bioRxiv Subject Collection: Neuroscience's Journal

Anodal tsDCS restores the structure and function of the disrupted proprioceptive Ia synapses on spinal motoneurons in the SOD1 G93A mouse model of ALS
An imbalance between cells' intrinsic excitability and synaptic excitation levels is the basis of spinal motoneuron (MN) pathophysiology in Amyotrophic Lateral Sclerosis. Recently, a restoration of the deficient Ia synaptic excitation of spinal MNs was achieved by applying acute trans-spinal direct current stimulation (tsDCS) to presymptomatic SOD1 G93A mice. Here we investigate whether two-week repeated tsDCS applied to presymptomatic SOD1 animals can provoke spinal MN neuroplasticity and reduce the disease burden. Anodal, cathodal or sham polarisation of 100 microA was applied to P30-P35 SOD1 G93A mice; passive membrane properties and Ia excitatory post-synaptic potential (EPSP) characteristics were investigated by intracellular recordings of spinal MNs in vivo. A second cohort of polarized animals was used to test the impact of our intervention on Ia synapse morphology, MN intracellular metabolic pathways activity, and disease markers. Anodal tsDCS evoked a strong increase in maximal Ia EPSPs, coupled with a significant upregulation of vesicular glutamate transporter levels and GlurR4 subunits of AMPA receptors at the Ia synapse. On the other hand, cathodal polarisation failed to induce any significant alteration to Ia synapse morphology but did increase both peak and plateau input resistance and recovered the abnormal paired-pulse ratio. Unexpectedly, the changes in MN electrophysiological profile and Ia synapse morphology did not translate into alterations of intracellular pathways activity and did not decrease the disease burden. Altogether our results indicate a strong polarity-dependent plasticity of spinal MNs in SOD1 G93A mice in response to tsDCS, which nevertheless appears insufficient to alter disease dynamics.

Temporal kinetics of brain state effects on visual perception
We investigated the effects of brain states on human perception and early visual response comparing focused wakefulness (ON state) to external inattention (OFF state). In two experiments, we investigated the temporal kinetics of brain states changes during stimulus processing and assessed fluctuations across extended periods of time. We used a classifier to distinguish between these states on a single trial level using theta activity in MEG sensors. We found that participants shifted from an ON to an OFF state as rapidly as two seconds. Visual target discrimination was comparable in both states, but reaction times were slower and more variable during the OFF state. Broad band high-frequency activity (BHA) recorded in MEG sensors covering the occipital cortex tracked target grating orientation. BHA was reduced during the OFF state but participants were still able to distinguish sensory information highlighting the role of BHA in visual perception across cognitive brain states.

Minimally invasive activation of spared interneurons alleviates local CA1 hypersynchrony and behavioral deficits in a model of temporal lobe epilepsy
Background: Temporal lobe epilepsy (TLE) is associated with severe cognitive impairments including memory deficits. The dysfunction of hippocampal inhibitory neurons is proposed as a key mechanism and possible target for therapeutic approaches. However, the nature and extent of alterations in hippocampal inhibitory neurons remain unclear, as does their impact on behavioral impairments associated with TLE. Methods: We investigated the role of inhibitory neurons from the CA1 hippocampal region on memory deficits associated with TLE, considering both the survival and changes in the activity of a large population of interneurons. To this end, we used a combination of immunolabelling, calcium imaging, electrophysiology, human-applicable chemogenetic tools, and behavioral testing on a reliable mouse pilocarpine TLE model. Results: We show that in TLE mice with severely disturbed spatial behavior, CA1 major interneuron populations are spared from histological damages that affect the epileptic hippocampus (e.g., sclerosis). However, CA1 interneurons fire less in epileptic than in control conditions, resulting in increased synchronization and activity of the epileptic CA1 network in vitro. Restoring CA1 interneuron discharge using a chemogenetic strategy rescued CA1 activity and synchronization in vitro. In vivo, the minimally invasive chemogenetic activation of hippocampal interneurons does not affect generalized seizures but reduces behavioral alterations. Conclusions: Our data suggest that rescuing CA1 local network dynamics using interneurons as a lever could be sufficient to decrease behavioral deficits related to TLE.

VR HMD color calibration and accurate control of emitted light using Three.js
Virtual Reality (VR) can be used to design and create new types of psychophysical experiments. Its main advantage is that it frees us from the physical limitations of real-life experiments and the hardware and software limitations of experiments running on 2D displays and computer graphics. However, color calibration of the displays is often required in vision science studies. Recent studies have shown that a standard color calibration of a Head-Mounted Display (HMD) can be very challenging and comes with significant drawbacks. In this paper, we introduce a new approach that allows for successful color calibration of an HMD and overcomes the disadvantages associated with other solutions. We utilize a new VR engine, Three.js, which offers several advantages. This paper details our setup and methodology, and provides all the elements required to reproduce the method, including the source code. We also apply our method to evaluate and compare three different HMDs: HTC Vive Pro Eye, Meta Quest Pro, and Meta Quest 3. The results show that the HTC Vive Pro Eye performs excellently, the Meta Quest Pro performs well, and the Meta Quest 3 performs poorly.

