bioRxiv Subject Collection: Neuroscience's Journal

Self-Motion Perception Influences Postural Sway More than Environmental Motion Perception
Motion of the visual field can alter postural sway and cause illusions of self-motion. The relative perceptual sensitivity of self-motion versus visual field motion induced by virtual reality (VR) stimulation and which one drives observable postural sway is unknown. Healthy adults stood wearing a VR headset that presented two interleaved adaptive staircases of virtual sinusoidal pitch rotation about the ankle axis. In separate conditions of randomly ordered blocks, subjects were asked to indicate (yes/no) if the room moved (regardless of perceived postural sway) or if their postural sway increased (regardless of perceived room motion). Head sway area was measured by tracking movement of the VR headset. Binary response data were fit with psychometric curves to determine points of subjective equality (PSEs) for room motion and postural sway. PSEs were compared between conditions. Effects of motion perception (binary responses) on head sway area before, during, and after visual stimulation were examined. The mean PSE for room motion (0.42 degrees) was significantly lower than for postural sway (2.02 degrees) [t(1,18) = 4.4714, p = 0.00029]. Head sway area was significantly larger during (z = 11.53, p < 0.001) and after (z = 5.09, p < 0.001) visual stimulation only when participants perceived increased postural sway. Nearly 5-fold greater amplitudes of oscillating VR visual stimuli were required to induce perceptions of altered self- versus visual field motion. Accurate perceptions of head motion relative to observed head sway were found only when participants focused internally on self-motion, not externally on room motion.

Summation of contrast across the visual field: a common "fourth root" rule holds from the fovea to the periphery
Increasing the area of a grating stimulus tends to reduce the contrast at which it can be detected. We can use the relationship between stimulus area and this "threshold" contrast to study the detection process. Contrast signals combine linearly over short distances, as if summed within the receptive fields that define the inputs to early visual neurons. Beyond this range, the effects of area summation decrease. We set out to find whether the relationship between stimulus area and threshold is the same across the visual field. We measured thresholds for detecting "tiger tail" strips of grating (that grow orthogonal to the major axis of those presumed early receptive fields) in the fovea, parafovea (3 deg), and periphery (10.5 deg). The interpretation of previous studies taking similar approaches has been complicated by the variation in local contrast sensitivity across the visual field. In our study, we have mapped a detailed "Witch Hat" attenuation surface of this inhomogeneity for our three participants. We used this both in our model to account for the results, as well as to generate "compensated" stimuli that are equally detectable at each location within the stimulus extent. Our results follow a common fourth root summation rule in the fovea, parafovea, and periphery. Our "noisy energy" model predicts this behaviour through a combination of: i) the Witch Hat surface, ii) linear filtering by receptive fields that mimic those of V1 simple cells, iii) square-law contrast transduction, and iv) the application of an internal template that devotes the participant's attention to the extent of the stimulus. Fitting this model with one global sensitivity parameter (per participant) accounts for the foveal and parafoveal data (56 thresholds), with one further parameter allowing us to also model the periphery (84 thresholds).

Oxysterol Alterations in SOD1G93A ALS Rats: 25-Hydroxycholesterol and LPS-Binding Protein in Disease Progression
Background: Disruptions in cholesterol and oxysterol metabolism, along with neuroinflammation, are linked to amyotrophic lateral sclerosis (ALS), though the underlying mechanisms remain unclear. Given evidence of increased intestinal permeability in ALS, we investigated its link to neuroinflammation and oxysterol alterations in SOD1G93A rats. Methods: Oxysterols were quantified in plasma and spinal cord from presymptomatic and symptomatic SOD1G93A rats and age-matched controls via ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry. Circulating LBP, a marker of intestinal permeability, was quantified via ELISA. Results: Oxysterols involved in bile acid biosynthesis - 7-hydroxycholesterol, 27-hydroxycholesterol (27-OH), and 3{beta}-hydroxycholestenoic acid - were increased in the plasma of symptomatic rats. The neuronal oxysterol 24(S)-hydroxycholesterol (24(S)-OH) decreased in the spinal cord but increased in the plasma. In contrast, 27-OH and 25-hydroxycholesterol (25-OH) levels were elevated in both plasma and spinal cord, with 25-OH rising during the presymptomatic stage. Presymptomatic animals also exhibited elevated LBP levels, which strongly correlated with spinal cord 25-OH levels, suggesting a link between systemic inflammation and neuroinflammation in ALS. Conclusion: Oxysterol alterations in plasma and spinal cord suggest compromised blood-spinal cord barrier integrity and early neuroinflammation. Elevated LBP levels indicate increased intestinal permeability and circulating LPS as contributors to neuroinflammation and neurodegeneration. These findings highlight 25-OH and LBP as markers and mediators of gut-brain axis interactions in ALS pathogenesis, particularly in the presymptomatic phase.

Vitamin D regulates olfactory function via dual transcriptional and mTOR-dependent translational control of synaptic proteins
Vitamin D (VitD) deficiency, affecting over 1 billion people worldwide, is associated with neurological dysfunction, but its cell-type-specific neural mechanisms remain unclear. Using a dietary mouse model, we show that VitD bidirectionally regulates olfactory acuity: deficiency impairs odor discrimination, while supplementation enhances sensitivity. Single-nucleus and spatial transcriptomics pinpoint selective vitamin D receptor (VDR) expression in olfactory bulb (OB) tufted cells, where it drives synaptic protein expression. Genetic VDR knockdown replicates deficiency-associated olfactory deficits, establishing VDR as essential for synaptic and translational regulation. Notably, we identify mTOR-mediated protein synthesis as a critical convergence point pharmacological mTOR inhibition (rapamycin) rescues synaptic protein deficits and behavioral impairments in VitD-deficient mice. These findings delineate a noncanonical VDR-mTOR-translational axis complementing conventional transcriptional regulation through which VitD serves as a nutrient-sensitive neuromodulator that integrates dietary status with synaptic functions and sensory processing. Our study expands the physiological role of VitD beyond traditional endocrine signaling and reveals mechanistic insights that may inform novel therapeutic strategies for neurological and psychiatric conditions associated with VitD deficiency.

Anticipated action goals structure spatial organisation in visual working memory following self-movement
Working memory enables the retention of relevant visual information in service of anticipated behaviour. Consequently, the goal for which information is retained may crucially sculpt the way we retain and organise information in visual working memory. Here, we investigated how anticipated action goals structure the spatial organisation used for visual working memory following self movement. Participants encoded two tilted objects (left and right) in working memory, then turned around 180 degrees before being cued to either reproduce the tilt of the cued object from memory (report session) or manually reach back to it (reach session). The 180-degree self-movement uniquely enabled us to oppose and disentangle two potential spatial frames for immersive working memory in moving participants: the native spatial frame of how the objects were registered during encoding and an updated spatial frame keeping track where the objects are in the external world behind the participant after self-movement. Behavioural memory reports and spatial biases in gaze converged on the use of distinct spatial frames in the two tasks. This reveals how a foundational aspect of working memory in behaving humans - the spatial frame used to organise memories following self movement - is critically sculpted by anticipated action goals.

