bioRxiv Subject Collection: Neuroscience's Journal

Non-Invasive Photoacoustic Imaging of Cerebral Oxygenation and Hemoglobin Content in Awake Mice
Introduction: Investigating cerebral oxygen saturation dynamics in awake animal models remains technically challenging due to motion artifacts and anesthesia-related biases. Here, we introduce a novel high-resolution ultrasound-photoacoustic (PA) imaging approach enabling real-time, non-invasive monitoring of deep cerebrovascular oxygenation dynamics in awake mice with intact skulls. Materials and Methods: Swiss male and female mice (n = 5-6) were head-fixed using a customized holder adapted to the Neurotar Mobile HomeCage floating platform. High-resolution ultrasound combined with PA imaging (VevoLAZR-X, VisualSonics) was used to discriminate oxyhemoglobin, deoxyhemoglobin, and total hemoglobin in multiple brain regions. Cerebrovascular responses were assessed under three paradigms: (i) baseline awake state vs. 2% isoflurane anesthesia, and (ii) right whisker stimulation to probe sensory-driven hemodynamics. Results: PA imaging successfully resolved deep-brain oxygenation in awake, intact-skull mice. Under isoflurane anesthesia, we observed a rapid and transient increase in cerebrovascular sO2; (p < 0.01). During whisker stimulation, we detected robust, region-specific increases in total hemoglobin, reflecting localized neurovascular coupling in awake mice. Conclusions: This study establishes high-resolution PA imaging as a powerful, non-invasive tool to monitor cerebrovascular oxygenation dynamics in awake mice. By integrating baseline, anesthetic, and sensory paradigms, we demonstrate its potential to dissect neurovascular physiology without the confounding effects of anesthesia. These findings provide new opportunities for preclinical neuroscience research and translational applications investigating cerebral oxygen metabolism.

Biological age acceleration is more prevalent in men than in women at time of spontaneous intracerebral hemorrhage
Objective:Spontaneous intracerebral hemorrhage (ICH) occurs later in life in women compared to men. Although previous studies have demonstrated epigenetic age acceleration (EAA) differences in ischemic stroke (IS) patients - a measure of an individual's biological aging -it remains unknown whether this sex dimorphism also applies to ICH patients. Approach and Results: We joined two ICH cohorts (N= 200, 45% women: 76.8{+/-}13 years; 55% men: 67.9{+/-}14 years). DNAm levels were obtained from whole blood samples using Illumina EPIC array. We evaluated three age-predictor clocks (Horvath, Hannum and Zang-BLUP) and one health-status clock (Levine) and their respective EAA metrics including extrinsic EAA (EEAA) and intrinsic EAA (IEAA) measures. We compared aging measures between women and men, then performed an ICH-subtype stratification, a specificity analysis evaluating sex differences in non-stroke samples (N= 350, 54% women 60.8{+/-}8 years, men: 60.8{+/-}10 years) and replication of previous result in a new IS cohort (N= 657, 43% women 73.6{+/-}12 years, men: 70.1{+/-}11 years). Women at time of ICH present lower EAA values than men (Horvath-EAA, p-value=1x10-04; Hannum-EAA, p-value=8.1x10-06; BLUP-EAA, p-value=4.4x10-04) as well as lower extrinsic EAA values (Horvath-IEAA, p-value=3.1x10-03; Hannum-IEAA, p-value=6.5x10-04). These differences seemed to be driven by differences in deep-ICH patients. Non-ICH females have lower acceleration values (Hannum-EAA: -10,37) than non-ICH men (Hannum-EAA: -8,01), but the differences are smaller than in ICH cases (ICH-women Hannum-EAA: -9,26, ICH-men Hannum-EAA: -2,6). This pattern was consistent in the IS cohort, where women were chronologically older than men but had similar biological age and significantly lower epigenetic age acceleration across multiple measures (Horvath-EAA, p = 2.6x10^-3; Hannum-EAA, p = 7.1x10^-3; Horvath-IEAA, p = 1.6x10^-2; Hannum-IEAA, p = 4.5x10^-2). Conclusion:This study shows that biological age difference between women and men are not exclusive of ischemic stroke but also observed in ICH.

