groups, highlighting differential neuron engagement during motor learning. Our findings provide novel insights into single-neuron mechanisms underlying neurofeedback adaptation and emphasize the distinct functional roles of neuronal phenotypes in rapid learning processes.
    10:32a
    Differential Astrocyte-supplied NMDAR Co-Agonist for CA1 versus Dentate Gyrus Long-term Potentiation
    In the hippocampus, there is a region and synapse-specific N-methyl-D-aspartate receptor (NMDAR) co-agonist preference for induction of long-term potentiation (LTP). Schaffer collateral (SC)-CA1 synapses, enriched in GluN2A-containing NMDARs, favor D-serine, while medial perforant path (MPP) to dentate gyrus (DG) synapses that are rich in GluN2B-containing NMDARs prefer glycine for LTP induction. This study investigated the role of astrocytes in providing these co-agonists. We confirmed in rat hippocampal slices that exogenous D-serine (10 {micro}M) is sufficient to restore LTP at SC-CA1 synapses blocked under astrocyte calcium (Ca2+) -clamp conditions, consistent with previous findings. However, exogenous glycine (10 M) also rescued the LTP. In contrast, at MPP-DG synapses, 100 {micro}M exogenous glycine, but not 10 {micro}M nor 100 {micro}M D-serine, restored the LTP blocked by astrocyte Ca2+-clamping. Our findings support the view that, as for serine in CA1, astrocytes are the cellular source of the glycine required for LTP induction at MPP-DG synapses.
    12:30p
    The Slowest Timescales of Neural Synchronization Reveal the Strongest Influence of Auditory Distraction
    Among all the sounds occurring at any given time, people are often interested in listening to just one. Some competing sounds are merely background noise, whereas others distract attention from target sounds and are less easily suppressed. During active listening, the central auditory pathway unmixes target and distractor sounds based on temporal differences that vary across three orders of magnitude, from millisecond differences in acoustic temporal fine structure to slower perceptual grouping factors that stretch out to multiple seconds. Here, we developed an approach to directly measure central auditory encoding of multiplexed target and distractor sound features in human listeners to determine which timescales are most impacted by the presence of distracting sounds. Target sounds contained nested features along four timescales, including temporal fine structure (~500 Hz), temporal envelope (~25-80 Hz), envelope changes (~5 Hz), and slower changes in embedded context reflecting whether target stimuli were randomly arranged or formed a repeating pattern (~0.5 Hz). Targets were presented with competing sounds that provided variable levels of distraction: either a highly distracting melody or a less distracting noise. Neural synchronization to each timescale was simultaneously and independently measured for target and distractor sounds from electroencephalogram (EEG) recordings during a listening task. Sustained shifts from random to regular arrangements of temporal sequences were reliably perceived, yet did not evoke a pattern recognition potential, nor neural synchronization changes at any timescale. Synchronization to relatively slow changes in envelope transitions (<10Hz) of the target sound deteriorated with the addition of a more distracting sound while synchronization to more rapid fluctuations in the fine structure or envelope modulation rate were unaffected by varying levels of distraction. Categorizing trials according to task performance revealed a conjunction of enhanced entrainment to slower temporal features in the distractor sound and reduced synchronization to the target sound on error trials. By designing a stimulus paradigm that leveraged the remarkable temporal processing capabilities of the auditory nervous system, we were able to simultaneously quantify multiple target and distractor sound features reproduced in the EEG. This paradigm identified synchronization processes in the 7-10 Hz alpha range that has been linked to distractor suppression, which may prove valuable for research on clinical populations who report difficulty suppressing awareness of distracting sounds.
