bioRxiv Subject Collection: Neuroscience's Journal

Non-invasive neuromodulation of cerebello-hippocampal volume-behavior relationships
The study here explores the link between transcranial direct current stimulation (tDCS) and brain-behavior relationships. We propose that tDCS may indirectly influence the complex relationships between brain volume and behavior. We focused on the dynamics between the hippocampus (HPC) and cerebellum (CB) in cognitive processes, a relationship with significant implications for understanding memory and motor skills. Seventy-four young adults (mean age: 22(0.42) years, mean education: 14.7(0.25) years) were randomly assigned to receive either anodal, cathodal, or sham stimulation. Following stimulation, participants completed computerized tasks assessing working memory and sequence learning in a magnetic resonance imaging (MRI) environment. We investigated the statistical interaction between CB and HPC volumes. Our findings showed that individuals with larger cerebellar volumes had shorter reaction times (RT) on a high-load working memory task in the sham stimulation group. In contrast, the anodal stimulation group exhibited faster RTs during the low-load working memory condition. These RT differences were associated with the cortical volumetric interaction between CB-HPC. Literature suggests that anodal stimulation down-regulates the CB and here, those with larger volumes perform more quickly, suggesting the potential need for additional cognitive resources to compensate for cerebellar downregulation. This new insight suggests that tDCS can aid in revealing structure-function relationships, due to greater performance variability, especially in young adults. It may also reveal new targets of interest in the study of aging or in diseases where there is also greater behavioral variability.

Investigating the 'Atypical Rhythm Risk' hypothesis in children with developmental language disorder using an EEG rhythmic speech paradigm
Sensitivity to rhythmic and prosodic cues in speech has been described as a precursor of language acquisition. Consequently, atypical rhythmic processing during infancy and early childhood has been considered a risk factor for developmental language disorders. This is the 'atypical rhythm risk' (ARR) hypothesis. The neural processing of rhythmic speech has not yet been explored in children with developmental language disorder (DLD). Here we utilise EEG and a rhythmic speech paradigm previously utilised for dyslexia to investigate the ARR hypothesis in 9-year-old children with and without DLD. We investigate angular velocity, power, ERPs, phase-amplitude coupling (PAC) and phase-phase coupling (PPC), at three frequency bands, delta, theta and low gamma. Both groups demonstrated significant and equivalent phase entrainment in the delta and theta bands, but only the control children showed significant phase entrainment in the low gamma band. Further, while angular velocity in the delta and theta bands was equivalent by group, there was a significant gamma-band difference. The children with DLD also exhibited significantly more theta and gamma power compared to the control children. Regarding PAC and PPC, both groups showed significant and equivalent coupling strength. However, group resultant phase differences showed that low-frequency phase (delta and theta) affected gamma oscillations differently by group. The EEG data show important differences between children with and without DLD in the neural mechanisms underpinning the processing of rhythmic speech. The findings are discussed in terms of auditory theories of DLD.

Observational activation of anterior cingulate cortical neurons coordinates hippocampal replay in social learning
Social learning enables a subject to make decisions by observing the actions of another. How neural circuits acquire relevant information during observation to guide subsequent behavior is unknown. Utilizing an observational spatial working memory task, we show that neurons in the rat anterior cingulate cortex (ACC) associated with spatial trajectories during self-running in a maze are activated when observing another rat running the same maze. The observation-induced ACC activities are reduced in error trials and are correlated with activities of hippocampal place cells representing the same trajectories. The ACC activities during observation also predict subsequent hippocampal place cell activities during sharp-wave ripples and spatial contents of hippocampal replay prior to self-running. The results support that ACC neurons involved in decisions during self-running are reactivated during observation and coordinate hippocampal replay to guide subsequent spatial navigation.

Level Dependent Subcortical EEG Responses to Continuous Speech
The auditory brainstem response (ABR) is a measure of subcortical activity in response to auditory stimuli. The wave V peak of the ABR depends on stimulus intensity level, and has been widely used for clinical hearing assessment. Conventional methods to estimate the ABR average electroencephalography (EEG) responses to short unnatural stimuli such as clicks. Recent work has moved towards more ecologically relevant continuous speech stimuli using linear deconvolution models called Temporal Response Functions (TRFs). Investigating whether the TRF waveform changes with stimulus intensity is a crucial step towards the use of natural speech stimuli for hearing assessments involving subcortical responses. Here, we develop methods to estimate level-dependent subcortical TRFs using EEG data collected from 21 participants listening to continuous speech presented at 4 different intensity levels. We find that level-dependent changes can be detected in the wave V peak of the subcortical TRF for almost all participants, and are consistent with level-dependent changes in click-ABR wave V. We also investigate the most suitable peripheral auditory model to generate predictors for level-dependent subcortical TRFs and find that simple gammatone filterbanks perform the best. Additionally, around 6 minutes of data may be sufficient for detecting level-dependent effects and wave V peaks above the noise floor for speech segments with higher intensity. Finally, we show a proof-of-concept that level dependent subcortical TRFs can be detected even for the inherent intensity fluctuations in natural continuous speech.