Bridging tuning and invariance with equivariant neuronal representations
As we move through the world, we see the same visual scenes from different perspectives. Although we experience perspective deformations, our perception of a scene remains stable. This raises the question of which neuronal representations in visual brain areas are perspective-tuned and which are invariant. Focusing on planar rotations, we introduce a mathematical framework based on the principle of equivariance, which asserts that an image rotation results in a corresponding rotation of neuronal representations, to explain how the same representation can range from being fully tuned to fully invariant. We applied this framework to large-scale simultaneous neuronal recordings from four visual cortical areas in mice, where we found that representations are both tuned and invariant but become more invariant across higher-order areas. While common deep convolutional neural networks show similar trends in orientation-invariance across layers, they are not rotation-equivariant. We propose that equivariance is a prevalent computation of populations of biological neurons to gradually achieve invariance through structured tuning.

Constraint Induced Movement Therapy Confers only a Transient Behavioral Benefit but Enduring Functional Circuit-Level Changes after Experimental TBI.
Although the behavioral outcome of Constraint-Induced Movement Therapy (CIMT) is well known, and that a combination of CIMT and arm use training potentiates the effect, there has been limited study of the brain circuits involved that respond to therapy. An understanding of CIMT from a brain network level would be useful for guiding the duration of effective therapy, the type of training regime to potentiate the outcome, as well as brain regional targets that might be amenable for direct neuromodulation. Here we investigated the effect of CIMT therapy alone unconfounded by additional rehabilitation training in order to determine the impact of intervention at the circuit level. Adult rats were injured by controlled cortical impact injury and studied before and then after 2wks of CIMT or noCIMT at 1-3wks post-injury using a combination of forelimb behavioral tasks and task-based and resting state functional magnetic resonance imaging at 3 and 7wks post-injury and compared to sham rats. There was no difference in behavior or functional imaging between CIMT and noCIMT after injury before intervention so that data are unlikely to be confounded by differences in injury severity. CIMT produced only a transient reduction in limb deficits compared to noCIMT immediately after the intervention, but no difference thereafter. However, CIMT resulted in a persistent reduction in contralesional limb-evoked activation and a corresponding ipsilesional cortical plasticity compared to noCIMT that endured 4wks after intervention. This was associated with a significant amelioration of intra and inter-hemispheric connectivity present in the noCIMT group at 7wks post-injury.

Geometry representations along visual pathways in human spatial navigation
The representation of geometric structures in the environments is key to self-localization during human spatial navigation. Its spatial organization in the visual system is not fully characterized. Using brain activity from 20 participants watching videos from identical realistic virtual environments under different weather and lighting conditions, we found a compact representation of scene geometric structures encoded in a large network of brain regions, allowing for reconstructing depth. It forms a continuous map composed of three parallel pathways that we jointly coin as "geometry visual pathways", starting from the primary visual cortex: the dorsal and medial pathways end in the intraparietal areas, while the ventral pathway arrives at the hippocampus via the parahippocampal gyrus. Furthermore, road types, a more abstract representation of geometry, are encoded in overlapping pathways excluding early visual cortex (V1, V2, V3). The geometry visual pathways provide new insights into the traditional dichotomy between "what" and "where" pathways.

Cortical Complexity Alterations in Motor Subtypes of Parkinson's Disease: A Surface-Based Morphometry Analysis of Fractal Dimension
Background: Based on motor symptoms, Parkinson's disease (PD) can be classified into tremor dominant (TD) and postural instability gait difficulty (PIGD) subtypes. This study aimed to investigate differences in cortical complexity and gray matter volume (GMV) between TD and PIGD. Methods: We enrolled 36 TD patients, 27 PIGD patients, and 66 healthy controls (HC) from the PPMI (Parkinson's Progression Markers Initiative) database. Voxel-based morphometry (VBM) and surface-based morphometry (SBM) were utilized to assess differences in GMV, cortical thickness, and cortical complexity. Additionally, correlations between clinical data and structural changes were examined. Results: In comparison with HCs, PIGD patients exhibited a significant fractal dimension (FD) decrease in many cortical regions, such as the bilateral insula, right superior temporal, and left rostral middle frontal. Moreover, PIGD patients showed significant FD reduction in various regions, including the left supramarginal gyrus, left lateral orbitofrontal gyrus, right superior temporal gyrus, left lateral occipital gyrus, and bilateral insula, compared to the TD group. A significant negative correlation between age and FD was observed in the left insula for the PIGD patients and in the bilateral insula for the TD patients. However, no significant differences were found in GMV, cortical thickness, or other complexity indices. Conclusion: Altered FD, particularly in bilateral insula, indicates that postural instability and gait disturbances in PD may result from a failure to integrate information from various structures, whereas parkinsonian tremor is not associated with this integration.