Identification of modulated whole-brain dynamical models from nonstationary electrophysiological data
Objective. Understanding the mechanisms underlying brain dynamics is a long-held goal in neuroscience. However, these dynamics are both individualized and nonstationary, making modeling challenging. Here, we present a data-driven approach to modeling nonstationary dynamics based on principles of neuromodulation, at the level of individual subjects. Approach. Previously, we developed the mesoscale individualized neural dynamics (MINDy) modeling approach to capture individualized brain dynamics which do not change over time. Here, we extend the MINDy approach by adding a modulatory component which is multiplied by a set of baseline, stationary connectivity weights. We validate this model on both synthetic data and publicly available EEG data in the context of anesthesia, a known modulator of neural dynamics. Main Results. We find that our modulated MINDy approach is accurate, individualized, and reliable. Additionally, we find that our models yield biologically interpretable inferences regarding the effects of propofol anesthesia on mesoscale cortical networks, consistent with previous literature on the neuromodulatory effects of propofol. Significance. Ultimately, our data-driven modeling approach is reliable and scalable, and provides insight into mechanisms underlying observed brain dynamics. Our modeling methodology can be used to infer insights about modulation dynamics in the brain in a number of different contexts.

Adaptive learning of a naturalistic bimanual task in virtual reality
Traditional motor adaptation studies often use constrained tasks that limit natural movement strategies. Using virtual reality, we studied people performing a realistic bimanual plate-lifting task while learning to account for a visual gain distortion applied to the right hand. We measured adaptation of early hand speed and the final plate position in three task conditions: bimanual lifting to a narrow target, unimanual lifting to a narrow target, and bimanual lifting to a wide target. As in previous studies, both hands initially adjusted to the distortion in bimanual conditions. But ultimately only the right hand adapted its speed and showed after-effects, contrasting prior reports. Contrary to our expectation, participants did not adapt early speed more when using one versus two hands. When we widened the target zone, participants achieved greater success in final plate position without reducing adaptation of early speed. Finally, both bimanual groups used a strategy of tilting the plate to be successful and showed no after-effects in final plate position when the distortion was removed. In contrast, the unimanual group did not tilt the plate and did show after-effects in final plate position. These findings reveal that in naturalistic tasks, people leverage multiple movement strategies to achieve goals. Overall, our findings support established principles of adaptation but also challenge expectations derived from more constrained motor learning paradigms, highlighting the importance of studying motor learning in more naturalistic contexts.

Anxiety state-related task disengagement varies with trait anxiety
Cognitively demanding tasks are often perceived as costly due to the cognitive control resources they require, leading to effort avoidance, particularly in psychiatric populations with motivational impairments. Research on anxiety and cognitive effort are mixed: some studies suggest anxiety increases the perceived effort cost and avoidance, while others indicate that cognitive effort engagement can serve as an adaptive coping strategy. To reconcile these perspectives, we examined the interaction between state and trait anxiety on cognitive effort evaluation and engagement in two experiments. We hypothesized that state anxiety enhances task engagement as difficulty increases, and that this effect is diminished in individuals with high trait anxiety. Experiment 1 assessed self-reported anxiety in an online sample, while Experiment 2 manipulated state anxiety through autobiographical recall. Both experiments employed flow induction and effort discounting paradigms. Across both studies, the effect of state anxiety on task engagement depended on trait anxiety, but the direction of the state anxiety effect was opposite to the effect we predicted. In Experiment 1, participants with low trait anxiety reported reduced task engagement, as indexed by lower flow scores, when state anxiety was higher, but only in easy tasks. This effect was attenuated in participants with higher trait anxiety. The same pattern was observed in Experiment 2, but this time the interaction between trait and state anxiety was present regardless of task difficulty. These findings suggest that trait anxiety may reflect reduced impact of state anxiety on task disengagement.

A mouse model of hemochromatosis-related mutations with brain iron dyshomeostasis exhibits loss of tyrosine hydroxylase expression in dopaminergic neurons and motor control impairment relevant to Parkinson's disease
UK Biobank studies show Parkinson''s disease (PD) risk is almost doubled in men homozygous for the homeostatic iron regulator gene HFE p.C282Y polymorphism, associated with the common genetic iron disorder hemochromatosis. Whether this relationship is causal or spurious is unknown. We previously reported a novel Hfe-/-xTfr2mut mouse model of hemochromatosis with elevated brain iron (~1.5-1.8x). We now show these mice have reduced substantia nigra tyrosine hydroxylase expression at 3 months and 9 months age, sometimes exhibit severe hindlimb clasping by 7-8 months, have impaired rotarod and balance beam performance at 9 months and are untestable on the pole test. These parkinsonian features place the model at the forefront of genetic mouse models of PD, which generally do not show both TH loss and motor impairment. This confirms hemochromatosis-related mutations can cause parkinsonian features, substantiating causality of epidemiological relationships. Despite total brain iron elevation, neuronal iron remains low in Hfe-/-xTfr2mut mice, consistent with hemochromatosis-related mutations disrupting the normal, iron-responsive regulation of the neuronal iron exporter ferroportin by hepcidin. Parkinsonian features may reflect reduced mitochondrial respiratory complex (MRC) activity due to functional neuronal iron depletion. This may be exacerbated by indiscriminate chelation and could instead respond to drugs targeting the hepcidin-ferroportin axis or MRC activity. This new model of chronic parkinsonism that increases with age provides unprecedented insights into the complex relationships of brain iron regulation and movement impairment. Since parkinsonism of diverse etiologies can exhibit iron dysregulation, the model may facilitate pre-clinical to end-stage studies relevant to both sporadic and genetic PD.