Functional Inertia Index of Memory-Retaining Brain Dynamics: A Measure of Large-Scale Brain Adaptability
Adaptive cognition relies on brain activity that is both flexible and resilient to noise, a property we term functional inertia. Conventional dynamic fMRI metrics treat networks as memoryless and cannot capture the persistence that makes some states fleeting and others entrenched. We introduce the functional inertia index (FII), the first index to quantify temporal momentum by measuring the force required to deviate from a brain's long-running trajectory. Applied to resting-state fMRI from a multisite schizophrenia cohort, FII revealed distinct recurrent states, with prolonged residence in a high-inertia plateau predicting greater symptom severity. This effect was mediated by whole-brain FII, which also showed a positive relationship with cognition in patients but a negative relationship in controls, revealing a dissociation between adaptive and maladaptive rigidity. At the regional level, FII unifies two long-standing observations in schizophrenia: excessive rigidity in associative hubs and pathological volatility in sensory pathways, situating both within a single inertial framework and offering a candidate dynamic biomarker.

Electroencephalography, pupillometry, and behavioral evidence for locus coeruleus-noradrenaline system related tonic hyperactivity in older adults
Neuroimaging studies have shown that age-related dysregulation of the locus coeruleus-noradrenaline (LC-NA) system is associated with cognitive decline. However, due to limitations in directly measuring LC function in vivo, it remains unclear whether age-related alterations in humans reflect tonic LC-NA system hyper- or hypoactivity, constraining our understanding of underlying mechanisms and hampers the development of targeted preventative interventions. In this study, we tested the hypothesis that cognitively healthy older adults sustain tonic LC hyperactivity, by acquiring electrophysiological, pupillometric, and behavioral measures during a passive and active auditory oddball paradigm. We capitalized on the LC-NA system's role in arousal regulation and manipulated state arousal using the unpredictable threat of electric shock. We hypothesized that if older adults maintain elevated LC activity compared with young adults, task-evoked noradrenergic responses would be less responsive to arousal in older adults. Consistent with this hypothesis, arousal elicited weaker behavioral responses, pupil dilation responses, and P300 event-related potentials in older adults compared with young adults. Linear mixed models revealed an arousal by modality interaction, showing that arousal differentially modulated attentional control to salient but task-irrelevant distractors between both age groups. Collectively, these findings support the hypothesis that aging is associated with tonic LC-NA system hyperactivity in humans, with neuromodulatory consequences for mechanisms of attentional control. Furthermore, the multimodal approach underscores the potential of non-invasive physiological markers to assess LC-NA system function throughout aging and identify individuals at elevated risk for neurodegenerative progression prior to the emergence of clinical biomarkers.

Tracking attention using RIFT with a consumer-monitor setup
Rapid Invisible Frequency Tagging (RIFT) is a recent technique that extends the traditional frequency tagging approach by stimulating at frequencies beyond the threshold of perception ([≥]60Hz). By doing so, it offers a measure of early visual processing without the confounding effect of introducing visible stimuli. This ability is most frequently harnessed as a tracker of covert attention in experimental paradigms across various disciplines in cognitive neuroscience. However, almost all existing RIFT work so far has made use of expensive display hardware limited in its accessibility. Recent work has successfully measured a RIFT response in combination with a 480Hz refresh consumer monitor, but it is not yet clear whether this setup can be utilized to track the locus of attention. Using a spatial cueing paradigm (n=24) while simultaneously tagging two locations (60Hz and 65.5Hz) on a 360Hz refresh rate monitor, we show that attentional modulations of early visual processing can be reliably measured with RIFT on a consumer monitor. We hope that this study will facilitate the widespread application of using consumer-grade high-refresh-rate gaming monitors with RIFT for future research.

Disrupted hierarchical organization in disorders of consciousness revealed by fluctuation-dissipation deviations
Evaluating consciousness levels after coma remains clinically challenging, and probing the brain's functional hierarchy offers model-based biomarkers of brain states. We characterize the hierarchy loss in disorders of consciousness (DoC) via departures from non-equilibrium dynamics. Irreversible, directed interactions are indexed by deviation from the fluctuation-dissipation theorem (FDT), computed from individualized whole-brain models fit to fMRI from controls and patients in minimally conscious state (MCS) or unresponsive wakefulness syndrome (UWS). Global and resting-state network dynamics in DoC were closer to equilibrium than in controls, decreasing stepwise with decreasing levels of consciousness. Mapping site specific hierarchical drive over the system revealed disruptions within default-mode network components (e.g., medial and dorsolateral superior frontal gyrus) and subcortical hubs (e.g., thalamus, pallidum and putamen) differentiating between all groups. Recovery of near-control hierarchy in the visual network differentiated MCS from UWS, whereas multiple limbic areas showed similar abnormalities across both DoC groups. Together, these results identify non-equilibrium dynamics as a signature of conscious capacity and stablish FDT deviation as a principled, model-based hierarchy measure that can be operationalised for clinical stratification and monitoring, opening avenues for targeted in silico intervention planing.