Understanding Electric Brain Stimulation Through the Reciprocity Theorem
Lee et al. recently reported robust, frequency-independent subthreshold membrane coupling to extracellular current stimulation across cell classes and brain regions, in both human and mice cortical slices. Specifically, small extracellular sinusoidal electrical stimulations (ES) at frequencies between 1-140 Hz induced a local oscillation in the extracellular potential, leading to sub-threshold (< 0.5 mV) sinusoidal potentials across the cell membrane of nearby cell bodies. Surprisingly, these induced changes in Vm did not decrease with frequency. This seems to imply that ES is a fundamentally different stimulus than equivalent intracellular stimulation that results in strong membrane filtering, caused by the frequency-dependent membrane capacitance. Here we would like to draw attention to the reciprocity theorem as a powerful and (to the best of our knowledge) as-of-yet-unused tool for understanding the effects of ES on neural dynamics, and this counterintuitive result in particular.

A dorsal hippocampus-prodynorphinergic dorsolateral septum-to-lateral hypothalamus circuit mediates contextual gating of feeding
Adaptive regulation of feeding depends on linkage of internal states and food outcomes with contextual cues. Human brain imaging has identified dysregulation of a hippocampal-lateral hypothalamic area (LHA) network in binge eating, but mechanistic instantiation of underlying cell-types and circuitry is lacking. Here, we identify an evolutionary conserved and discrete Prodynorphin (Pdyn)-expressing subpopulation of Somatostatin (Sst)-expressing inhibitory neurons in the dorsolateral septum (DLS) that receives primarily dorsal, but not ventral, hippocampal inputs. DLS(Pdyn) neurons inhibit LHA GABAergic neurons and confer context- and internal state-dependent calibration of feeding. Viral deletion of Pdyn in the DLS mimicked effects seen with optogenetic silencing of DLS Pdyn INs, suggesting a potential role for DYNORPHIN-KAPPA OPIOID RECEPTOR signaling in contextual regulation of food-seeking. Together, our findings illustrate how the dorsal hippocampus has evolved to recruit an ancient LHA feeding circuit module through Pdyn DLS inhibitory neurons to link contextual information with regulation of food consumption.

Generating Synthetic Task-based Brain Fingerprints for Population Neuroscience Using Deep Learning
Task-based functional magnetic resonance imaging (tb-fMRI) provides valuable insights into individual differences in the neural basis of cognitive functions because it links specific cognitive tasks to their evoked neural responses. Yet, it is challenging to scale to population-level data due to its cognitive demands, variations in task design across studies, and a limited number of tasks acquired in typical large-scale studies. Here, we present DeepTaskGen, a convolutional neural network (CNN) approach that enables us to generate synthetic task-based contrast maps from resting-state fMRI (rs-fMRI) data. Our method outperforms several benchmarks, exhibiting superior reconstruction performance while retaining inter-individual variation essential for biomarker development. We showcase DeepTaskGen by generating synthetic task images from the UK Biobank cohort, achieving competitive or greater performance compared to actual task contrast maps and resting-state connectomes for predicting a wide range of demographic, cognitive, and clinical variables. This approach will facilitate the study of individual differences and the generation of task-related biomarkers by enabling the generation of arbitrary functional cognitive tasks from readily available rs-fMRI data.

Integrated Single-Cell Multiomic Profiling of Caudate Nucleus Suggests Key Mechanisms in Alcohol Use Disorder
Alcohol use disorder (AUD) is likely associated with complex transcriptional alterations in addiction-relevant brain regions. We characterize AUD-associated differences in cell type-specific gene expression and chromatin accessibility in the caudate nucleus by conducting a single-nucleus RNA-seq assay and a single-nucleus RNA-seq + ATAC-seq (multiome) assay on caudate tissue from 143 human postmortem brains (74 with AUD). We identified 17 cell types. AUD was associated with a higher proportion of microglia in an activated state and more astrocytes in a reactive state. There was widespread evidence for differentially expressed genes across cell types with the most identified in oligodendrocytes and astrocytes, including genes involved in immune response and synaptic regulation, many of which appeared to be regulated in part by JUND and OLIG2. Microglia-astrocyte communication via interleukin-1 beta, and microglia-astrocyte-oligodendrocyte interaction via transforming growth factor beta 1 were increased in individuals with AUD. Expression quantitative trait loci analysis revealed potential driver genes of AUD, including ADAL, that may protect against AUD in medium spiny neurons and interneurons. This work provides a thorough profile of the effects of AUD in the human brain and identifies several promising genes for further study.

The interplay between motor cost and self-efficacy related to walking across terrain in gaze and walking decisions
Movement-related decisions, such as where to step and which path to take, happen throughout each day. Shifts in gaze serve to extract task-relevant information necessary to make these decisions. We are only beginning to appreciate the factors that affect this information-seeking gaze behaviour. Here, we aimed to determine how a person's belief in their ability to perform an action (i.e., self-efficacy) affected gaze and path choice when choosing between walking paths with different terrains and/or lengths (reflecting different energetic costs). We demonstrated that, when manipulated separately (i.e., paths had different lengths or different terrains), participants looked longer and more frequently and chose the paths with either less expected energetic cost or those for which they had a higher self-efficacy rating. When encountering environments where paths differed in both length and terrain, participants directed gaze progressively more to the longer path as the self-efficacy rating of this path increased and the disparity in rating with the shorter (less costly) path grew; they also chose the higher-rated path more frequently regardless of path length. These results provide evidence for a contribution of self-efficacy and energetic cost in guiding gaze and walking decisions. Interestingly, self-efficacy beliefs appear to play a more dominant role in both behaviours.