Developmental convergence and divergence in human stem cell models of autism spectrum disorder
Two decades of genetic studies in autism spectrum disorder (ASD) have identified over a hundred genes harboring rare risk mutations. Despite this substantial heterogeneity, transcriptomic and epigenetic analyses have identified convergent patterns of dysregulation across ASD post-mortem brain tissue. To identify shared and distinct mutational mechanisms, we assembled the largest hiPS cell patient cohort to date, consisting of 70 hiPS cell lines after stringent quality control representing 8 ASD-associated mutations, idiopathic ASD, and 20 lines from non-affected controls. We used these hiPS lines to generate human cortical organoids (hCO), profiling by RNAseq at four distinct timepoints up to 100 days of in vitro differentiation. Early timepoints harbored the largest mutation-specific changes, but different genetic forms converged on shared transcriptional changes as development progressed. We identified a shared RNA and protein interaction network, which was enriched in ASD risk genes and predicted to drive the observed down-stream changes in gene expression. CRISPR-Cas9 screening of these candidate transcriptional regulators in induced human neural progenitors validated their downstream molecular convergent effects. These data illustrate how genetic risk can propagate via transcriptional regulation to impact convergently dysregulated pathways, providing new insight into the convergent impact of ASD genetic risk on human neurodevelopment.

Unilateral auditory deprivation reveals brainstem origin of a sensitive period for spatial hearing
Early sensory experience can exert lasting perceptual consequences. For example, a brief period of auditory deprivation early in life can lead to persistent spatial hearing deficits. Some forms of hearing loss (i.e., conductive; CHL) can distort acoustical cues needed for spatial hearing, which depend on inputs from both ears. We hypothesize that asymmetric acoustic input during development disrupts auditory circuits that integrate binaural information. Here, we identify prolonged maturation of the binaural auditory brainstem in the guinea pig by tracking auditory evoked potentials across development. Using this age range, we induce a reversible unilateral CHL and ask whether behavioral and neural maturation are disrupted. We find that developmental CHL alters a brainstem readout of binaural function which is not observed when the CHL is induced in adulthood. Startle-based behavioral measures reveal poorer spatial resolution of sound sources, but only for high-frequency sound stimuli. Finally, single-unit recordings of auditory midbrain neurons reveal significantly poorer neural acuity to a sound location cue that largely depends on high-frequency sounds. Thus, these findings show that unilateral deprivation can disrupt developing auditory circuits that integrate binaural information and may give rise to lingering spatial hearing deficits.

Dynamic population coding of social novelty in the insular cortex
The familiarity of socially interacting peers has a profound impact on behavior, but little is known about the neuronal representations distinguishing familiar from novel conspecifics. The insular cortex (IC) regulates social behavior, and our previous study revealed that neurons in the agranular IC (aIC) encode ongoing social interactions. To elucidate how these neurons discriminate between interactions with familiar and novel conspecifics, we monitored neuronal activity in mice by microendoscopic calcium imaging during social recognition memory (SRM) and linear chamber social discrimination (LCSD) tasks. In the SRM task, repeated interactions with the same target activated largely nonoverlapping cells during each session. The fraction of cells associated with social investigation (social cells) decreased as the subject repeatedly interacted with the same target, whereas substitution of a second novel target and subsequent exchange with the first familiar target recruited more new social cells. In the LCSD task, the addition of a novel target to an area containing a familiar target transiently increased the number of cells responding to both targets, followed by an eventual increase in the number of cells responding to the novel target. These results support the view that the aIC dynamically encodes social novelty, rather than consistently encode social identity, by rapidly reorganizing the neural representations of conspecific information.

Sexual representation of social memory in the ventral CA1 neurons
Recognizing familiar individuals is crucial for adaptive social interactions among animals. However, the multidimensional nature of social memory encompassing sexual information remains unelucidated. We found that neurons in the ventral CA1 region (vCA1) of the mouse hippocampus encoded the identities and social properties, specifically sex and strain, of familiar conspecifics by using both rate and theta-based temporal coding. Optogenetic reactivation of social memories of females, but not males, induced place preference. Ablation of the upstream medial amygdala (MeA) or the hippocampal dorsal CA2 region (dCA2) disrupted the representation of sex and the sexual dimorphism of social memory valence. Selective reactivation of overlapping neural populations of distinct female social memories representing the female sex was sufficient to induce preference. Thus, vCA1 neurons employ dual coding schemes to represent the identities and social properties of familiar conspecifics as a cohesive memory.