Neural signature underlying the effect of intranasal vasopressin on emotional responses to spontaneous social comparison
Vasopressin, a key molecular regulator of social behavior, is implicated in promoting self-protective responses to threats against physical safety and resources. However, its role in defending against self-view threat, common in social interactions and critical to well-being, remains unclear. This study investigates the neural mechanisms through which vasopressin modulates self-protective responses to spontaneous social comparison. In a double-blind, placebo-controlled neuroimaging experiment, participants rated their satisfaction with social evaluations and monetary outcomes assigned to a stranger, friend, or themselves. Compared to placebo, vasopressin selectively intensified contrastive emotional responses to social evaluations of the stranger, decreasing satisfaction with positive evaluations and increasing satisfaction with negative evaluations, relative to those of the self or friend. At the neural level, vasopressin reduced the distinctions between the stranger and the self/friend in the medial prefrontal cortex activity, multivariate response patterns, and functional connectivity with the temporoparietal junction and precuneus, with this effect being especially pronounced among socially dominant individuals. These converging neuroimaging findings support the hypothesis that vasopressin alters the neural representation of the stranger, shifting it from a socially irrelevant figure under placebo to a psychologically salient competitor, thereby triggering self-protective emotional processes. These findings elucidate novel neuropsychological mechanisms through which vasopressin amplifies emotional defense against social threats and offer insights into potential clinical applications for psychiatric conditions characterized by impaired self-protection.

Chronic nicotine treatment enhanced cognition and reduced neuroinflammation in the gp120 transgenic mouse model of neuroHIV
Rationale: Antiretroviral development has improved the longevity of people with HIV (PWH), but many experience impaired cognition potentially due to neuroinflammation. PWH smoke cigarettes at higher rates than the general population, possibly for self medication given cognitive-enhancing and anti-inflammatory properties of nicotine, the primary psychoactive ingredient cigarette smoke. We hypothesized that chronic nicotine would improve cognition in a mouse model of HIV, gp120 transgenic (Tg) mice, and reduce neuroinflammation. Methods: Male and female gp120 Tg mice (n=64) and littermate controls (n=67) were operantly trained then tested for effortful motivation in the progressive ratio breakpoint task (PRBT). Mice were counter-balanced into three groups for saline or nicotine minipump implantation (0, 14 or 40 mg/kg/day) then retested 25 days later in the PRBT, probabilistic reversal learning task (PRLT; reinforcement learning and cognitive flexibility), and Iowa Gambling Task (IGT; risk-based decision-making), with a subset tested for neuroinflammation (Iba1 levels). Results: Gp120-Tg mice exhibited worse PRLT performance, attenuated by nicotine. Furthermore, nicotine selectively optimized their response strategies in the PRLT and IGT, increasing loss sensitivity, shifting animals towards safer responses. No motivation effects were observed. Nicotine also reduced Iba1 expression, suggesting that its cognitive-enhancing effects may relate to reduced neuroinflammation. Conclusion: Gp120 Tg mice exhibited deficits in the PRLT, which are attenuated by chronic nicotine. Furthermore, nicotine improved reinforcement learning and risky decision-making supporting its therapeutic potential for cognitive deficits in PWH, possibly via reducing neuroinflammation. With potential negative consequences of long-term nicotine use, future studies should determine its mechanism of action to develop more targeted therapeutics.

Alzheimer's disease risk gene Wwox protects against amyloid pathology through metabolic reprogramming
Genome wide association studies have identified multiple loci that mediate the risk of developing late-onset Alzheimer's Disease (LOAD). The gene WW-domain containing oxidoreductase (WWOX) has been identified in recent LOAD risk meta-analyses, yet its function in the brain is poorly understood. Using Drosophila, we discovered that knockdown of the highly conserved Wwox gene impacts longevity and sleep, having roles in both neuronal and glial subtypes. In an amyloid beta 42 (A{beta}42) transgenic model of AD, RNAi- mediated knockdown of Wwox significantly decreased both lifespan and locomotion whilst elevating soluble A{beta}42. Transcriptomic and metabolomic analyses revealed that these effects were accompanied by elevated lactate dehydrogenase (Ldh) mRNA and lactate levels, downstream of an increase in the key unfolded protein response protein Atf4. Strikingly, we found that upregulation of Wwox in the A{beta}42 model through CRISPR activation significantly reduced amyloid load, improved longevity and locomotion. Multi-omics analysis revealed Wwox upregulation partially reversed several key A{beta}42-induced transcriptional pathways in the brain and reduced levels of L-methionine and associated enzymes. These findings support a role for reduced WWOX levels in the genetic risk of developing LOAD via pyruvate metabolism and point towards WWOX activation as a protective therapeutic strategy.

Staphylococcus aureus-Induced Degeneration of Nociceptive Neurons in Caenorhabditis elegans
Background In all animals, the nervous system senses microbial signals to influence host defense. Despite emerging as important sensors of infection to regulate immunity and inflammation, the mechanisms by which pain-sensing nociceptor neurons can detect infections are poorly defined. Using C. elegans as a tractable model host that shares many features with mammalian systems, we investigated nociceptor function during bacterial infection. Results In vivo intracellular Ca2+ imaging of nociceptor ASH neurons revealed a drastic reduction in ASH responses to aversive stimuli in Staphylococcus aureus-infected animals compared to noninfected controls. Morphological examination showed that the ASH neurons lost integrity in the sensory processes that extend to the mouth, in a pathogen growth phase-dependent manner. Neighboring neurons did not exhibit this pathogen-induced neurodegeneration (PaIN) phenotype. Genetic analysis suggested that apoptosis, necrosis, ferroptosis, and autophagy are dispensable for the PaIN phenotype. In contrast, loss of the evolutionarily conserved stress-response transcription factor HLH-30/TFEB reduced the penetrance of ASH PaIN by about 50%. Moreover, infected animals showed defective ASH-mediated evasive behaviors, suggesting that the S. aureus-triggered drop in ASH activation and morphological degeneration are physiologically relevant. Conclusions Collectively, these findings reveal that nociceptor neurons lose functional and morphological integrity during infection with S. aureus, with severe consequences for animal behavior. Because S. aureus is a critical human pathogen, the induction of nociceptor PaIN may have important implications for human health.

Chronic HDACi emends microglial differentiation and neurological disease in a mouse model of intellectual disability
Defect in lysine-specific methyltransferase 2D (KMT2D) underlies a rare intellectual disability disorder, Kabuki Syndrome (KS). We show that in addition to reduction in post-natal neurogenesis, KS mice present small, arrested hippocampal microglia which single cell RNA sequence analyses revealed as globally downregulated, occupying neither activated nor surveillance states. Weekly administration of a triple combination formulation (TCF) containing the FDA-approved HDAC inhibitor Vorinostat, HPBCD and PEG-400 for three months, boosted microglia. Transcriptomic, pseudotime cell trajectory analyses, imaging and behavioral data suggest that TCF differentiated KS microglia from arrested to non-diseased and non-activated surveillance forms by selective acetylation of histone H3, that restored the open chromatin mark H3K4me3 independent of Kmt2D, to improve cognitive and nociceptive responses. Wild-type microglia showed no substantial transcriptional or histone changes, intimating normal heterochromatin resisted TCF. These findings reveal a novel chromatin-mediated mechanism of microglial differentiation uncoupled from activation, with therapeutic potential for KS and related disorders.