TAM receptors mediate the Fpr2-driven pain resolution and fibrinolysis after nerve injury
Nerve injury causes neuropathic pain and multilevel nerve barrier disruption. Nerve barriers consist of perineurial, endothelial, and myelin barriers. So far, it is unclear whether resealing nerve barriers fosters pain resolution and recovery. To this end, we analysed the nerve barrier property portfolio, pain behaviour battery, and lipidomics for precursors of specialized pro-resolving meditators (SPMs) and their receptors in chronic constriction injury of rat sciatic nerve to identify targets for pain resolution by resealing the selected nerve barriers. Of the three nerve barriers - perineurium, capillaries, and myelin - only capillary tightness specifically against larger molecules, such as fibrinogen, recuperated with pain resolution. Fibrinogen immunoreactivity was not only elevated in rats at the time of neuropathic pain but also in nerve biopsies from patients with (but not without) painful polyneuropathy indicating that sealing of the vascular barrier might be novel approach in pain treatment. 15R-HETE (hydroxyeicosatetraenoic acid), a precursor of aspirin-triggered lipoxin A4, were specifically upregulated at the beginning of pain resolution. Repeated local application of resolvin D1-laden nanoparticles or Fpr2 agonists sex-independently resulted in accelerated pain resolution and fibrinogen removal. Clearing macrophages (Cd206) and fibrinolytic pathways (Plat) were also induced while inflammation (Tnf) and inflammasomes (Nlrp3) were unaffected by this treatment. Blocking TAM receptors (Tyro3, Axl, and Mer) and tyrosine kinase receptors linking haemostasis and inflammation completely inhibited all the effects. In summary, nanoparticles can be used as transporters for fleeting lipids, such as SPMs, and therefore expand the array of possible therapeutic agents. Thus, the Fpr2-Cd206-TAM receptor axis may be a suitable target for strengthening the capillary barrier, removing endoneurial fibrinogen, and boosting pain resolution in patients with chronic neuropathic pain.

Dynamic adaptation to novelty in the brain is related to arousal and intelligence
How does the human brain respond to novelty? Here, we address this question using fMRI data wherein human participants watch the same movie scene four times. On the first viewing, this movie scene is novel, and on later viewings it is not. We find that brain activity is lower-dimensional in response to novelty. At a finer scale, we find that this reduction in the dimensionality of brain activity is the result of increased coupling in specific brain systems, most specifically within and between the control and dorsal attention systems. Additionally, we found that novelty induced an increase in between-subject synchronization of brain activity in the same brain systems. We also find evidence that adaptation to novelty, herein operationalized as the difference between baseline coupling and novelty-response coupling, is related to fluid intelligence. Finally, using separately collected out-of-sample data, we find that the above results may be linked to psychological arousal.

Synergistic control of axon regeneration and functional recovery by let-7 miRNA and Insulin signalling (IIs) pathways
The capability of neurons to regenerate after injury becomes poor in adulthood. Previous studies indicated that loss of either let-7 miRNA or components of Insulin signalling (IIs) can overcome the age-related decline in axon regeneration in C. elegans. In this study, we wanted to understand the relationship between these two pathways in axon regeneration. We found that the simultaneous removal of let-7 and the gene for insulin receptor daf-2 synergistically increased the functional recovery involving posterior touch sensation following axotomy of PLM neuron in adulthood. Conversely, the loss of let-7 could bypass the regeneration block due to the loss of DAF-16, a transcriptional target of DAF-2. Similarly, the loss of daf-2 could bypass the requirement of LIN-41, a transcriptional co-factor of the let-7 pathway. Our analysis revealed that these two pathways synergistically control targeting of the regenerating axon to the ventral nerve cord, which leads to functional recovery. The computational analysis of the gene expression data revealed a large number of genes, their interacting modules, and hub genes under let-7 and IIs pathway are exclusive in nature. Our study highlights a potential to promote neurite regeneration by harnessing the independent gene expression program involving the let-7 and Insulin signalling pathways.