Extending tactile space with hand-held tools: A re-analysis and review
Tools can extend the sense of touch beyond the body, allowing the user to extract sensory information about distal objects in their environment. Though research on this topic has trickled in over the last few decades, little is known about the neurocomputational mechanisms of extended touch. In 2016, along with our late collaborator Vincent Hayward, we began a series of studies that attempted to fill this gap. We specifically focused on the ability to localize touch on the surface of a rod, as if it were part of the body. We have conducted eight behavioral experiments over the last several years, all of which have found that humans are incredibly accurate at tool-extended tactile localization. In the present article, we perform a model-driven reanalysis of these findings with an eye towards estimating the underlying parameters that map sensory input into spatial perception. This reanalysis revealed that users can almost perfectly localize touch on hand-held tools. This raises the question of how humans can be so good at localizing touch on an inert non-corporeal object. The remainder of the paper focuses on three aspects of this process that occupied much of our collaboration with Vincent: the mechanical information used by participants for localization; the speed by which the nervous system can transform this information into a spatial percept; and whether body-based computations are repurposed for tool-extended touch. In all, these studies underscore the special relationship between bodies and tools.

Changes in taste palatability across the estrous cycle are modulated by hypothalamic estradiol signaling
Food intake varies across the stages of a rat's estrous cycle. It is reasonable to hypothesize that this cyclic fluctuation in consumption reflects an impact of hormones on taste palatability/preference, but evidence for this hypothesis has been mixed, and critical within-subject experiments in which rats sample multiple tastes during each of the four main estrous phases (metestrus, diestrus, proestrus, and estrus) have been scarce. Here, we assayed licking for pleasant (sucrose, NaCl, saccharin) and aversive (quinine-HCl, citric acid) tastes each day for 5-10 days while tracking rats' estrous cycles through vaginal cytology. Initial analyses confirmed the previously-described increased consumption of pleasant stimuli 24-48 hours following the time of high estradiol. A closer look, however, revealed this effect to reflect a general magnification of palatability -- higher than normal preferences for pleasant tastes and lower than normal preferences for aversive tastes -- during metestrus. We hypothesized that this phenomenon might be related to estradiol processing in the lateral hypothalamus (LH), and tested this hypothesis by inhibiting LH estrogen receptor activity with ICI182,780 during tasting. Control infusions replicated the metestrus magnification of palatability pattern; ICI infusions blocked this effect as predicted, but failed to render preferences "cycle free," instead delaying the palatability magnification until diestrus. Clearly, estrous phase mediates details of taste palatability in a manner involving hypothalamic actions of estradiol; further work will be needed to explain the lack of a flat response across the cycle with hypothalamic estradiol binding inhibited, a result which perhaps suggests dynamic interplay between brain regions or hormones.

State-specific inhibition of NMDA receptors by memantine depends on intracellular calcium and provides insights into NMDAR channel blocker tolerability
NMDA receptors (NMDARs) are key mediators of neuronal Ca2+ influx. NMDAR-mediated Ca2+ influx plays a central role in synaptogenesis, synaptic plasticity, dendritic integration, and neuronal survival. However, excessive NMDAR-mediated Ca2+ influx initiates cellular signaling pathways that result in neuronal death and is broadly associated with neurological disease. Drugs targeting NMDARs are of great clinical interest, but widespread alteration of NMDAR activity can generate negative side effects. The NMDAR channel blocker memantine is a well-tolerated Alzheimer's disease medication that shows promise in treatment of other neurological disorders. Memantine enhances desensitization of NMDARs in a subtype- and Ca2+-dependent manner, thereby more effectively inhibiting NMDARs on neurons that experience increased buildup of intracellular Ca2+. However, little is known about the properties or implications of the interaction between intracellular Ca2+ and NMDAR inhibition by memantine or other NMDAR channel blockers. Utilizing customized Ca2+ buffering solutions and whole-cell patch-clamp recordings, we demonstrated that memantine inhibition of both recombinant and native NMDARs increases with increasing intracellular Ca2+ and that the effect of intracellular Ca2+ on memantine action depends on NMDAR subtype. Neuroprotection assays and recordings of postsynaptic currents revealed that memantine preferentially inhibits NMDARs under neurotoxic conditions whereas ketamine, a clinically useful NMDAR channel blocker with strong side effects, inhibits strongly across contexts. Our results present a previously unexamined form of state-specific antagonism, Ca2+-dependent NMDAR channel block, that could have a profound impact on the design of drugs that selectively target NMDAR subpopulations involved in disease.