Phenotype of mice carrying an NMDA receptor GluN2B protein-truncating variant associated with intellectual disability
Pathogenic variants in GRIN2B, encoding the NMDA receptor (NMDAR) GluN2B subunit, are linked to intellectual disability (ID) and related neurodevelopmental disorders. While most disease-associated variants are missense, protein-truncating variants (PTVs) may cause haploinsufficiency with less severe phenotypes. Here, we characterize a knock-in mouse model carrying the GluN2B-L825Ffs*15 PTV (Grin2b+/{Delta}). Proteomic analysis revealed markedly reduced full-length GluN2B protein and no detectable truncated GluN2B, accompanied by a compensatory increase in GluN2A. Electrophysiology in hippocampal neurons demonstrated reduced NMDA-induced currents, diminished ifenprodil sensitivity, and accelerated NMDAR-mediated EPSC deactivation, consistent with a shift toward GluN2A-containing receptors. AMPAR-mEPSC amplitudes were increased, indicating altered excitatory synaptic function. Behaviorally, Grin2b+/{Delta} mice exhibited hypoactivity, increased anxiety in males, and impaired sensorimotor gating in both sexes, while learning, memory, and social behaviors remained largely intact. These results demonstrate that a monoallelic GluN2B PTV alters NMDAR subunit composition and function, producing moderate behavioral effects, and provide insight into mechanisms underlying GRIN2B-associated ID.

Brain Iron as a Surrogate Biomarker of Pathological TDP-43 Identifies Brain Region-Specific Signatures in Ageing, Alzheimer's Disease and Amyotrophic Lateral Sclerosis
Background: TDP-43 pathology is a defining feature of several neurodegenerative diseases, but its prevalence and regional distribution in ageing and disease are not well characterised. We investigated the burden of brain TDP-43 pathology across ageing, Alzheimer's disease (AD), and amyotrophic lateral sclerosis (ALS), and examined ferritin as a region-specific correlate of TDP-43 pathology. Methods: Pathological TDP-43 was detected using an HDGFL2 cryptic exon in situ hybridisation probe and a TDP-43 RNA aptamer, providing greater sensitivity and specificity than antibody-based approaches. Amygdala, hippocampus, and frontal cortex tissue was analysed from non-neurological controls (ages 40-80), AD cases, and ALS cases. Ferritin (as a proxy for iron accumulation) was quantified in parallel to assess its association with TDP-43 pathology. Findings: TDP-43 pathology was detectable from the fourth decade of life, with a 4.5-fold increase in hippocampal involvement after age 60 years. In AD, pathology was present in 90% of cases and distinguished from ageing by selective amygdala involvement. In ALS, TDP-43 pathology was nearly ubiquitous across all regions studied. Regional ferritin strongly predicted TDP-43 burden: amygdala ferritin explained 87% of TDP-43 variance in ALS and 66% in AD, while hippocampal ferritin differentiated AD from controls. Across AD, ferritin explained between 43-81% of regional TDP-43 variance. Interpretation: TDP-43 brain pathology emerges in midlife with increased involvement after age 60 years, exhibits disease-specific regional signatures in AD and ALS, and is closely linked to ferritin accumulation. As TDP-43 confers a worse prognosis in AD, the capacity of ferritin, detectable with iron-sensitive MRI, to serve as a proxy for regional TDP-43 burden highlights its promise as a biomarker for disease stratification and prognosis.

Quantum-like dynamics in the human brain
Emerging new research indicates evidence of quantum-like (QL) probability laws, including interference effects, in non-quantum physical systems using coupled oscillators. This can produce QL states which can compute in a QL fashion. Given the success of using coupled oscillators for human whole-brain modelling, we investigate the possibility of QL dynamics in the human brain. Here, we investigate how the special topology of human brain anatomy together with QL bits can promote the rich dynamic repertoire necessary for human advanced cognition. We systematically changed the level of QL processing in a whole-brain model. We found the QL regime provided the best whole-brain model fit to large-scale human empirical neuroimaging data. Extraordinarily, at this optimum point we found significantly lower energy consumption than for the non-QL networks. Mechanistically, this implies that the significantly larger whole-brain spectral gap for QL networks offers a backbone to the functional metastability needed to provide the necessary dynamical regime for efficient computation. The underlying QL spectral gaps amplify through interference the metastability and richness of repertoire of the human brain. Overall, we found that the special topology of the human brain promotes QL information processing.