Complex impact of stimulus envelope on motor synchronization to sound
The human brain tracks temporal regularities in acoustic signals faithfully. Recent neuroimaging studies have shown complex modulations of synchronized neural activities to the shape of stimulus envelopes. How to connect neural responses to different envelope shapes with listeners' perceptual ability to synchronize to acoustic rhythms requires further characterization. Here we examine participants' motor and sensory synchronization to noise stimuli with periodic amplitude modulations (AM). We used three envelope shapes that varied in the sharpness of amplitude onset. In a synchronous motor finger-tapping task, we show that participants more consistently align their taps to the same phase of stimulus envelope when listening to stimuli with sharp onsets than to those with gradual onsets. This effect is replicated in a sensory synchronization task, suggesting a sensory basis for the facilitated phase alignment to sharp-onset stimuli. Surprisingly, despite less consistent tap alignments to the envelope of gradual-onset stimuli, participants are equally effective in extracting the rate of amplitude modulation from both sharp and gradual-onset stimuli, and they tapped consistently at that rate alongside the acoustic input. This result demonstrates that robust tracking of the rate of acoustic periodicity is achievable without the presence of sharp acoustic edges or consistent phase alignment to stimulus envelope. Our findings are consistent with assuming distinct processes for phase and rate tracking during sensorimotor synchronization. These processes may be underpinned by different neural mechanisms whose relative strengths are modulated by specific temporal dynamics of stimulus envelope characteristics.

Early life stress induced sex-specific changes in behavior is paralleled by altered locus coeruleus physiology in BALB/cJ mice
Adverse childhood experiences have been associated with many neurodevelopmental and affective disorders including attention deficit hyperactivity disorder and generalized anxiety disorder, with more exposures increasing negative risks. Sex and genetic background are biological variables involved in adverse psychiatric outcomes due to early life trauma. Females in general have an increased prevalence of stress-related psychopathologies beginning after adolescence, indicative of the adolescent time period being a female-specific sensitive period. To understand the underlying neuronal components responsible for this relationship between genetic background, sex, stress/trauma, and cognitive/affective behaviors, we assessed behavioral and neuronal changes in a novel animal model of early life stress exposure. Male and female BALB/cJ mice that express elevated basal anxiety-like behaviors and differences in monoamine associated genes, were exposed to an early life variable stress protocol that combined deprivation in early life with unpredictability in adolescence. Stress exposure produced hyperlocomotion and attention (5 choice serial reaction time task) in male and female mice along with female-specific increased anxiety-like behavior. These behavioral changes were paralleled by reduced excitability of locus coeruleus (LC) neurons, due to resting membrane potential hyperpolarization in males and a female specific increase in action potential delay time. These data describe a novel interaction between sex, genetic background, and early life stress that results in behavioral changes in clinically-relevant domains and potential underlying mechanistic lasting changes in physiological properties of neurons in the LC.

Inhibitory basal ganglia nuclei differentially innervate pedunculopontine nucleus subpopulations and evoke opposite motor and valence behaviors.
The canonical basal ganglia model predicts that the substantia nigra pars reticulata (SNr) and the globus pallidus externa (GPe) will have specific effects on locomotion: the SNr inhibiting locomotion and the GPe enhancing it. In this manuscript, we use in vivo optogenetics to show that a projection-defined neural subpopulation within each structure exerts non-canonical effects on locomotion. These non-canonical subpopulations are defined by their projection to the pedunculopontine nucleus (PPN) and mediate opposing effects on reward. To understand how these structures differentially modulate the PPN, we use ex vivo whole-cell recording with optogenetics to comprehensively dissect the SNr and GPe connections to regionally- and molecularly-defined populations of PPN neurons. The SNr inhibits all PPN subtypes, but most strongly inhibits caudal glutamatergic neurons. The GPe selectively inhibits caudal glutamatergic and GABAergic neurons, avoiding both cholinergic and rostral cells. This circuit characterization reveals non-canonical basal ganglia pathways for locomotion and valence.

Aperiodic and oscillatory systems underpinning human domain-general cognition
Domain-general cognitive systems are essential for adaptive human behaviour, supporting various cognitive tasks through flexible neural mechanisms. From decades of fMRI studies, we know that a particular network of frontoparietal brain regions plays a role in supporting many different kinds of cognitive activity, with increased activity and information coding in response to increasing task demands. However, it is not clear whether there is a corresponding domain-general electrophysiological response to demand, such as a change in aperiodic or oscillatory power. Here we used irregular-resampling auto-spectral analysis (IRASA) to separate the aperiodic and oscillatory components of MEG/EEG signals, and analysed them with multivariate pattern analysis (MVPA) to investigate their roles in domain-general cognition. We found that both aperiodic (broadband power, slope, and intercept) and oscillatory (theta, alpha, and beta power) components coded both task demand and content across three cognitive tasks. Aperiodic broadband power in particular strongly coded task demand, in a manner that generalised across all subtasks, suggesting that modulation of aperiodic broadband power may reflect a domain-general response to multiple sorts of cognitive demand. Source estimation suggested that increasing cognitive demand decreased aperiodic activity across most of the brain, with the strongest modulations partially overlapping with the frontoparietal multiple-demand network. In contrast, oscillatory activity in the theta, alpha and beta bands showed more localised patterns of modulation, primarily in frontal (beta, theta) or occipital (alpha, theta) regions. The spatial pattern of demand-related modulation was significantly correlated across space in individuals, with positive correlations between theta and beta power, while both were negatively correlated with alpha power. These results provide novel insights into the electrophysiological underpinnings of human domain-general cognition, suggesting roles for both aperiodic and oscillatory systems, with changes in aperiodic broadband power being the clearest domain-general electrophysiological correlate of demanding cognitive activity.