Detecting neuroplastic effects induced by ketamine in healthy human subjects: a multimodal approach
We investigated ketamine's neuroplastic effects in healthy human subjects using integrated Positron Emission Tomography (PET)/Magnetic Resonance Imaging (MRI) measures before and 1-8 days after a single psychedelic dose of ketamine (1 mg/kg, intravenous). Eleven participants underwent two PET/MRI scans with [11C]-UCBJ (synaptic density/plasticity), 1H-MRS (Glutamate and GABA), and resting-state fMRI (intrinsic brain activity, functional connectivity, graph-theoretic metrics), before and after ketamine. While group-level analyses showed only trend-level increases in PET synaptic markers, we observed significantly elevated Anterior Cingulate Cortex (ACC) glutamate levels post-ketamine. Functional connectivity analyses revealed decreased within-network integrity, particularly in high-order networks like the default mode network (DMN), alongside increased low-to-high-order network integration. Our multimodal analysis showed that increased [11C]-UCBJ volume distribution (VT), a putative index of synaptic plasticity, correlated with reduced intrinsic activity in DMN regions and decreased influence of the posterior cingulate cortex (PCC) in global network dynamics. By linking molecular and network-level changes, our results point to the PCC as a central hub where ketamine may reshape brain hierarchies in the long term, providing new directions for understanding its therapeutic mechanisms and developing targeted treatments.

Locus Coeruleus to Medial Prefrontal Cortex Noradrenergic Neural Circuit Modulates States of Consciousness during Sevoflurane Anesthesia in Mice
How exactly does general anesthesia achieve its effects? It is so widely used in surgeries and medical treatments to enhance comfort for nearly one hundred years, yet its precise mechanisms underlying the loss and recovery of consciousness still remain unclear. Utilizing a variety of research methods- pharmacological, optogenetic, chemogenetic, fiber photometry, and gene knockdown approaches- our study has shed light on the significant modulatory function of locus coeruleus noradrenergic neurons during the transition from sevoflurane anesthesia to awakening. Furthermore, the activation of the LC-mPFC circuit has been found to have a substantial arousal effect, with 1-AR playing a crucial role in this process. Additionally, GABAA-R has been identified as the key binding site for sevoflurane within the locus coeruleus. These findings collectively offer novel insights into the neural network mechanisms underlying general anesthesia, advancing our understanding of this

Early Emergence of Projection-subtype fate-restricted Radial Glial Progenitors Orchestrates Neocortical Neurogenesis.
Radial glial progenitors (RGPs) generate all projection neurons (PNs) in the cerebral cortex through incompletely understood processes. Herein, we combine Mosaic Analysis with Double Markers (MADM)-based clonal analysis at embryonic days 12.5 and 13.5 with early postnatal callosal tracing to reveal a lineage progression that challenges the inside-outside model of cortical development and the conventional view of an invariable sequence of asymmetric neurogenic divisions. Our data demonstrate that early multipotent RGPs generate all extra-telencephalic (ET) and intra-telencephalic (IT) PNs across all layers through parallel sublineages and the random specification, during the earliest neurogenic divisions, of fate-restricted daughter RGPs. While the neuronal production of the parental multipotent RGPs consists of small ET-PN or IT-PN outputs, fate-restricted RGPs produce larger translaminar outputs spanning deep and upper layers of only IT-PNs, the predominant mammalian PN subtype. We further show that the emergence of IT-PN fate-restricted RGPs also leads to quantitatively and temporally stereotyped neurogenesis population-wise.

Lateralised modulation of posterior alpha oscillations by closed loop auditory stimulation during memory retention
Alpha oscillations have been implicated in the maintenance of working memory representations. Notably, when memorised content is spatially lateralised, the power of posterior alpha activity exhibits corresponding lateralisation during the retention interval, consistent with the retinotopic organisation of the visual cortex. Beyond power, alpha frequency has also been linked to memory performance, with faster alpha rhythms associated with enhanced retention. These findings position alpha oscillations as a promising target for neuromodulation. In this study, we demonstrate that although alpha frequency is not typically lateralised in a retinotopic manner during working memory retention, such lateralisation can be externally induced. Using alpha closed-loop auditory stimulation (CLAS), and leveraging the phase-dependent responsiveness of alpha oscillations to sound, we successfully modulated alpha frequency asymmetrically between the visual cortices. The extent of induced frequency lateralisation was associated with the behavioural asymmetry in task performance.

Synergistic short-term synaptic plasticity mechanisms for working memory
Working memory (WM) is essential for almost every cognitive task and behavior. The neural and synaptic mechanisms supporting the rapid encoding and maintenance of memories in diverse tasks are the subject of an ongoing debate. The traditional view of WM as stationary persistent firing of selective neuronal populations has given room to newer ideas regarding mechanisms that support a more dynamic maintenance of multiple items, which may also tolerate more activity disruption. Various computational WM models based on different biologically plausible synaptic and neural plasticity mechanisms have been proposed. We show that these proposed short-term plasticity mechanisms may not necessarily be competing explanations, but instead yield interesting functional interactions on a wide set of WM tasks and enhance the biological plausibility of spiking neural network models, in particular of the underlying synaptic plasticity. While monolithic models (WM function explained by one particular mechanism) are theoretically appealing and have increased our understanding of specific mechanisms, they are narrow explanations. WM models need to become more capable, robust and flexible to account for new experimental evidence of bursty and activity-silent multi-item maintenance in more challenging WM tasks, and generally solve more than one particular task. More detailed models also allow for electrophysiological constraints from recordings. In this study we evaluate the interactions between three commonly used classes of plasticity, namely intrinsic excitability, synaptic facilitation/augmentation and Hebbian plasticity. Combinations of these are systematically tested in a spiking neural network model on a broad suite of tasks or functional motifs deemed principally important for WM operation, such as one-shot encoding, free and cued recall, delay maintenance and updating. In our evaluation we focus on the operational task performance and biological plausibility. Our results indicate that a composite model, combining several commonly proposed plasticity mechanisms for WM function, is superior to more reductionist variants. Importantly, we attribute the observable differences to the principle nature of specific types of plasticity.

Neural dynamics of an extended frontal lobe network in goal-subgoal problem solving
Complex behavior calls for hierarchical representation of current state, goal, and component moves. In the human brain, a network of "multiple-demand" (MD) regions underpins cognitive control. We recorded from four putative homologs to human MD regions in the frontal lobe - ventrolateral (vlPFC), dorsomedial (dmPFC), dorsal premotor (dPM) and insula/orbitofrontal (I/O) cortex - as monkeys solved an on-screen spatial maze. Across regions there was wide variation in strength of encoding task features. Sensory input and current state were strongly coded in vlPFC, goal most stably in dmPFC, and move most rapidly in vlPFC and dPM. I/O responded during revision of a prepared route. Across regions, an abstract, hierarchical code of problem structure marked progress from problem start to end. We suggest that, across an extended frontal network, partially separated but widely reproduced codes build the structured control program of organized behavior.