Desensitization of opsin responses during all-optical interrogation depends on imaging parameters
The combination of two-photon calcium imaging and two-photon optogenetic stimulation, termed all-optical interrogation, provides spatial and temporal precision when recording and manipulating neural circuit activity in vivo. All-optical experiments often use red-shifted opsins in combination with green fluorescent reporters of neuronal activity. However, their excitation spectra still partially overlap, meaning that the imaging laser can excite the opsin. Though some care has been taken in the past to understand the effects of this spectral overlap, further work is required to understand its impact on the findings of all-optical studies. We aimed to investigate whether two-photon imaging of the green fluorescent calcium reporter GCaMP6s at 920 nm increases the rate of desensitization in neurons expressing the red-shifted opsin C1V1. We systematically varied either the inter-stimulus interval or the duration of two-photon calcium imaging during two-photon optogenetic stimulation of mouse layer 2/3 barrel cortex or visual cortex neurons. We found that two-photon imaging at 920 nm increases the desensitization of photostimulation responses across trials in C1V1-expressing neurons - an effect that is exacerbated at shorter inter-stimulus intervals. Reduced photostimulation responses are not limited to targeted cells, and are found across the entire field of view. Such network effects are less pronounced at shorter imaging doses. Our results provide methodological optimizations that enable opsin desensitization to be mitigated in all-optical experiments. This will reduce an external source of trial-by-trial variability in future all-optical experiments.

From episodes to concepts and back: Semantic representations in episodic memory enhance recall, replay, and compositional consolidation
Episodic and semantic memory are classically thought to play distinct roles: episodic memory encodes unique experiences, while semantic memory generalizes across them. Current conceptualizations of episodic and semantic memory interactions emphasize a one-way consolidation from episodic traces in the medial temporal lobe (MTL) to semantic knowledge in neocortex (CTX). However, this tradition has left largely unexplored how semantic memory may affect episodic encoding of new memories. Here we introduce a cognitive model in which the code used in episodic memories shifts from purely sensorial to including explicit semantic representations of stored events. Simultaneously, we propose a computational circuit model of how such a cognitive strategy could be implemented in the brain using biologically-plausible learning rules. We show that increased sparsity during replay enables neocortex to extract compositional structure from overlapping episodes, which creates a dictionary of inter-connected concepts in semantic memory. Furthermore, we show that spontaneous activity in neocortical areas can imprint the abstracted representations into the medial temporal lobe, giving rise to concept-like cells. This bidirectional interaction improves episodic recall and replay fidelity, and facilitates the consolidation of higher-order representations based on previous semantic knowledge. The model accounts for behavioural advantages of schema-congruent learning, the emergence of concept neurons, and enhanced memory performance for semantically familiar stimuli. Together, our results provide a mechanistic account of how episodes and concepts reinforce each other, extending standard consolidation theories and suggesting a cooperative framework where semantic knowledge scaffolds episodic encoding, which in turn favours compositional abstraction.

Rehabilitative Experience Interacts With FGF-2 to Facilitate Functional Improvement After Motor Cortex Injury
This experiment compared the effects of a structured rehabilitation regime (skilled reaching for 5 mo) and more varied training (complex environment for 5 mo) with and without postlesion infusion of FGF-2 for 7 days in rats having unilateral motor cortex lesions. Animals were tested on a motor battery throughout the five-month recovery period. The structured rehabilitation alone was ineffective in improving function whereas complex housing did improve performance on several measures. FGF-2 alone was ineffective but in combination with either the rehabilitation training or complex housing it did provide functional benefit. The combination of complex housing and FGF-2 was most effective as all motor measures showed significant improvement. Golgi analysis of layer III cortical pyramidal neurons showed that the complex housing essentially reversed the dendritic loss in the lesion animals. Curiously, there was no effect of FGF-2 on the cells measured, even though there was a beneficial effect of the combined FGF-2 and complex housing. It appears that varied rehabilitative programs, in combination with factors that promote neuronal plasticity are far more beneficial than similar training alone.