Sphingosine-1-phosphate signaling regulates the ability of Müller glia to become neurogenic, proliferating progenitor-like cells
The purpose of these studies is to investigate how Sphingosine-1-phosphate (S1P) signaling regulates glial phenotype, dedifferentiation of Muller glia (MG), reprogramming into proliferating MG-derived progenitor cells (MGPCs), and neuronal differentiation of the progeny of MGPCs. We found that S1P-related genes are highly expressed by retinal neurons and glia, and levels of expression were dynamically regulated following retinal damage. S1PR1 is highly expressed by resting MG and is rapidly downregulated following acute retinal damage. Drug treatments that activate S1PR1 or increase levels of S1P suppressed the formation of MGPCs, whereas treatments that inhibit S1PR1 or decreased levels of S1P stimulated the formation of MGPCs. Inhibition of S1PR1 or SPHK1 significantly enhanced the neuronal differentiation of the progeny of MGPCs. Further, ablation of microglia from the retina, wherein the formation of MGPCs in damaged retinas is impaired, has a significant impact upon expression patterns of S1P-related genes in MG. Inhibition of S1PR1 and SPHK1 partially rescued the formation of MGPCs in damaged retinas missing microglia. Finally, we show that TGF{beta}/Smad3 signaling in the resting retina maintains S1PR1 expression in MG. We conclude that the S1P signaling is dynamically regulated in MG and MGPCs and activation of S1P signaling depends, in part, on signals produced by reactive microglia.

Astrocyte extracellular matrix modulate neuronal dendritic development
Major developmental events occurring in the hippocampus during the third trimester of human gestation and neonatally in altricial rodents include rapid and synchronized dendritic arborization and astrocyte proliferation and maturation. We tested the hypothesis that signals sent by developing astrocytes to developing neurons modulate dendritic development in vivo. We altered neuronal development by neonatal (third trimester-equivalent) ethanol exposure in mice; this treatment increased dendritic arborization in hippocampal pyramidal neurons. We next assessed concurrent changes in the mouse astrocyte translatome by translating ribosomal affinity purification (TRAP)-seq. We followed up on ethanol-inhibition of astrocyte Chpf2 and Chsy1 gene translation because these genes encode for biosynthetic enzymes of chondroitin sulfate glycosaminoglycan (CS-GAG) chains (extracellular matrix components that inhibit neuronal development and plasticity) and have not been explored before for their roles in dendritic arborization. We report that Chpf2 and Chsy1 are enriched in astrocytes and their translation is inhibited by ethanol, which also reduces the levels of CS-GAGs measured by Liquid Chromatography/Mass Spectrometry. Finally, astrocyte-conditioned medium derived from Chfp2-silenced astrocytes increased neurite branching of hippocampal neurons in vitro. These results demonstrate that CS-GAG biosynthetic enzymes in astrocytes regulates dendritic arborization in developing neurons.

Altered activity of mPFC pyramidal neurons and parvalbumin-expressing interneurons during social interactions in a Mecp2 mouse model for Rett syndrome
Social memory impairments in Mecp2 knockout (KO) mice result from altered neuronal activity in the monosynaptic projection from the ventral hippocampus (vHIP) to the medial prefrontal cortex (mPFC). The hippocampal network is hyperactive in this model for Rett syndrome, and such atypically heightened neuronal activity propagates to the mPFC through this monosynaptic projection, resulting in altered mPFC network activity and social memory deficits. However, the underlying mechanism of cellular dysfunction within this projection between vHIP pyramidal neurons (PYR) and mPFC PYRs and parvalbumin interneurons (PV-IN) resulting in social memory impairments in Mecp2 KO mice has yet to be elucidated. We confirmed social memory (but not sociability) deficits in Mecp2 KO mice using a new 4-chamber social memory arena, designed to minimize the impact of the tethering to optical fibers required for simultaneous in vivo fiber photometry of Ca2+-sensor signals during social interactions. mPFC PYRs of wildtype (WT) mice showed increases in Ca2+ signal amplitude during explorations of a novel toy mouse and interactions with both familiar and novel mice, while PYRs of Mecp2 KO mice showed smaller Ca2+ signals during interactions only with live mice. On the other hand, mPFC PV-INs of Mecp2 KO mice showed larger Ca2+ signals during interactions with a familiar cage-mate compared to those signals in PYRs, a difference absent in the WT mice. These observations suggest atypically heightened inhibition and impaired excitation in the mPFC network of Mecp2 KO mice during social interactions, potentially driving their deficit in social memory.