Stretch and flow at the gliovascular interface: high-fidelity modelling of the mechanics of astrocyte endfeet
Astrocyte endfeet form a near-continuous sheath around the brain's vasculature, defining the perivascular space (PVS) implicated in fluid flow and solute transport. Yet, their precise physiological role remains incompletely understood. This study combines electron microscopy data with a high-fidelity poroelastic computational model to investigate the mechanical interplay at the gliovascular interface. We simulated tissue displacement and fluid flow within detailed reconstructions of the PVS, endfeet, and extracellular space (ECS) in response to cardiac-induced arteriole pulsations. Our model predicts that arteriole dilation compresses the PVS while expanding the overall endfoot sheath volume due to tangential stretch. Fluid exchange primarily occurs through inter-endfoot gaps, driven by pressure differences, rather than across the aquaporin-4 (AQP4) rich endfoot membrane. PVS stiffness critically modulates these dynamics: increased stiffness can reverse PVS volume changes and flow directionality, potentially minimizing fluid exchange at intermediate stiffness levels. While AQP4 has negligible impact on pulsation-driven mechanics, it significantly enhances osmotically driven fluid flow. These findings highlight the complex balance of forces governing gliovascular mechanics and suggest PVS composition strongly influences endfoot-parenchymal fluid exchange.

Altered perceptual integration and learning in autism revealed by games inspired by rodent operant tasks
Altered perception is a key feature of autism spectrum disorder (ASD), yet its precise nature and variability across individuals remain unclear. We developed an online video game, inspired by rodent operant tasks, to assess visual evidence integration. The game employs nonverbal, reward-based training and a pulsed stimulus design for precise control of sensory input, enabling detailed individual-level behavioral analysis. It was playable by typically developing adolescents and their autistic siblings, who spanned the spectrum, including those with profound autism. Game performance correlated with standard ASD survey scores, with ASD participants exhibiting slower learning and altered perceptual integration. Behavioral data were well fit by computational models in which perceptual and learning deficits in ASD arose from increased noise in higher-order visual processing. Our findings reveal that deficits in perceptual integration are widespread across ASD, correlate with symptom severity in social and adaptive domains, and may arise from instability of sensory representations.

The Association Between SLIT2 in Human Vitreous Humor and Plasma and Neurocognitive Test Scores
Background: Slit Guidance Ligand 2 (SLIT2) binds Roundabout (ROBO) guidance receptors to direct axon pathfinding and neuron migration during nervous system development. SLIT2 expression has previously been linked to dementia risk. Objective: To study the association between SLIT2 expression in human vitreous humor and plasma samples and neurocognitive test scores in a cross-sectional cohort study utilizing a novel, highly-sensitive Meso Scale Discovery (MSD) assay for SLIT2 detection. Methods: Seventy-nine individuals with a mean age of 55.79 {+/-} 12.03 years underwent eye surgery with collection of vitreous humor, blood (plasma) collection, and neurocognitive assessment. Vitreous humor and plasma samples were analyzed by SLIT2 MSD electrochemiluminescence immunoassay. Associations between SLIT2 levels in vitreous humor and plasma were analyzed using GraphPad Prism. Results: We found up to a 7-fold higher level of SLIT2 in human vitreous humor compared to plasma. Lower vitreous SLIT2 levels were associated with a lower Montreal Cognitive Assessment (MoCA) score and Immediate Recall Verbatim (IRV) z-score, and higher plasma SLIT2 was associated with a lower MoCA score. In multivariate analysis using single and multiple predictor models, the same significant associations were found when adjusted for age, sex, race, diabetic status, diabetic retinopathy status, glaucoma status, and Apolipoprotein E (APOE) genotype. Conclusions: SLIT2 protein levels are significantly associated with MoCA score and IRV z-score in middle-aged individuals. The relationship remained significant when adjusted for demographics, co-morbidity, and APOE genotype, suggesting SLIT2 may be a sensitive biomarker for early detection of dementia and Alzheimers disease, and warrants further studies.

Neuromodulation of risk preferences encoded in human orbitofrontal cortex activity
Human behavior presents a natural range of variation beyond which extreme behavior appears, often as a hallmark of psychiatric conditions. For example, risk preferences, which naturally range from risk-seeking to risk-averse, are characteristically affected in multiple pathologies, e.g. increased risk-taking in gambling disorders. Despite its basic and translational importance, how underlying brain activity reflects and determines behavioral variation is mostly unknown, in part due to the difficulty of directly examining neural activity in decision-relevant brain areas from cohorts of subjects with varying preferences. To address this, we combined human intracranial recordings (n=15 patients) from the orbitofrontal cortex (OFC), a key brain region in economic decision-making, with risky decision-making tasks and computational modeling. We observed significant behavioral variation in risk preferences, which was strongly correlated with low-frequency (delta-theta) oscillatory coherence in OFC. Low-frequency oscillatory phase was coupled to high-frequency activity amplitude, providing a potential neurophysiological mechanism for integrating preferences with trial-by-trial risk computations. Finally, targeted OFC electrical stimulation caused significantly decreased risk-taking behavior and faster reaction times without impairing overall decision-making. These results show a neural correlate for inter-individual variation in decision-making preferences and provide proof-of-principle evidence for modulation of risk-taking behavior through OFC-targeted neurostimulation, paving the way for developing neuromodulatory interventions for pathologies characterized by heightened risk-seeking, such as addiction and gambling disorders.

Transcriptome-informed brain cartography of polygenic risk and association with brain structure in major psychiatric disorders
Psychiatric disorders are complex, polygenic conditions characterized by patterned structural brain alterations. Whether these changes reflect transcriptional dysregulation driven by genetic risk remains unclear. We introduce a novel imaging-transcriptomics framework that integrates transcriptome-wide association studies (TWAS) with brain transcriptomic atlases to predict macroscale structural brain abnormalities across seven disorders: ADHD, ASD, AN, BD, MDD, OCD, and schizophrenia (SCZ). We generated disorder-specific Gene Expression-based Disorder Associated Risk (GEDAR) maps and assessed their spatial correlation with observed brain alterations thereby establishing a structured approach to map polygenic transcriptional risk onto macroscale brain phenotypes. We found significant transcriptomic-anatomical correlations in MDD (cortical and subcortical), SCZ (subcortical), and ADHD (subcortical), indicating that regional transcriptional vulnerability might contribute to varying extents to the anatomical expression of genetic risk in these disorders. Pathway enrichment analysis on genetically predicted differentially expressed genes for those disorders where we found spatial correlations between GEDAR maps and observed structural changes revealed immune-related processes as dominant in MDD and SCZ, and neurodevelopmental pathways in ADHD. ASD, AN, OCD, and cortical SCZ lacked significant associations. Importantly, spatial transcriptomic-anatomical alignment did not scale with between-disorder differences in heritability, pointing instead toward additional influences like developmental timing or environmental interactions. These findings underscore the potential and limitations of imaging transcriptomics as a framework for bridging the gap between genetic architecture and systems-level brain changes in psychiatric disorders.