Cell type specific firing patterns in a V1 cortical column model depend on feedforward and feedback activity
Stimulation of specific cell groups under different network regimes (e.g., spontaneous activity or sensory-evoked activity) can provide insights into the neural dynamics of cortical columns. While these protocols are challenging to perform experimentally, modelling can serve as a powerful tool for such explorations. Using detailed electrophysiological and anatomical data from mouse V1, we modeled a spiking network model of the cortical column microcircuit. This model incorporates pyramidal cells and three distinct interneuron types (PV, SST, and VIP cells, specified per lamina), as well as the dynamic and voltage-dependent properties of AMPA, GABA, and NMDA receptors. We first demonstrate that thalamocortical feedforward (FF) and feedback (FB) stimuli arriving in the column have opposite effects, leading to net columnar excitation and inhibition respectively and revealing translaminar gain control via full-column inhibition by layer 6. We then perturb one cell group (defined by a cell type in a specific layer) at a time and observe the effects on other cell groups under distinct network states: spontaneous, feedforward-driven, feedback-driven, and a combination of feedforward and feedback. Our findings reveal that when the same group is perturbed, the columnar response may vary significantly based on its state, with strong sensory feedforward input decreasing columnar sensitivity to all perturbations and feedback input serving as modulator of intra columnar interactions. Given that activity changes within specific neuronal populations are difficult to predict a priori and considering the practical challenges of conducting experiments, our computational simulations can serve as a critical tool to predict outcomes of perturbations and assist in the design of future experimental planning.

Photophysics-informed two-photon voltage imaging using FRET-opsin voltage indicators
Microbial rhodopsin-derived genetically encoded voltage indicators (GEVIs) are powerful tools for mapping bioelectrical dynamics in cell culture and in live animals. Forster resonance energy transfer (FRET)-opsin GEVIs use voltage-dependent changes in opsin absorption to modulate the fluorescence of an attached fluorophore, achieving high brightness, speed, and voltage sensitivity. However, the voltage sensitivity of most FRET-opsin GEVIs has been reported to decrease or vanish under two-photon (2P) excitation. Here we investigated the photophysics of the FRET-opsin GEVIs Voltron1 and 2. We found that the voltage sensitivity came from a photocycle intermediate, not from the opsin ground state. The voltage sensitivities of both GEVIs were nonlinear functions of illumination intensity; for Voltron1, the sensitivity reversed sign under low-intensity illumination. Using photocycle-optimized 2P illumination protocols, we demonstrate 2P voltage imaging with Voltron2 in barrel cortex of a live mouse. These results open the door to high-speed 2P voltage imaging of FRET-opsin GEVIs in vivo.

A pathogenic role for IL-10 signalling in capillary stalling and cognitive impairment in type 1 diabetes
Vascular pathology is associated with cognitive impairment in diseases such as type 1 diabetes, but precisely how capillary flow is affected and the underlying mechanisms remain elusive. Here we show that capillaries in the diabetic mouse brain are prone to stalling, with blocks composed primarily of erythrocyte plugs in branches off penetrating venules. Increased capillary obstructions were evident in both sexes and only partially reversed by insulin. Screening for circulating inflammatory cytokines revealed persistently high levels of interleukin-10 (IL-10) in diabetic mice. Contrary to expectation, stimulating IL-10 signalling increased capillary obstructions, whereas inhibiting IL-10 receptors with neutralizing antibodies or endothelial specific knockdown in diabetic mice, reversed these impairments. Chronic IL-10R blocking antibody treatment in diabetic mice also improved stimulus evoked cerebral blood flow, increased capillary widths in lower-order branches and reversed cognitive deficits. These data suggest IL-10 signalling plays an unexpected pathogenic role in cerebral microcirculatory defects and cognitive impairment.

Dissecting Reactive Astrocyte Responses: Lineage Tracing and Morphology-based Clustering
Brain damage triggers diverse cellular and molecular events, with astrocytes playing a crucial role in activating local neuroprotective and reparative signaling within damaged neuronal circuits. Here, we investigated reactive astrocytes using a multidimensional approach to categorize their responses into different subtypes based on morphology using the StarTrack lineage tracer, single-cell imaging reconstruction and multivariate data analysis. Our findings revealed three profiles of reactive astrocyte responses affecting cell size- and shape- related morphological parameters: "moderate," "strong," and "very strong". We also explored the heterogeneity in astrocyte reactivity, with a particular emphasis in the spatial and clonal distribution. Our research highlights the importance of the relationships between the different astrocyte subpopulations with their reactive responses, showing an enrichment of protoplasmic and fibrous astrocytes within the "strong" and "very strong" subtypes. Overall, our study contributes to a better understanding of astrocyte heterogeneity in response to an injury. By elucidating the diverse reactive responses among astrocyte subpopulations, we pave the way for future research aimed at uncovering novel therapeutic targets for mitigating the effects of brain damage and promoting neural repair.