Entropy of the resting state cortex in epilepsy
Background: Epilepsy has long been conceptualised as a disorder in which aberrant brain dynamics extend beyond the epileptogenic zone. Evidence demonstrates that loss of entropy is a generic feature of pathological dynamics in the brain, including the ictal state. However, the impact of recurrent seizures on entropy in the interictal state remains unknown. Methods: Resting state magnetoencephalography (MEG) scans and resection masks of 32 individuals with epilepsy who had Engel I outcome post-surgery were retrospectively retrieved. Using co-registered FreeSurfer parcellations, we reconstructed the source localised MEG time series and computed sample entropy for 114 regions of interest. We then tested the association of entropy with the resected volume of the brain, and additional clinical variables including the age of seizure onset, seizure frequency and duration of epilepsy. To further understand the temporal relationship between seizure onset and entropy in the interictal state, we collected and computed sample entropy for week-long EEG traces from leucine-rich glioma inactivated 1 monoclonal antibody (LGI1-mAb) rodent models of autoimmune encephalitis (n=5) and control rats (n=5). Results: In individuals with epilepsy, a lower age of seizure onset was associated with lower mean sample entropy of the whole cortex (Spearmans rho =0.60, p<0.001; partial correlation =0.41, p=0.021). Entropy did not differ between the resected and non-resected regions of the brain. Furthermore, LGI1-mAb treated rodents showed a persistent decrease in sample entropy as compared to control rats, after the onset of seizures, and this difference was greatest during periods of highest seizure frequency (p<0.001). Conclusion: Recurrent seizures are associated with a persistent decrease in entropy, even in the interictal state, and this decrease was found to be most profound and affecting the whole cortex in patients who had a lower age of seizure onset.

Positive Modulators of N-Methyl-D-Aspartate Receptor: Structure-Activity Relationship Study on Steroidal C-17 and C-20 Oxime Ethers
N-methyl-D-aspartate receptors (NMDARs) are crucial therapeutic targets, modulated by endogenous neurosteroids like pregnenolone sulfate (PES). This study investigates a novel structure-activity relationship approach focusing on the steroidal D-ring, employing the bioisosteric replacement of C-17 or C-20 keto groups with oximes and oxime ethers. We synthesized a series of pregn-5-ene and androst-5-ene derivatives (11-23) and evaluated their positive allosteric modulator (PAM) activity on recombinant rat GluN1/GluN2B receptors via patch-clamp in HEK293 cells. Our study revealed that pregnenolone-derived C-20 oxime ethers are potent and efficacious PAMs of NMDAR. Several analogues have been demonstrated as more potent then PES (Emax = 116%; EC50 = 21.7 ). Compound 12 (C-20 ethyl oxime ether, C-3 hemiglutarate) displayed the highest efficacy, potentiating NMDAR currents over 6-fold more than PES (Emax = 673 {+/-} 121%; EC50 = 8.7 {+/-} 1.1 ). Compound 17 (C-20 methyl oxime ether analogue) exhibited the highest potency, being over 3.5-fold more potent than PES (Emax = 503 {+/-} 68%; EC50 = 6.1 {+/-} 0.4 ). In contrast, some C-17 analogues and derivatives with bulkier C-20 oxime substituents showed complex modulatory behavior. Promisingly, key compounds demonstrated favorable in vitro ADME profiles, including high metabolic stability and, for 12, excellent thermodynamic solubility. These results validate C-20 oxime ether modification of the pregnenolone scaffold as an effective strategy for generating potent NMDAR PAMs with potentially superior efficacy and drug-like properties compared to endogenous modulators.

Feedforward and feedback population dynamics during binocular conflict in mouse visual cortex
Binocular rivalry arises when incongruent images are presented to the two eyes, producing stochastic alternations in perceptual dominance. While rivalry has been extensively studied in species with highly developed binocular vision, it is unclear whether similar representational dynamics occur in the mouse, a model system that allows large-scale cellular and circuit-level measurements. Here we used two-photon calcium imaging in awake mice to examine the population dynamics of primary visual cortex (V1) and long-range feedback axons from retrosplenial cortex (RSC) during presentation of dichoptically incongruent drifting gratings and natural movies. At the single-cell level, incongruent stimulation increased trial-to-trial variability of visually evoked responses relative to monocular stimulation. Linear SVM decoders trained on monocular responses revealed that during prolonged incongruent stimulation, V1 population activity alternated stochastically between representations of the two competing stimuli in a contrast-dependent manner. Decoder confidence was independent of pupil-indexed arousal state suggesting the dynamics observed may depend mostly on feedforward mechanisms. Transition analyses showed that switches in decoder output were typically driven by the emergence of responses to the ipsilateral stimulus, consistent with release from suppression of the non-dominant population. During incongruent presentation of natural movies, similar representational alternations were observed, indicating that rivalry-like dynamics were not dependent on orientation-selective adaptation. Imaging of RSC[->]V1 feedback axons revealed retinotopically specific, eye and orientation-selective signals that also alternated in dominance across time. These results establish the mouse as a model of rivalry-like cortical dynamics, demonstrate that both feedforward and feedback circuits contribute to representational alternation during binocular conflict, and provide a framework for mechanistic dissection of bistable perception.