Nutritional Ketosis Attenuates Sucrose Bingeing-Induced Behavioral Deficits by Improving Synaptic Plasticity and Anti-Inflammatory Signalling in the Prefrontal Cortex of Male and Female Mice
Binge eating, one of the defining characteristics of binge eating disorder, has been linked to poor health span. Animals, like humans, selectively binge on highly palatable foods, implying that the binge-like behavior is motivated by hedonic rather than metabolic signals. Given the association between reward processing and food intake, this study explored sex-specific underlying biological mechanisms, including synaptic, neuroimmune and neurometabolic correlates of binge-like sucrose drinking, compulsivity and anxiety-like behaviors, utilizing a preclinical model of hedonic sucrose drinking. Throughout the experiment, male and female mice binged on a sweet solution when given food ad libitum with free access and a choice between water and a 10% (w/v) sucrose solution, with females consuming more sucrose. The sucrose intake was positively correlated with transcription of genes for dopamine receptors (Drd1, Drd2) in the PFC of male and female mice. Sucrose-bingeing increased PFC neuroinflammation, concomitantly increasing region-specific blood-brain barrier permeability in males. Sucrose bingeing elevated the transcription of glucose metabolism genes (Slc2a3, Glo1) while inhibiting ketone oxidation pathway genes (Slc16a1, Oxct1, Acat1) in the PFC of males and females. Nutritional ketosis attenuated sucrose bingeing, compulsivity and anxiety-like behaviors in sucrose-dependent male and female mice by suppressing the transcription of reward-related genes (Drd1, Drd2) while promoting an anti-inflammatory neuroimmune microenvironment in the PFC of male and female mice in a sex-dependent manner. Overall, this study identified synaptic, neuroimmune and neurometabolic mechanisms as novel druggable targets and nutritional ketosis as a potential therapy for diseases where binge-like eating, compulsivity and anxiety-like behaviors are the main symptoms, such as binge eating disorder.

Modeling Dyslexia in Neurotypical Adults by Combining Neuroimaging and Neuromodulation Techniques: A Hypothesis Paper
Dyslexia is a prevalent developmental disorder marked by deficits in literacy skills. Given that the core deficits of dyslexia are uniquely human, animal models have not been as useful in dyslexia research as they have been in other areas of research. While significant progress has been made through behavioral and neuroimaging studies, a viable model could facilitate controlled investigations into the neural mechanisms underlying dyslexia and accelerate the development of targeted interventions. In this hypothesis article, we propose a two-pronged approach to model dyslexia in neurotypical adults using neuroimaging and neuromodulation techniques. First, we propose using functional and structural MRI data to cluster individuals into neuropathologically derived subgroups in order to facilitate the classification of dyslexia subtypes based on neuropathological characteristics. Second, we propose employing transcranial temporal interference stimulation (tTIS) to temporarily downregulate activity in brain regions specified in the clustering analysis, inducing subtype-specific dyslexic symptoms in neurotypical individuals. This approach enables the establishment of causal or probabilistic relationships between neuropathologies and dyslexia subtypes, while at the same time creating dyslexia models to facilitate investigation into subtype-specific interventions. By integrating neuroimaging and neuromodulation, we hope to offer a viable substitute for animal models in dyslexia and accelerate the development of personalized therapeutic strategies for dyslexia.

A hierarchical cascade of sleep rhythms drive memory consolidation in humans and are disrupted in epilepsy.
The cross-regional interplay of slow oscillations, sleep spindles, and ripples during sleep is believed to support systems memory consolidation but is understudied in humans. Using a validated behavioral task and intracranial neural recordings from orbitofrontal cortex, thalamus, and hippocampus in 19 epilepsy patients, we examined the cross-regional interplay of sleep-oscillations and their role in memory consolidation. Orbitofrontal slow oscillations robustly modulate sleep rhythms both within and across regions. Most combinations of oscillation rates predict overnight memory consolidation, but hippocampal ripple rate and coupled hippocampal-orbitofrontal ripples were the strongest positive predictors of memory consolidation. In contrast, epileptic spikes coupled to sleep oscillations strongly predicted reduced memory consolidation, with the strongest negative effect observed when epileptic spikes were coupled to slow oscillations. These findings provide direct evidence of the hierarchical cascade of sleep oscillations in human memory processing and reveal how epileptic spikes disrupt this process in patients with epilepsy.

Neural rhythms as priors of speech computations
The transformation of continuous speech into discrete linguistic representations forms the basis of speech recognition. Natural speech encodes cues at distinct timescales. Phonetic features have modulation frequencies of 30-50 Hz, syllables and words around 4-7 Hz, and phrases 1-2 Hz. Strikingly, these frequencies mirror frequencies of endogenous network rhythms of the brain and synaptic time constants of the underlying neural circuits. Here, we suggest that endogenous brain rhythms serve as priors for speech recognition, encoding knowledge of speech structure in the dynamics of network computations. In a network of coupled oscillators, we find that speech is readily identified when characteristic frequencies of the oscillators match frequencies of circuit rhythms in the brain. When signal and circuit rhythms are mismatched, speech identification is impaired. Compared to a baseline recurrent neural network without intrinsic oscillations, the coupled oscillatory network has significantly higher performance in speech recognition across languages, but not in the recognition of signals that lack speech-like structure, such as urban sounds. Our results suggest a central computational role of brain rhythms in speech processing.