    12:30p
    A network of face patches in human prefrontal cortex for social processing of faces
    The human cerebral cortex contains localized regions for processing faces. These regions or patches, which are classically found in the occipito-temporal cortex, encode visual properties of faces. Using naturalistic movie-watching fMRI data from 176 human subjects and multivariate functional connectivity analysis, here we comprehensively characterize a novel network of four frontal face patches (FFPs) arranged dorsoventrally in the lateral prefrontal cortex. FFPs are strongly coupled with a face-selective region in the middle superior temporal sulcus, appear to be primarily involved in processing high-level social aspects of faces during movie-watching, and show partial correlations of activity with distinct cognitive networks. Activations in FFPs are correlated with the performance of subjects in a social cognition task. We further identify two groups of subjects who showed a remarkable difference in the topographical organization of FFPs. The discovery of FFPs provides new insights into the understanding of social processing in the brain.
    2:30p
    Integrative Single-Cell Analysis of Autism Spectrum Disorder Animal Models Reveal Convergent Transcriptomic Dysregulation Involved in Excitatory-Inhibitory Imbalance and Glial Disfunction
    Autism Spectrum Disorder (ASD) presents profound clinical and etiological heterogeneity, complicating the identification of core pathophysiological mechanisms. Single-cell RNA sequencing (scRNA-seq) offers cellular resolution but integrating findings across diverse studies remains challenging. Here, we constructed a unified single-cell reference framework by integrating scRNA-seq data from 11 distinct genetic and environmental ASD animal models, encompassing over 300.000 cells across various brain regions and developmental stages. Comparative analyses revealed convergent differentially expressed genes (DEGs) across neuronal and glial populations. Cross-model comparisons validated the integration, showing significant concordance between the unified dataset and individual studies, particularly for neuronal populations, and demonstrating how environmental models like valproic acid exposure recapitulate some of the transcriptomic alterations seen in genetic models. Cell communication analyses support widespread excitatory-inhibitory imbalance and with predicted signaling involving ligands like Pdgfa and Reln. Furthermore, we identified significant glial dysfunction, notably downregulation of crucial functional genes in astrocytes and signatures of metabolic dysregulation in mature oligodendrocytes. Cross-referencing with the SFARI database confirmed significant overlap with high-confidence ASD risk genes, with notable dysregulated in specific cell types included Ermn (upregulated in multiple glia), Foxg1 (downregulated in L5/6 NP neurons) and Mef2c (downregulated in MEIS2-like interneurons). Comparison with human scRNA-seq postmortem data revealed conserved dysregulation, highlighting enrichment of presynaptic/postsynaptic translation processes in neurons (implicating CACNAIA, GRIN2B, CAMK2A, ribosomal proteins) along with enrichment for neurodevelopmental disorder pathways in mature oligodendrocytes, involving NRXN and DLGAP gene networks. This integrative study provides unprecedented insight into the convergent cellular and molecular pathologies underlying ASD, establishing a valuable resource for understanding shared mechanisms and identifying new potential therapeutic targets.
    2:30p
    Constitutive activity of the inhibitory G protein pathway mediated by non-visual opsin Opn7b reduces cFos activity in stress and fear circuits and modulates avoidance behavior
    Constitutive activity of G protein-coupled receptors (GPCRs) plays an important role in brain function and disease including neurodegenerative and psychiatric disorders. The non-visual opsin Opn7b is a constitutively active Gi/o coupled GPCR which has been used to synchronize neuronal networks. Here we show that expression of Opn7b in the bed nucleus of the stria terminalis and the ventral tegmental area, two interconnected brain areas involved in modulating fear and stress responses, reduces the number of cFos positive neurons and modulates avoidance behavior in mice. Thus, by constitutively activating the Gi/o pathway Opn7b can be used as a tool to reduce cFos expression and to link cFos-expressing neurons to network- and pathway-specific behavior.