Patient-specific functional brain architecture explains cortical patterns of tau PET in Alzheimer's disease
The spatial distribution of tau pathology, the core driver of neurodegeneration in Alzheimer's disease (AD), varies markedly across individuals. While tau is thought to spread along brain networks, the role of inter-individual variability in shaping these patterns remains underexplored. Using resting-state fMRI and tau- PET from 805 participants across the AD continuum, we studied whether subject-specific functional connectivity (FC) profiles enhance the characterization of tau deposition patterns. A hybrid approach integrating individual and group- average FC outperformed both alone, particularly in symptomatic individuals and at finer spatial resolutions, the latter underscoring a critical but often overlooked role of spatial scale. Individualized FC also better captured individual tau topographies than canonical tau-PET maps derived from cohort-level data. These effects were specific to tau, and not seen for {beta}-amyloid, and their predictive power increased with spatial granularity. Furthermore, baseline FC also predicted future tau accumulation at the individual level, supporting its prognostic value. Together, these findings provide strong evidence that individual functional brain architecture shapes tau propagation in humans, supporting the network spread hypothesis by showing that variability in connectivity translates into heterogeneity in tau distribution. This work advances biological understanding of tau propagation in AD, highlighting functional connectivity as a mechanistic substrate that supports prognostic assessment of tau trajectories.

Olfactory proteomics reveals the capacity of the HDAC1 inhibitor pyroxamide to halt the α-synuclein preformed fibrils-induced damage in nasal epithelial, microglial and dopaminergic neuronal cell lines
Parkinson disease (PD) is the second most common neurodegenerative disorder mainly characterized by the degeneration of dopaminergic neurons originating in the substantia nigra (SN) pars compacta and projecting to other brain regions, giving rise to motor and non-motor symptoms. Despite significant progress in understanding the molecular and cellular disruptions associated with PD, there remains an unmet clinical need for effective therapies. In this study, proteomic analysis of the olfactory tract (OT) in controls with no known neurological history (n=17) and PD subjects (n=21) revealed Lewy body disease (LBD) stage-dependent proteostatic impairment, accompanied by progressive modulation of the alpha-synuclein (alpha-syn) functional interactome. Differential OT omic profiles (OMS) were used in a computational drug repurposing approach, reveling the HDAC1 inhibitor pyroxamide as one of the top drug candidates with in silico potential to restore altered OMS. To explore the potential therapeutic effects of pyroxamide, in vitro assays were performed using alpha-syn preformed fibrils (PFFs). Pyroxamide treatment reduced alpha-syn PFFs-induced toxicity in olfactory epithelial, microglial and dopaminergic neuronal cell lines, producing a protective effect against hydrogen peroxide-induced damage exclusively in brain-derived cell types. These findings confirm the suitability of omics profiles in drug repurposing workflows against PD, offering valuable insights into the potential of HDAC1 inhibitors in the therapeutic pipeline of PD.

Progressive Loss of Astrocytic AIBP Expression during Alzheimer's Disease Pathology
Astrocytes and microglia play crucial roles in mediating neuroinflammation during Alzheimer's disease (AD) progression. ApoA-I binding protein (APOA1BP, also known as AIBP/NAXE) attenuates neuroinflammation by blocking amyloid {beta}-induced TLR4 inflammaraft formation and oxidative stress. Apoa1bp knockout in APP/PS1 mice exacerbates microgliosis, increases amyloid plaque burden, neuronal cell loss, and reduces survival at 6 months. Although APOA1BP mRNA is ubiquitously expressed in humans, its cell-type-specific distribution in the brain remains unclear. To examine AIBP protein expression in the human brain, we performed immunohistochemistry on hippocampal sections from postmortem brain specimens from subjects aged 75-96 of both sexes. Using GFAP and IBA1 to label astrocytes and microglia, respectively, we found that AIBP protein was highly expressed in astrocytes, but not in microglia. Stratification of subjects by Braak stage (I-II, III-IV, V-VI) revealed a progressive decline in astrocytic AIBP expression with advancing AD pathology. Meta-analysis of RNA-seq profiling indicated enriched Apoa1bp expression in adult mouse astrocytes. Systemic Apoa1bp knockout in the APP/PS1 mouse exacerbated astrogliosis. These findings demonstrate that AIBP is predominantly expressed in astrocytes and its expression declines with AD progression, suggesting a potential role for AIBP in astrocyte-mediated neuroprotection and AD pathogenesis.