Modeling human retinal ganglion cell axonal outgrowth, development, and pathology using pluripotent stem cell-based microfluidic platforms
Retinal ganglion cells (RGCs) are highly compartmentalized cells, with long axons serving as the sole connection between the eye and the brain. RGC degeneration in injury and/or disease also occurs in a compartmentalized manner, with distinct injury responses in axonal and somatodendritic compartments. Thus, the goal of this study was to establish a novel microfluidic-based platform for the analysis of RGC compartmentalization in health and disease states. Human pluripotent stem cell (hPSC)-derived RGCs were seeded into microfluidics, enabling the recruitment and isolation of axons apart from the somatodendritic compartment. Initial studies explored axonal outgrowth and compartmentalization of axons and dendrites. We then compared the differential response of RGCs differentiated from hPSCs carrying the OPTN(E50K) glaucoma mutation with isogenic control RGCs in their respective axonal and somatodendritic compartments, followed by analysis of axonal transport. Further, we explored the axonal transcriptome via RNA-seq, focusing on disease-related axonal differences. Finally, we established models to uniquely orient astrocytes along the axonal compartment combined with modulation of astrocyte reactivity as a pathological feature of neurodegeneration. Overall, RGC culture within microfluidic chips allowed enhanced cell growth and maturation, including long-distance axonal projections and proper compartmentalization, while patient-specific RGCs exhibited axonal outgrowth deficits as well as decreased rate of axonal transport. Finally, the induction of astrocyte reactivity uniquely along the proximal region of RGC axons led to the onset of neurodegenerative phenotypes in RGCs. These results represent the first study to effectively recapitulate the highly compartmentalized properties of hPSC-derived RGCs in healthy and disease states, providing a more physiologically relevant in vitro model for neuronal development and degeneration.

A ubiquitous spectrolaminar motif across independent studies, including in the Mackey et al. dataset
Our study (Mendoza-Halliday et al., 2024) made two contributions: (1) discovery of a ubiquitous cortical motif and (2) a tool derived from it, the Frequency-based Layer Identification Procedure (FLIP and vFLIP). Mackey et al. critique the tool, questioning its advantage over classic current source density (CSD) analysis, and reason backwards to challenge the motif's ubiquity. In our rebuttal, we confirm the spectrolaminar motif in diverse cortical areas using data from multiple research groups (who joined us in this rebuttal) as well as in the dataset provided by Mackey et al. Additionally, we introduce vFLIP2, an improved version of our tool that addresses their comments. It reliably identified and localized the motif in our data and in the dataset of Mackey et al. Our findings reaffirm the motif's ubiquity. We value the comments of Mackey et al., which helped refine our tool.

Repetitive Neuronal Activation Regulates Cellular Maturation State via Nuclear Reprogramming
Neural stimulation, such as electroconvulsive therapy (ECT) and repetitive transcranial magnetic stimulation (rTMS), are highly effective clinical interventions for a broad spectrum of psychiatric disorders, including depression and schizophrenia. However, their mechanism of action at the cellular level remains poorly understood. Here, we modelled ECT with repeated optogenetic neuronal stimulation in the mouse dentate gyrus, and observed ECT-like behavioral effects, including decreased depression-like behavior and increased locomotor activity. At the cellular level, we found dematuration to a long-term stable state, persisting for more than one month, defined by changes in nuclear structure, gene expression patterns resembling the G2/M phase of the cell cycle, and altered neural coding of navigational information. Moreover, knockout of the G2/M master regulator Cyclin B rescued some of behavioral and cellular effects. These findings demonstrate that ECT-like brain stimulation triggers plasticity of the cellular state, revealing a form of stimulus-regulated nuclear reprogramming with potential clinical utility.

Seizure-induced Transient Disruptive Changes in Brain Microstructure
A leading hypothesis for the mechanisms of electroconvulsive therapy (ECT) posits an initial disruptive effect followed by enhanced neuroplasticity. However, direct evidence of the presumed early disruptive changes, potentially driven by seizures, remains limited. This study examined longitudinal changes in multishell diffusion MRI-derived metrics in 25 individuals with depression, with scans acquired two hours before and after their first ECT session. Follow-up scans were collected within 14 days and 6 months after the last ECT session. To control for potential confounding effects of anesthesia and repeated measurements, two additional groups were included: 16 individuals undergoing short-acting anesthesia and 16 healthy controls without interventions. A multicompartment model was applied to explore extracellular free water and microstructures in the intracellular/extracellular compartments. Whole-brain voxel-wise analyses identified a pattern consistent with vasogenic edema (e.g., increased extracellular free water) in widespread bilateral brain regions following a single ECT session. Increases in brain tissue free water were significantly correlated with electrical stimulus charge (r=0.51, p=0.01) but not with post-ictal reorientation time (r=0.11, p=0.92). These changes were not observed in either control group. Follow-up assessments confirmed that the alterations in tissue free water resolved within 14 days. A single ECT-induced seizure induces transient, reversible changes consistent with vasogenic edema, rather than irreversible cellular injury typically associated with cytotoxic edema. These reversible changes may represent an initial disruptive phase that facilitates subsequent adaptive brain responses, including neuroplasticity and network reorganization underlying the therapeutic effects of ECT.

Repositioning of polyubiquitin alters the pathologic tau filament structure
Structurally diverse tau filaments form proteinaceous aggregates in a heterogeneous group of neurodegenerative diseases called tauopathies1. The factors extrinsic to the highly ordered core structure that influence tau filament stability are not well understood. Here, we found that polyubiquitinated tau filaments from Alzheimer's disease and vacuolar tauopathy human brain tissue exhibit distinct seeding patterns in mice, in association with differences in tau filament ultrastructure determined by cryo-electron microscopy. Interestingly, chemical modulation of the polarity of polyubiquitin adjacent to the tau core with the small molecule ubistatin B resulted in the repositioning of poorly structured densities towards positively charged residues on the highly structured core filament, leading to shifting of the protofilament-protofilament interface of certain vacuolar tauopathy tau filaments. These results suggest that the structure of tau filaments that are associated with different seeding activities in vivo can be influenced by post-translational modifications.

iCSD can produce spurious results in dense electrode arrays
Estimation of the current source density (CSD) is a commonly-used method to interpret local field potential (LFP) signals by estimating the location of the neural sinks and sources of current that give rise to the LFP. We show analytically that, when the inter-electrode spacing is small relative to the width of the current distribution, commonly used methods to estimate the CSD produces spurious results, calculating true sources as sinks and vice versa. By simulating a biologically-detailed subvolume of the rat somatosensory cortex with over 200,000 biophysically-detailed neurons, we show that, for high-density recording electrodes, the estimated CSD diverges from expected results, necessitating awareness and careful interpretation of CSD results.