Computational Mechanisms of Neuroimaging Biomarkers Uncovered by Multicenter Resting-State fMRI Connectivity Variation Profile
Resting-state functional connectivity (rsFC) is increasingly used to develop biomarkers for psychiatric disorders. Despite progress, development of the reliable and practical FC biomarker remains an unmet goal, particularly one that is clinically predictive at the individual level with generalizability, robustness, and accuracy. In this study, we propose a new approach to profile each connectivity from diverse perspective, encompassing not only disorder-related differences but also disorder-unrelated variations attributed to individual difference, within-subject across-runs, imaging protocol, and scanner factors. By leveraging over 1500 runs of 10-minute resting-state data from 84 traveling-subjects across 29 sites and 900 participants of the case-control study with three psychiatric disorders, the disorder-related and disorder-unrelated FC variations were estimated for each individual FC. Using the FC profile information, we evaluated the effects of the disorder-related and disorder-unrelated variations on the output of the multi-connectivity biomarker trained with ensemble sparse classifiers and generalizable to the multicenter data. Our analysis revealed hierarchical variations in individual functional connectivity, ranging from within-subject across-run variations, individual differences, disease effects, inter-scanner discrepancies, and protocol differences, which were drastically inverted by the sparse machine-learning algorithm. We found this inversion mainly attributed to suppression of both individual difference and within-subject across-runs variations relative to the disorder-related difference by weighted-averaging of the selected FCs and ensemble computing. This comprehensive approach will provide an analytical tool to delineate future directions for developing reliable individual-level biomarkers.

The Role of Cilia in the Development, Survival, and Regeneration of Hair Cells
Mutations impacting cilia genes lead to a class of human diseases known as ciliopathies. This is due to the role of cilia in the development, survival, and regeneration of many cell types. We investigated the extent to which disrupting cilia impacted these processes in hair cells. We found that mutations in two intraflagellar transport (IFT) genes, ift88 and dync2h1, which lead to the loss of kinocilia, the primary cilia of hair cells, caused an increase in hair cell apoptosis in the zebrafish lateral line. These IFT gene mutants show a decreased mitochondrial membrane potential, and blocking the mitochondrial uniporter causes a loss of hair cells in wild-type zebrafish but not in IFT gene mutants. This suggests mitochondria dysfunction may contribute to the apoptosis seen in these mutants. In contrast to its role in hair cell survival, dync2h1 does not appear important for proliferation during hair cell development, but ift88 may be. There is also a reduction in both proliferation and the number of hair cells after regeneration in both IFT gene mutants. These results show that disruption of the cilia through either mutations in anterograde or retrograde IFT genes appear to decrease hair cell survival and regeneration in the lateral line, with ift88 specifically, potentially playing an additional role in hair cell development.

Recurrent issues with deep neural networks of visual recognition
Object recognition requires flexible and robust information processing, especially in view of the challenges posed by naturalistic visual settings. The ventral stream in visual cortex is provided with this robustness by its recurrent connectivity. Recurrent deep neural networks (DNNs) have recently emerged as promising models of the ventral stream. In this study, we asked whether DNNs could be used to explore the role of different recurrent computations during challenging visual recognition. We assembled a stimulus set that included manipulations that are often associated with recurrent processing in the literature, like occlusion, partial viewing, clutter, and spatial phase scrambling. We obtained a benchmark dataset from human participants performing a categorisation task on this stimulus set. By applying a wide range of model architectures to the same task, we uncovered a nuanced relationship between recurrence, model size, and performance. While recurrent models reach higher performance than their feedforward counterpart, we could not dissociate this improvement from that obtained by increasing model size. We found consistency between humans and models patterns of difficulty across the visual manipulations, but this was not modulated in an obvious way by the specific type of recurrence or size added to the model. Finally, depth/size rather than recurrence makes model confusion patterns more human-like. Contrary to previous assumptions, our findings challenge the notion that recurrent models are better models of human recognition behaviour than feedforward models, and emphasise the complexity of incorporating recurrence into computational models.

Enhancing altruism by electrically augmenting frontoparietal gamma-band phase coupling
Cooperation, productivity, and cohesion in human societies depend on altruism, the tendency to share resources with others even though this is costly. While altruism is a widely shared social norm, people vary strongly in their inclination to behave altruistically, in particular across situations with different types of inequality in resource distribution. What neurobiological factors underlie this variability? And can these be targeted by interventions to enhance altruistic behavior? Here, we build on recent EEG findings that altruistic choices during disadvantageous inequality correlate with oscillatory gamma-band coherence between frontal regions (representing other's interest) and parietal regions (representing neural evidence accumulation). We apply a transcranial alternating current stimulation (tACS) protocol designed to exogenously enhance this fronto-parietal coherence and find that this leads to increased altruism, specifically during disadvantageous inequality as hypothesized based on the EGG findings. Computational modeling reveals that this transcranial entrainment does not just add noise to the decision process but specifically increases the weight individuals assign to other-regarding concerns during choices. Our findings show that altruism can be enhanced by neurostimulation designed to enhance oscillatory synchronization between frontal and parietal areas. This establishes a neural basis for altruism and identifies a neural target for interventions aimed at improving prosocial behavior.