Suppressing cortical glutamatergic neurons produces paradoxical interictal discharges and seizures
Introduction: Seizures are traditionally attributed to excessive excitation or deficient inhibition, yet recent clinical and slice data show they can also paradoxically arise when inhibition outweighs excitation. We chemogenetically suppressed neocortical glutamatergic neurons to test whether such suppression elicits epileptic activity in vivo. Methods: CaMKII-driven Gi-coupled hM4Di or Gq-coupled hM3Dq Designer Receptor Exclusively Activated by Designer Drug (DREADDs) were expressed in cortical glutamatergic neurons of Rasgrf2-jGCaMP8m and wildtype C57BL/6J mice. Widefield calcium imaging and 32-channel transparent electrocorticography were performed before and after systemic clozapine-N-oxide (CNO; 1.25 ~ 5 mg/kg). Results: DREADD activation induced intermittent, large-amplitude, synchronized calcium transients confined to the CaMKII-hM4Di focus, accompanied by focal ECoG spikes that persisted for >3 h and sometimes evolved into seizures. By contrast, CNO activation of excitatory neurons via CaMKII-hM3Dq DREADDs desynchronized activity without epileptiform discharges. The same process duplicated in wild-type animals provoked similar epileptiform discharges. Conclusion: Selective suppression of excitation can paradoxically drive cortical networks into hypersynchronous, epileptic states, challenging the simple excess-excitation model of ictogenesis. These findings highlight that seizures may result from relative inhibitory dominance, and that considering this excess inhibition mechanism could inspire new therapeutic approaches.

Delayed protective effect of chronic variable stress on optic tract axonal degeneration after experimental TBI
Of the 2.8 million individuals who seek medical attention for traumatic brain injury (TBI) each year, nearly 300,000 require hospitalization, with up to 60% of these needing intensive care. Intensive care treatment of TBI involves stressful events such as sleep disruption, noise, and painful procedures, potentially leading to chronic stress in patients undergoing such treatment. Given that physiologic stress can exacerbate neuroinflammation and impair normal neural function, we hypothesized that chronic variable stress (CVS) following TBI would exacerbate behavioral and pathological outcomes. We tested this hypothesis by subjecting adolescent male mice to blunt TBI, followed by two weeks of CVS or control conditions. We assessed brain pathologic responses to injury 2-, 5-, 20-, and 28-weeks post-injury. We found chronic optic tract degeneration by Fluoro-jade B staining in TBI groups. Unexpectedly, CVS+TBI mice did not show evidence of optic tract axon degeneration 20 weeks after injury, but did at the other time points. CVS led to increased microglial phagocytic markers early after injury, regardless of TBI status, and TBI led to increased microglial phagocytic markers in a delayed fashion as well. Notably, microglial phagocytosis markers were not elevated in TBI+CVS groups compared to TBI only groups 20 weeks post-injury. There was no effect of TBI or CVS on behavioral measures taken at the end of CVS. These findings suggest a delayed, but not permanent, protective effect on axonal degeneration after TBI, potentially related to altered microglial and astrocytic phagocytic activity.

Mapping function in the tree shrew visual system using functional ultrasound imaging.
We adapted functional ultrasound imaging (fUSI) for awake, head-fixed northern tree shrews and used it to produce brain-wide functional maps of visual processing at ~100 microns spatial resolution and ~100 ms temporal resolution. Using classical retinotopic stimuli, full-field noise, motion localizers, and object versus scrambled object contrasts, we demonstrate robust, spatially specific hemodynamic responses across primary and extrastriate visual cortex, superior colliculus and subcortical structures. fUSI reliably reveals retinotopic reversals, laterality, and stimulus-selective modules, and yields high signal-to-noise %CBV changes that enable single-session mapping and targeting of electrophysiology or perturbations. These mesoscale maps provide a systems-level complement to recent high-density electrophysiological surveys of tree shrew visual cortex, which reported a compressed ventral-stream hierarchy and surprisingly early emergence of object coding in V2 (Lanfranchi et al., 2025). Together, our results establish fUSI as a powerful, scalable tool for brain-wide functional mapping in the tree shrew, bridging large-scale circuit measurement and single-neuron electrophysiology and accelerating this species utility as a bridge between rodent genetics and primate vision.