FLP-15 functions through the GPCR NPR-3 to regulate local and global search behaviours in Caenorhabditis elegans
Foraging is essential for sustenance and well-being of all organisms. The transition from well-fed to food-deprived conditions in C. elegans triggers a localized exploration of the environment characterized by frequent reorientations. However, over time the cumulative frequency of these reorientations decreases, facilitating the transition to global search behaviour. To investigate the genetic regulation of foraging in C. elegans, we conducted a screen of neuropeptide mutants and identified several candidates involved in modulating this behaviour. Among these, neuropeptide FLP-15 emerged as a key regulator of both local and global search behaviours. Our observations revealed that FLP-15 regulates the frequency and duration of reversals during foraging. Further investigation indicated that FLP-15 is expressed in and functions through the I2 pharyngeal neuron via the G-protein coupled receptor NPR-3. Mutants lacking either flp-15 or npr-3 displayed a significant decrease in reversal frequency during local search behaviours. Interestingly, unlike wild-type animals, the reversal frequency in flp-15 and npr-3 mutants did not decrease over time. This study also describes the expression pattern of NPR-3, in a subset of head neurons, predominantly comprising of dopaminergic neurons. This expression pattern highlights a potential link between neuropeptide signalling and dopaminergic modulation of behaviour. Finally, exogenous dopamine supplementation assays revealed that FLP-15 may regulate foraging by modulating dopamine transmission, highlighting a novel neuropeptide-dopamine interaction involved in the control of foraging behaviours.

Individualized AI-driven neuromodulation enhances tongue motor and sensory control: preliminary efficacy targeted towards the alleviation of chronic cranial neuropathies
Introduction: Adequate sensory inputs and motor control are essential components of safe swallowing, with significant impact on both quality of life and patient survival. Conversely, both of these neuronal activities are negatively impacted during the early phases of ALS development, following instrumentation of the cervical spine through an anterior approach and broadly by delivery of surgical and radiation-based treatments for head and neck cancer. Our goal is to demonstrate the feasibility, and preliminary efficacy of the individualized fMRI neuromodulation (iNM) intervention pioneered by the Papageorgiou Lab (U.S. Patent No.16/954,256; European Patent No. 19 753 851.5) in enhancing tongue motor and sensory control (TMSC) in these variable patient populations. Although clinical trials show that steroids (NCT04151082) and gabapentin (NCT03747562) temporarily reduce pain, their adverse effects compromise tolerance and adherence. Thus, we need new treatments. The goal here was to strengthen networks that regulate TMSC through our individualized fMRI AI-NeuroModulation, termed iNM fMRI measures the magnitude and spatial extent of the ratio of oxygenated (O2) to deoxygenated hemoglobin (Hb). Our non-invasive, precision-medicine AI-iNM intervention: (1) target primary motor and sensory areas in the brain that regulate swallowing with 1mm level precision, (2) targets each patient's unique anatomical motor and sensory extents , and (3) iNM is and are guided by reinforcing or inhibiting the HbO2 intensity and extent of each patient's unique brain network, as opposed to self-regulation of the HbO2 intensity. Methods: Thirty healthy subjects participated in a 2-day study which included iNM and control conditions. We first computed the individualized TMSC cortical selectivity to be targeted in the iNM condition. Support vector machine (SVM) classified cortical tongue direction and tongue-at-rest patterns generated via iNM and control. We quantified the BOLD magnitude for each network by computing the area under the curve (AUC), variance and association between brain states and TMSC responses via dynamic causal modeling (DCM). Results: The mechanisms associated with attention-memory and sensorimotor iNM are: 1. 45% increase in the AUC's BOLD magnitude (p<0.001); 2. 14% decrease in the BOLD's intensity variance (p<0.01); and 3. 20% increase in network expansion (p<0.001). DCM uncovered 97% of the trials as pure motor signal, while 3% were noise in the iNM condition (compared to 83% of the TMSC trials and 17% noise in the control condition): 1. 70% motor-to-motor (M1, motor cerebellum, basal ganglia) and 70% motor-to-sensory; 2. 69% sensory-to-sensory (intraparietal lobule, insula, claustrum, sensory cerebellum, ACC); and 3. 70% sensorimotor-to-attention-memory network connectivities. Conclusion: iNM showed spatiotemporal causality between networks that regulate motor and sensory control, which can serve as clinical biomarkers for the RICN alleviation in head and neck cancer survivors.

Correlates of head-fixed orienting movements in mouse superior colliculus and substantia nigra pars reticulata
Orienting movements are a critical component of the natural behavioral repertoire, but their underlying neural bases are not well understood. The deep superior colliculus (dSC) integrates input from several brain regions that influence the selection of targets for orienting movements and coordinates activity among brainstem motor nuclei to initiate and execute movement. Evidence suggests that one prominent dSC input, the substantia nigra pars reticulata (SNr), permits movement by disinhibiting its targets, but much is unknown about the relationship between SNr activity, dSC activity, and movement. Building on increasing application of the head-fixed mouse model to elucidate the neural basis of behavior, we examined neural activity recorded in dSC and SNr with high-density probes in mice performing several variants of a sensorimotor orienting task, from our labs and in data sets curated by the International Brain Laboratory. We found that dSC and SNr were active preceding and throughout movement, across task variants, suggesting that they were engaged by the required movements. Prior to movement, SNr activity reflected the outcome of the previous trial, consistent with a role in biasing movements towards the highest value target. However, the dependence of dSC activity on movement direction was weaker than in other directional orienting behaviors, and we found little evidence for strong suppression of dSC by SNr. These results complement and extend previous findings from other orienting tasks and suggest diverse roles for modulatory input from SNr to dSC in shaping motor behavior.

Short-Term Exposure to Polystyrene Microplastics Alters Cognition, Immune, and Metabolic Markers in an APOE Genotype and Sex-Dependent Manner
Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorders and one of the leading causes of death in individuals over the age of 65. Most cases of AD develop sporadically, however, there are several risk factors that have been identified which significantly increases an individual's risk for developing AD. The most prominent of these is Apolipoprotein E4 (APOE4), which can potentially result in an up to 10-fold greater risk of developing AD. The presence of APOE4 alone, however, cannot be solely responsible for AD as the disease may occur even in the absence of APOE4. Therefore, there must be other contributing factors such as exposure to environmental toxins including heavy metals and pesticides, which have independently been shown to contribute to AD. Nano- and microplastics (NMPs) are plastic particles less than 1 micrometers and 5 millimeters in size, respectively, and have only recently been identified as a major environmental pollutant with serious health concerns. Given the adverse health effects that are increasingly being associated with NMPs exposure, we sought to understand how the combination of APOE4 and NMPs exposure may work synergistically to promote cognitive dysfunction and alter key regulatory pathways to impact overall health. Following an acute (3 week) exposure to pristine spherical fluorescently-labeled 0.1 and 2 micrometer polystyrene (PS) NMPs, we found significant sex-dependent alterations in locomotor and recognition memory in APOE4 mice, but not in APOE3 controls. We additionally found that exposure to PS-NMPs resulted in sex and genotype specific alterations in astrocytic and microglial markers in the brain, and in CYP1A1, a major metabolizer of environmental polycyclic aromatic hydrocarbons, in the liver. These results suggest PS-NMPs may interact with the APOE4 allele to promote cognitive dysfunction and alter immune and metabolic pathways which may contribute to disease-like states.