RosetteArray Platform for Quantitative High-Throughput Screening of Human Neurodevelopmental Risk
Neural organoids have revolutionized how human neurodevelopmental disorders (NDDs) are studied. Yet, their utility for screening complex NDD etiologies and in drug discovery is limited by a lack of scalable and quantifiable derivation formats. Here, we describe the RosetteArray platform's ability to be used as an off-the-shelf, 96-well plate assay that standardizes incipient forebrain and spinal cord organoid morphogenesis as micropatterned, 3-D, singularly polarized neural rosette tissues (>9000 per plate). RosetteArrays are seeded from cryopreserved human pluripotent stem cells, cultured over 6-8 days, and immunostained images can be quantified using artificial intelligence-based software. We demonstrate the platform's suitability for screening developmental neurotoxicity and genetic and environmental factors known to cause neural tube defect risk. Given the presence of rosette morphogenesis perturbation in neural organoid models of NDDs and neurodegenerative disorders, the RosetteArray platform could enable quantitative high-throughput screening (qHTS) of human neurodevelopmental risk across regulatory and precision medicine applications.

Age-dependent regulation of axoglial interactions and behavior by oligodendrocyte AnkyrinG
The bipolar disorder (BD) risk gene ANK3 encodes the scaffolding protein AnkyrinG (AnkG). In neurons, AnkG regulates polarity and ion channel clustering at axon initial segments and nodes of Ranvier. Disruption of neuronal AnkG causes BD-like phenotypes in mice. During development, AnkG is also expressed at comparable levels in oligodendrocytes and facilitates the efficient assembly of paranodal junctions. However, the physiological roles of glial AnkG in the mature nervous system, and its contributions to BD-like phenotypes, remain unexplored. Here, we generated oligodendroglia-specific AnkG conditional knockout mice and observed the destabilization of axoglial interactions in aged but not young adult mice. In addition, these mice exhibited profound histological, electrophysiological, and behavioral pathophysiologies. Unbiased translatomic profiling revealed potential compensatory machineries. These results highlight the critical functions of glial AnkG in maintaining proper axoglial interactions throughout aging and suggests a previously unrecognized contribution of oligodendroglial AnkG to neuropsychiatric disorders.

Acute and Chronic Neural and Glial Response to Mild Traumatic Brain Injury in the Hippocampus
Traumatic brain injury (TBI) is an established risk factor for developing neurodegenerative disease. However, how TBI leads from acute injury to chronic neurodegeneration is limited to post-mortem models. There is a lack of connections between in vitro and in vivo TBI models that can relate injury forces to both macroscale tissue damage and brain function at the cellular level. Needle-induced cavitation (NIC) is a technique that can produce small cavitation bubbles in soft tissues, which allows us to relate small strains and strain rates in living tissue to ensuing acute and chronic cell death, tissue damage, and tissue remodeling. Here, we applied NIC to mouse brain slices to create a new model of TBI with high spatial and temporal resolution. We specifically targeted the hippocampus, which is a brain region critical for learning and memory and an area in which injury causes cognitive pathologies in humans and rodent models. By combining NIC with patch-clamp electrophysiology, we demonstrate that NIC in the Cornu Ammonis (CA)3 region of the hippocampus dynamically alters synaptic release onto CA1 pyramidal neurons in a cannabinoid 1 receptor (CB1R)-dependent manner. Further, we show that NIC induces an increase in extracellular matrix proteins associated with neural repair that is mitigated by CB1R antagonism. Together, these data lay the groundwork for advanced approaches in understanding how TBI impacts neural function at the cellular level, and the development of treatments that promote neural repair in response to brain injury.

During haptic communication, the central nervous system compensates distinctly for delay and noise
Connected humans have been previously shown to exploit the exchange of haptic forces and tactile information to improve their performance in joint action tasks. As human interactions are increasingly mediated through robots and networks it is important to understand the impact that network features such as lag and noise may have on human behaviour. In this paper, we investigated the interaction with a human-like robot controller that provides similar haptic communication behaviour as human-human interaction and examined the influence and compensation mechanisms for delay and noise on haptic communication. The results of our experiments show that participants can distinguish between noise and delay, and make use of compensation mechanisms to preserve performance in both cases. However, while noise is compensated for by increasing co-contraction, delay compensation could not be explained by this strategy. Instead, computational modelling suggested that a feed-forward prediction mechanism is used to compensate for the temporal delay and yield an efficient haptic communication.

Perceptual Resolution of Ambiguity: Can Tuned, Divisive Normalization Account for both Interocular Similarity Grouping and Difference Enhancement
Our visual system usually provides a unique and functional representation of the external world. At times, however, the visual system has more than one compelling interpretation of the same retinal stimulus; in this case, neural populations compete for perceptual dominance to resolve ambiguity. Spatial and temporal context can guide perceptual experience. Recent evidence shows that ambiguous retinal stimuli are sometimes resolved by enhancing either similarity or differences among multiple percepts. Divisive normalization is a canonical neural computation that enables context-dependent sensory processing by attenuating a neuron's response by other neurons. Experiments here show that divisive normalization can account for perceptual representations of either similarity enhancement (so-called grouping) or difference enhancement, offering a unified framework for opposite perceptual outcomes.