Computational model for synthesizing auditory brainstem responses to assess neuronal alterations in aging and autistic animal models
The auditory brainstem response (ABR) is a widely used objective electrophysiology measure for non-invasively assessing auditory function and neural activities in the auditory brainstem, but its ability to reflect detailed neuronal processes is limited due to the averaging nature of the electroencephalogram recordings. This study addresses this limitation by developing a computational model of the auditory brainstem which is capable of synthesizing ABR traces based on a large, population scale neural extrapolation of a spiking neuronal network of auditory brainstem neural circuitry. The model was able to recapitulate alterations in ABR waveform morphology that have been shown to be present in two medical conditions: animal models of autism and aging. Moreover, in both of these conditions, these ABR alterations are caused by known distinct changes in auditory brainstem physiology, and the model could recapitulate these changes. In the autism model, the simulation revealed myelin deficits and hyperexcitability, which caused a decreased wave III amplitude and a prolonged wave III-V interval, consistent with experimentally recorded ABRs in Fmr1-KO mice. In the aging model, the model recapitulated ABRs recorded in aged gerbils and indicated a reduction in activity in the medial nucleus of the trapezoid body (MNTB), a finding validated by confocal imaging data. These results demonstrate not only the model's accuracy but also its capability of linking features of ABR morphologies to underlying neuronal properties and suggesting follow-up physiological experiments.

Circular RNAs exhibit exceptional stability in the aging brain and serve as reliable age and experience indicators
Circular RNAs (circRNAs) comprise a large class of stable RNAs produced through backsplicing. While circRNAs have been shown to be very stable in cell culture, it is unknown how stable they are in vivo. Interestingly, studies across various animal systems demonstrated that circRNAs levels increase with age in neural tissue. However, the underlying reasons for this age-related accumulation are still unclear. To address these questions, we profiled circRNAs from fly heads at six timepoints across their lifespan. We found that circRNA levels increase linearly with age, independent of changes in mRNA levels, overall transcription, intron retention, or host genes splicing. This indicates that the age-related accumulation is attributed to their extraordinary stability in neural tissue rather than changes in biosynthesis. Furthermore, exposure to environmental stimuli like different temperatures, resulted in the increase but not decrease of circRNAs subsets, further confirming their stability in vivo. This exceptional stability implies that circRNAs can serve as markers of environmental experience. Indeed, flies subjected to a ten-day regimen at 29C exhibit higher levels of specific brain circRNAs even six weeks after returning to standard conditions, indicating that circRNAs can reveal past environmental stimuli. Additionally, circRNA half-life measurements revealed values exceeding 20 days, with some showing no degradation over the animal lifetime. These findings demonstrate the extreme stability of circRNAs in vivo and their use as markers for aging, stress and life experiences.

Delineating In-Vivo T1-Weighted Intensity Profiles Within the Human Insula Cortex Using 7-Tesla MRI
The integral role of the insula cortex in sensory and cognitive function has been well documented in humans, and fine anatomical details characterising the insula have been extensively investigated ex-vivo in both human and non-human primates. However, in-vivo studies of insula anatomy in humans (in general), and within-insula parcellation (in particular) have been limited. The current study leverages 7 tesla magnetic resonance imaging to delineate T1-weighted intensity profiles within the human cortex, serving as an indirect proxy of myelination. Our analysis revealed two separate clusters of relatively high and low T1-weighted signal intensity across the insula cortex located in three distinct cortical locations within the posterior, anterior, and middle insula. The posterior and anterior cortical locations are characterised by elevated T1-weighted signal intensities, contrasting with lower intensity observed in the middle insular cortical location, compatible with ex-vivo studies. Importantly, the detection of the high T1-weighted anterior cluster is determined by the choice of brain atlas employed to define the insular ROI. We obtain reliable in-vivo within-insula parcellation at the individual and group levels, across two separate cohorts acquired in two separate sites (n1 = 21, Glasgow, UK; n2 = 101, Amsterdam, NL). These results reflect new insights into the insula anatomical structure, in-vivo, while highlighting the use of 7 tesla in neuroimaging. Specifically, the current study also paves the way to study within-insula parcellation at 7 tesla and above, and discusses further implications for individualised medicine approaches.

GBA1 MUTATIONS ALTER THE PHENOTYPE AND BEHAVIOUR OF DOPAMINERGIC NEURONS IN PARKINSON DISEASE, INFLUENCING VGLUT2 AND CRYAB EXPRESSION
Mutations in the glucocerebrosidase 1 (GBA1) gene, encoding a lysosomal enzyme, are major risk factors for Parkinso[n]s disease (PD). The impact of GBA1 mutations on neuronal maturation, function and degeneration was investigated in dopaminergic (DA) neurons obtained from our repository of induced pluripotent stem cells (iPS cells or iPSCs), cells derived from PD patients carrying the heterozygous N370S or L444P mutation in GBA1, or from healthy subjects (controls). DA neurons co-expressing TH and VGLUT2 were detected in the cultures, and their number and/or expression of SLC17A6/VGLUT2 mRNA was markedly reduced in both N370S and L444P cultures. Electrophysiological recordings revealed a significant increase in the firing rate of N370S but not L444P neurons, whereas evoked dopamine release was stronger from neurons carrying either mutation than from the controls. Remarkably, neurons carrying either GBA1 mutation accumulated abundant degenerative bodies, multilamellar bodies, autophagosomes and Golgi apparatus vacuolated dictyosomes, with some differences in neurons carrying the N370S or L444P mutation. Furthermore, there was a significant accumulation of -synuclein aggregates in the cell body and dendrites of N370S neurons. Notably, a significant upregulation of the small chaperone CRYAB (HSPB5/alpha-crystallin-B) was found early in DA neuron differentiation and in the Substantia Nigra of PD patients. Our findings indicate that N370S and L444P GBA1 mutations produce some similar and other distinct molecular, electrical and ultrastructural alterations in DA neurons. They suggest that these mutations impair the VGLUT2 subpopulation of midbrain DA neurons, and provoke stress responses early in the neuronal differentiation programme.