    2:30p
    Neural Mechanisms of Cognitive Flexibility and Interference Control in a Stroop Task Switching Paradigm
    Task-switching paradigms, often used to study cognitive flexibility, frequently employ incongruent bivalent stimuli, triggering two tasks and potentially conflating cognitive flexibility with interference control. This study assesses cognitive flexibility using univalent stimuli (triggering one task) and congruent bivalent stimuli (same response across tasks) in a modified Stroop task to investigate well-established neural activity correlates of cognitive flexibility, manifested in human (females and males) electroencephalography (EEG) recordings, while isolating switch process from the influence of interference control at the response level. In particular, we analyzed EEG theta-band activity and event-related potential (ERP) components in switch (N2, P3a, P3b, late sustained potential (LSP)) and interference (N400, LSP and mid-frontal theta activity) conditions. We compared each of the switch and the interference condition to the control condition using cluster-based permutation test. In the switch condition, we observed fronto-central N2, reduced frontal P3a, and a positive occipital LSP. The interference condition showed increased frontal theta, parietal N400, and a positive occipital LSP. We also compared switch and interference conditions using cluster-based permutation test. We observed a larger N2 in the frontocentral regions during the switch condition and higher frontal theta activity during the interference condition, which aligns with their comparisons to the control condition. This result suggests that distinct neural mechanisms are used for each of the processes involved in conflict monitoring. Specifically, the theta activity may reflect sustained monitoring and conflict resolution during interference, while the N2 may reflect more transient conflict detection and the need to switch task sets.

    Significance StatementCognitive flexibility--the ability to adapt behavior to a changing environment--is essential for goal-directed actions. For assessing cognitive flexibility unlike the typical approach, we did not use incongruent bivalent stimuli. We used univalent and congruent bivalent stimuli to isolate cognitive flexibility while assessing interference control separately with incongruent bivalent stimuli. We analyzed well-documented brain activities related to cognitive flexibility (P3b, N2, P3a, LSP) and interference control (N400, LSP), and mid-frontal EEG theta activity. Despite using different stimuli, we observed all expected components associated with the switch process except for the P3b. Both processes share common parietal activity, and while the frontal lobe plays a role in both, its activity differs between them.
    6:01p
    The Optimal Retinal Locus for High-Resolution Vision in Space and Time
    Humans exhibit machine-like eye-movement behavior in space and time while performing challenging visual resolution tasks. Fewer microsaccades occur as stimulus presentation is imminent. Drifts and microsaccades combine to confine the landing location of an anticipated visual stimulus to a tiny retinal region: the preferred retinal locus (PRL). We find that this location confers the best visual acuity despite it being offset from the anatomical fovea (the location of maximum cone density). We also find that acuity is best when the last microsaccade occurs ~400msec or longer before stimulus presentation. The machine-like eye movements are involuntary and not perceived. Our findings thus reveal a highly evolved oculomotor system such that gaze direction during fixation is rarely far enough from the PRL to cause a decline in visual resolution.
    6:01p
    When do peripherally encoded memories generalize in visual working memory?
    Previous work has demonstrated that visual working memory of peripherally presented patterns transitions from location-specific to spatially generalized representations. It remains unclear what the temporal dynamics are of this generalization, and to which processing stages it is linked. Here we investigated the neural correlates of peripherally encoded memoranda before and after an item was selected for response, focusing on when the representation changes from a location-specific to a spatially generalized code. Thirty healthy participants memorized two orientations presented serially at 15 degrees eccentricity to the left and right of central fixation. One of the two items was subsequently cued, for which memory performance was then assessed. During the delays between each of these events, impulse signals were presented to trace memoranda in potentially activity-silent or activity-reduced states. Replicating prior findings, we observed that neural codes transitioned from dynamic, location-specific states to spatially and temporally generalized stable states post-encoding, here emerging from about 400 ms onwards. Importantly, this already occurred during maintenance, prior to selection of the response-relevant item. After the cue, first the location, and then the identity of the cued item emerged in the signal, suggesting that, despite the by then generalized code, location remained a useful basis for selection. The results suggest that spatial generalization is predominantly a maintenance-related rather than a selection-related process.
    6:01p
    An in vivo model for transcranial direct current stimulation of the motor cortex in awake mice.
    Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique mainly used in humans, in which weak direct currents are applied over the scalp to alter cortical excitability and induce neuroplasticity. Previous studies have demonstrated the value of tDCS for modulating sensory, motor, and cognitive functions, nevertheless, knowledge about how externally applied electric fields affect different components of neuronal networks is still incomplete, and in vivo animal models, which are required for a deeper understanding, are not fully developed. To evaluate the impact of tDCS on cortical excitability, many human experiments assess motor evoked potentials elicited by motor cortex (M1) stimulation. To develop a related in vivo animal model, we recorded electrical activity in M1 of alert mice during and after administration of tDCS over M1. M1 excitability was chronically recorded from layers 2-3, layer 5 and layer 6, evoked by stimulation of the ventral lateral nucleus of the thalamus (VAL). M1-tDCS was applied at 100 and 200 A for 5 s to test the acute effects on neuronal excitability, and for 15 min to induce after-effects. Acute M1-tDCS increased and decreased the amplitude of VAL-evoked potentials in a polarity-, layer- and intensity-dependent manner. For 15 minutes of anodal or cathodal tDCS, a similar polarity- and intensity-dependent modulation of VAL-evoked potential amplitudes during the 15 minutes of stimulation was observed. After tDCS was switched off, the highest intensity of anodal stimulation induced a significant excitability enhancement during at least two hours after stimulation, whereas the after-effects of cathodal tDCS were less pronounced. The current study demonstrates the feasibility of a mouse model of M1-tDCS to accomplish similar modulatory effects of tDCS on cortical excitability as observed in human experiments. A proper adjustment of tDCS parameters, as compared to application in humans, is however required to obtain these translational effects.
    8:02p
    H2O2-induced astrocytic collagen triggers neuronal death via fucosylation-dependent glial barrier formation upon ischemic stroke
    The cascade of molecular and cellular events leading to neuronal death after a focal ischemic stroke remains enigmatic. Although astrocytes form glial barriers that may protect surrounding tissue, how barriers develop and contribute to neuronal death is unclear. Here, we show that H2O2 induces astrocytic type I collagen (COL1) production via miR-29 mediated post-transcriptional and fucosylation-dependent post-translational regulations, leading to integrin activation and neuronal death. In photothrombosis (PT)-induced cortical stroke model, PT triggered H2O2 surge, astrogliosis, glial barrier formation, COL1 expression, fibrotic scarring, altered N-glycosylation, neuronal loss, and neurological deficits. Remarkably, these effects were reversed by astrocyte-specific COL1 or FUT8 gene-silencing or treatment with KDS12025, an H2O2 decomposing peroxidase enhancer. KDS12025s neuroprotective effects were also recapitulated in non-human primate stroke model. These findings delineate a previously unrecognized astrocyte-driven mechanism in which oxidative stress induces COL1 production, promoting neuronal death, and position H2O2 and astrocytic COL1 and FUT8 as promising therapeutic targets for ischemic stroke.
    8:31p
    Mycobacterial Phenolic Glycolipid Triggers ATP-Mediated Neuronal P2X3 Signaling and Cough
    Cough drives respiratory pathogen transmission, yet how microbes directly engage host sensory neurons to trigger cough is largely unknown. We previously demonstrated that the Mycobacterium tuberculosis (Mtb) glycolipid sulfolipid-1 (SL-1) activates neurons and induces cough. Here, we reveal that phenolic glycolipid (PGL) produced by the hypertransmissible HN878 Mtb strain activates both mouse and human nociceptive neurons in vitro using calcium imaging and electrophysiology and is sufficient to induce cough using plethysmography. Combined with SL-1, PGL potently triggers neuronal activation. By synthesizing various PGL analogs, we show that neuroactivity is proportional to saccharide chain length and structure. Mechanistically, PGL stimulates rapid extracellular ATP release, which engages neuronal P2X3 purinergic receptors - an effect blocked by a P2X3 antagonist. These findings uncover a neuronal activation pathway co-opted by certain Mtb strains to enhance transmission via cough and suggest inhibition of purinergic signaling as a potential strategy to block airborne spread of Mtb.

    << Previous Day 2025/05/06
    [Calendar]
    Next Day >>

bioRxiv Subject Collection: Neuroscience   About LJ.Rossia.org