Cardiovascular and vasomotor pulsations in the brain and periphery during awake and NREM sleep in a multimodal fMRI study
The glymphatic brain clearance mechanism convects brain cerebrospinal fluid driven by physiological pulsations such as cardiovascular and very low-frequency (VLF < 0.1 Hz) vasomotor waves. Presently, ultrafast functional magnetic resonance imaging (fMRI) facilitates the measurement of these signals from both venous and arterial compartments. In this study, we compared the interaction of these two pulsations in awake and sleep using fMRI and peripheral fingertip photoplethysmography in both arterial and venous signals in ten subjects (5 female). Sleep increased the power of brain cardiovascular pulsations, decreased peripheral pulsation and desynchronized them. Vasomotor waves, however, increase in both power and synchronicity in brain and peripheral signals during sleep. Peculiarly, vasomotor lag reversed in sleep within the default mode network vs. peripheral signal. Finally, sleep synchronized cerebral arterial vasomotion measured with cardiovascular hemodynamic envelope (CHe) vs. venous blood oxygenation level dependent (BOLD) signals in parasagittal brain tissue. These changes in power and pulsation synchrony may reflect differential changes in vascular control between the periphery and brain vasculature, while the increased synchrony of arterial and venous compartments may reflect increased convection of neurofluids in parasagittal areas in sleep.

Morphological and functional convergence of visual projections neurons from diverse neurogenic origins in Drosophila
The Drosophila visual system is a powerful model to study the development of neural circuits. Projection neurons that relay visual information from the lobula part of the optic lobe to the central brain (the lobula columnar neurons-LCNs), are thought to encode different visual features relevant to natural behavior. There are ~20 classes of LCNs whose projections form highly specific, non-overlapping synaptic domains in the brain called optic glomeruli. Although functional investigations of several LCN circuits have been carried out, very little is known about their developmental origin and the stem cell lineages that generate the LCN subtypes. To address their origin, we used single-cell mRNA sequencing to define the transcriptome of each LCN subtype and identified driver lines that are expressed in specific LCNs throughout development. We show that LCNs originate from neural stem cells in four distinct regions in the fly brain that exhibit different modes of neurogenesis, including the ventral and dorsal tips of the outer proliferation center (tOPC), the ventral tips of the inner proliferation center (vtIPC) and the central brain (CB). This convergence of similar neurons illustrates the complexity of generating neuronal diversity in the brain and likely reflects the evolutionary origin of each LCN subtype that detects a highly specific visual feature and influence behaviors that might be specific to each species.

The MET growth signaling complex drives Alzheimers Disease-associated brain pathology in aged Shugoshin 1 mouse cohesinopathy model
The understanding on molecular processes toward Late-onset Alzheimers Disease (LOAD) has been insufficient to design LOAD intervention drugs. Previously, we discovered transgenic genomic instability model mice Sgo1-/+ accumulate cerebral amyloid-beta in old age. We pro-posed the amyloid-beta accumulation cycle hypothesis, in which cytotoxic, mitogenic and aneuploidgenic amyloid can create an autonomous mitotic cycle leading to accumulation of itself. However, the nature of the growth signaling that drives cells toward pathogenic mitotic cycle remained unidentified. In this study, we hypothesized that the aged Sgo1-/+ mice brains would show signs of mitogenic signaling activation, and searched for growth signaling activated in the vicinity of amyloid-beta, with spatial analysis on the cortex and hippocampus of Sgo1-/+ mice in middle-age and old-age. The analysis indicated activations of kinase signaling p42/44 MAPK ERK1/2, AMPK, JNK, Wnt signaling via GSK3 inactivation, as well as increases of p-TAU and other AD biomarkers, PLCG1, EGFR, MET, Neurofibromin and RAS. Immune activation markers CD45 and CD31 were also elevated in the microenvironment. A majority of activated growth signaling components are of the oncogenic MET signaling complex. The discovery supports re-purposing of cancer drugs targeting the MET signaling complex and EGFR-RAS-MAPK axis for intervention and/or treatment of genomic instability-driven AD.