The scope and limits of fine-grained category information in the ventral visual pathway
Humans can easily abstract incoming visual information into discrete semantic categories. Previous research employing functional MRI (fMRI) in humans has identified cortical organizing principles that allow not only for coarse-scale distinctions such as animate versus inanimate objects but also more fine-grained distinctions at the level of individual objects. This suggests that fMRI carries rather fine-grained information about individual objects. However, most previous work investigating fine-grained category representations either additionally included coarse-scale category comparisons of objects, which confounds fine-grained and coarse-scale distinctions, or only used a single exemplar of each object, which confounds visual and semantic information. To address these challenges, here we used multisession fMRI paired with a broad yet homogenous stimulus class of 48 terrestrial mammals, with 2 exemplars per mammal. Multivariate decoding and representational similarity analysis (RSA) revealed high image-specific reliability in low- and high-level visual regions, indicating stable representational patterns at the image level. In contrast, analyses across exemplars of the same animal yielded only small effects in the lateral occipital complex (LOC), indicating rather subtle category effects in this region. Variance partitioning with a deep neural network and shape model showed that across exemplar effects in EVC were largely explained by low-level visual appearance, while representations in LOC appeared to also contain higher category-specific information. These results suggest that representations typically measured with fMRI are dominated by image-specific visual or coarse-grained category information but demonstrate that commonly employed fMRI protocols can reveal subtle yet reliable distinctions between individual objects.

Sound preferences in mice are sex-dependent
We investigated the impact of early exposure to sound and to silence on sound preferences later in life in mice. We exposed young mice during the critical periods to excerpts of music (first movement of Beethovens symphony no. 9), non-music sounds, or to silence. We tested the sound preference behavior a few weeks later. Music exposure affected mouse behavior in a sex-dependent manner: male mice largely preferred the environment to which they were exposed, while female mice showed a weak reduction in their seemingly inborn aversion to sound. The neural activity in auditory cortex was suppressed in exposed compared to naive mice, regardless of exposure type. Remarkably, a robust negative correlation was found between neural response and behavior in female, but not in male, mice.

A Small Interfering Peptide Potentiates AMPA Receptor Diffusional Trapping and Prevents Social-Isolation-Induced Forgetting of Fear Memory
Regulation and dysregulation of AMPA receptor (AMPAR) diffusional trapping at synapses are critical for synaptic efficacy and are implicated in various neurological and neuropsychiatric disorders. However, the limited availability of reliable tools to modulate this process hinders our ability to explore its role in both physiological conditions and disease, as well as in drug development. In this study, we designed and characterized a 21-amino-acid trans-activator of transcription (TAT)-fused peptide that mimics the binding region of the transmembrane AMPAR regulatory proteins (TARPs) C-tail to the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) N-lobe. Acute intrahippocampal infusion of this peptide enhanced perforant path-evoked synaptic transmission in the rat dentate gyrus (DG) in vivo, likely by strengthening the interaction between TARP and postsynaptic density protein 95 (PSD-95), a mechanism crucial for the synaptic anchoring of AMPARs. Additionally, the peptide also slowed AMPAR lateral diffusion and blocked KCl-induced AMPAR endocytosis, likely by enhancing the diffusional trapping of AMPARs at the synapse. Remarkably, a 7-day peptide infusion prevented social-isolation-induced forgetting of fear memory. Our findings suggest that targeting AMPAR diffusional trapping, particularly through disrupting the TARP-Arc N-lobe interaction, could hold promise as a therapeutic approach for neurological and neuropsychiatric disorders associated with impaired AMPAR synaptic retention.

Formation of brain-wide neural geometry during visual item recognition in monkeys
Neural dynamics reflect canonical computations that relay and transform information in the brain. Previous studies have identified the neural population dynamics in many individual brain regions as a trajectory geometry, a manifest of some computational motifs. However, whether these populations share particular geometric patterns across brain-wide neural populations remains unclear. Here, by mapping neural dynamics widely across temporal/frontal/limbic regions in the cortical and subcortical structures of monkeys, we show that 10 neural populations, including 2,500 neurons, propagate visual item information in a stochastic manner. We found that the visual inputs predominantly evoked rotational dynamics in the higher-order visual area, the TE and its downstream striatum tail, while curvy/straight dynamics appeared more frequently downstream in the orbitofrontal/hippocampal network. These geometric changes were not deterministic but rather stochastic according to their respective emergence rates. These results indicated that visual information propagates as a heterogeneous mixture of stochastic neural population signals in the brain.