Probiotic treatment causes sex-specific neuroprotection after traumatic brain injury in mice
Background: Recent studies have shed light on the potential role of gut dysbiosis in shaping traumatic brain injury (TBI) outcomes. Changes in the levels and types of Lactobacillus bacteria present might impact the immune system disturbances, neuroinflammatory responses, anxiety and depressive-like behaviors, and compromised neuroprotection mechanisms triggered by TBI. Objective: This study aimed to investigate the effects of a daily pan-probiotic (PP) mixture in drinking water containing strains of Lactobacillus plantarum, L. reuteri, L. helveticus, L. fermentum, L. rhamnosus, L. gasseri, and L. casei, administered for either two or seven weeks before inducing TBI on both male and female mice. Methods: Mice were subjected to controlled cortical impact (CCI) injury. Short-chain fatty acids (SCFAs) analysis was performed for metabolite measurements. The taxonomic profiles of murine fecal samples were evaluated using 16S rRNA V1-V3 sequencing analysis. Histological analyses were used to assess neuroinflammation and gut changes post-TBI, while behavioral tests were conducted to evaluate sensorimotor and cognitive functions. Results: Our findings suggest that PP administration modulates the diversity and composition of the microbiome and increases the levels of SCFAs in a sex-dependent manner. We also observed a reduction of lesion volume, cell death, and microglial and macrophage activation after PP treatment following TBI in male mice. Furthermore, PP-treated mice show motor function improvements and decreases in anxiety and depressive-like behaviors. Conclusion: Our findings suggest that PP administration can mitigate neuroinflammation and ameliorate motor and anxiety and depressive-like behavior deficits following TBI. These results underscore the potential of probiotic interventions as a viable therapeutic strategy to address TBI-induced impairments, emphasizing the need for gender-specific treatment approaches.

Human intralaminar and medial thalamic nuclei transiently gate conscious perception through the thalamocortical loop
Human high-order thalamic nuclei have been known to closely correlate with conscious states. However, given the great difference of conscious states and contents (conscious perception), it is nearly unknown how those thalamic nuclei and thalamocortical interactions directly contribute to the transient process of conscious perception. To address this question, we simultaneously recorded local field potentials (LFP) in the human intralaminar, medial and ventral thalamic nuclei as well as in the prefrontal cortex (PFC), while patients with implanted electrodes performing a visual consciousness task. Overall, compared to the ventral nuclei, intralaminar and medial nuclei showed earlier and stronger consciousness-related activity. Moreover, the transient thalamocortical neural synchrony and cross-frequency coupling were both driven by the theta phase of the intralaminar and medial nuclei during conscious perception. These results indicated that the intralaminar and medial thalamic nuclei, rather than the commonly believed PFC, play a decisive gate role in conscious perception.

TAU FILAMENTS WITH THE CHRONIC TRAUMATIC ENCEPHALOPATHY FOLD IN A CASE OF VACUOLAR TAUOPATHY WITH VCP MUTATION D395G
Dominantly inherited mutation D395G in the gene encoding valosin-containing protein causes vacuolar tauopathy, a type of behavioural-variant frontotemporal dementia, with marked vacuolation and abundant filamentous tau inclusions made of all six brain isoforms. Here we report that tau inclusions were concentrated in layers II/III of the frontotemporal cortex in a case of vacuolar tauopathy. By electron cryo-microscopy, tau filaments had the chronic traumatic encephalopathy (CTE) fold. Tau inclusions of vacuolar tauopathy share this cortical location and the tau fold with CTE, subacute sclerosing panencephalitis and amyotrophic lateral sclerosis/parkinsonism-dementia complex, which are believed to be environmentally induced. Vacuolar tauopathy is the first inherited disease with the CTE tau fold.

The cytokine receptor Fn14 is a molecular brake on neuronal activity that mediates circadian function in vivo
To survive, organisms must adapt to a staggering diversity of environmental signals, ranging from sensory information to pathogenic infection, across the lifespan. At the same time, organisms intrinsically generate biological oscillations, such as circadian rhythms, without input from the environment. While the nervous system is well-suited to integrate extrinsic and intrinsic cues, how the brain balances these influences to shape biological function system-wide is not well understood at the molecular level. Here, we demonstrate that the cytokine receptor Fn14, previously identified as a mediator of sensory experience-dependent synaptic refinement during brain development, regulates neuronal activity and function in adult mice in a time-of-day-dependent manner. We show that a subset of excitatory pyramidal (PYR) neurons in the CA1 subregion of the hippocampus increase Fn14 expression when neuronal activity is heightened. Once expressed, Fn14 constrains the activity of these same PYR neurons, suggesting that Fn14 operates as a molecular brake on neuronal activity. Strikingly, differences in PYR neuron activity between mice lacking or expressing Fn14 were most robust at daily transitions between light and dark, and genetic ablation of Fn14 caused aberrations in circadian rhythms, sleep-wake states, and sensory-cued and spatial memory. At the cellular level, microglia contacted fewer, but larger, excitatory synapses in CA1 in the absence of Fn14, suggesting that these brain-resident immune cells may dampen neuronal activity by modifying synaptic inputs onto PYR neurons. Finally, mice lacking Fn14 exhibited heightened susceptibility to chemically induced seizures, implicating Fn14 in disorders characterized by hyperexcitation, such as epilepsy. Altogether, these findings reveal that cytokine receptors that mediates inflammation in the periphery, such as Fn14, can also play major roles in healthy neurological function in the adult brain downstream of both extrinsic and intrinsic cues.