Integrative lipidomics of brain and plasma uncovers sex-specific metabolic signatures in Parkinson's disease
Lipid dysregulation is increasingly recognized as a key feature of Parkinson's disease (PD). A central unresolved question, however, is whether lipidomic signatures identified in accessible peripheral biofluids faithfully recapitulate the pathogenic alterations within the central nervous system (CNS). This gap impedes the development of reliable biomarkers and constrains a comprehensive understanding of PD pathophysiology. To address this challenge, we employed a cross-species lipidomic approach. We modeled PD in both male and female mice by injecting human -synuclein preformed fibrils into the substantia nigra. Three months post-injection, lipidomic profiles of the midbrain and plasma were generated and compared. These findings were further validated in plasma from male and female PD patients and age-matched controls, enabling the identification of conserved alterations. We identified shared dysregulation of sphingolipids, glycerophospholipids, and fatty acids in the brains and plasma of diseased mice as well as in plasma from PD patients. Notably, lipids associated with lipid droplet biogenesis, including triacylglycerols and monoacylglycerols, were elevated in diseased mouse brains and patient plasma. These alterations coincided with a marked accumulation of lipid droplets in the mouse midbrain and were further corroborated by increased lipid droplet abundance in macrophages derived from PD patients. Interestingly, lipid droplet accumulation exhibited sex-specific patterns: male mice displayed greater microglial accumulation, whereas female mice showed enhanced neuronal deposition. Together, these findings demonstrate that peripheral lipidomic signatures reflect CNS pathology in PD, highlighting new opportunities for biomarker discovery and therapeutic intervention. Furthermore, sex-specific lipid droplet accumulation in innate immune cells and neurons implicates these pathways as mechanistic contributors to PD and underscores the necessity of sex-stratified strategies in biomarker discovery and disease modeling.

Highly Correlated Activity across Higher-Order Thalamic Nuclei in Awake and Anesthetized States
Higher-order (HO) thalamic nuclei are enigmatic. Unlike first-order thalamic regions which are known to primarily relay sensory signals to the neocortex, the functions of HO thalamic nuclei remain far less clear. Although previous studies indicate HO thalamic nuclei influence cortical processing and consciousness, most studies examined single nuclei in isolation. To investigate the effect of conscious state across nuclei, we simultaneously recorded local field potentials (LFP) and multi-unit activity (MUA) across multiple thalamic nuclei in awake and anesthetized mice during sensory stimulation. The effect of voluntary locomotion was also studied in the awake state. Surprisingly, we found that LFP traces were strongly correlated across HO nuclei in both states, which cannot be explained by volume conduction alone, suggesting the existence of shared synaptic inputs. Anesthesia significantly reduced MUA across HO nuclei, while in the awake state locomotion and sensory stimuli activated many nuclei, including those that have not classically been regarded as sensory or motor. Moreover, we found that sensory responses of HO nuclei depended on the sensory modality and conscious state of the animal. These findings challenge the classical view of the higher-order thalamus being the aggregate of isolated, independent nuclei.

Representations in the hippocampal-entorhinal system emerge from learning sensory predictions
The hippocampal formation and adjacent parahippocampal areas are central to intelligent behaviour such as memory and navigation. Understanding how systems in the brain generate structured representations from experience remains a fundamental goal in neuroscience. A central open question is whether a single computational principle can account for the diverse neural responses observed across the hippocampal-entorhinal circuit. Existing models often rely on hand-crafted features or specialized learning mechanisms unrelated to sensory observations, and typically express representations of only a small subset of known cell types. Further, representations learned in such models are often not empirically evaluated against neural representations observed in the navigating brain. Here, we introduce a neurobiologically-inspired and robust computational model in which diverse cell types emerge from a single learning objective with minimal hand-engineered assumptions. Our model applies contrastive graph representation learning to transitions between high-dimensional visual observations, constructing a metric space in which temporally adjacent sensory observations are mapped to nearby states. Inspired by the anatomical information flow of the hippocampal-entorhinal system, and anchored in output representations based on neural coding in the entorhinal cortex, the model gives rise to activity resembling place cells, grid cells, boundary vector cells, band cells, corner cells, and conjunctive cells among others. Across varied environments and sensory streams, the framework captures not only diverse neural response patterns but also the functional dependencies between them, mirroring the proposed sequential representational structure observed in the hippocampal-entorhinal system. Crucially, place-cell-like features of the model quantitatively reproduce remapping dynamics observed in CA1 of freely moving animals, and afford theoretical explanatory power of existing neurobiologically-informed models. This work thus offers a unified computational model of spatial coding in the hippocampal-entorhinal system and a testable framework for generating mechanistic hypotheses in silico, to be evaluated in vivo.

Homeostatic Binary Networks: A simple framework for learning with overlapping patterns
Memories are rarely stored in isolation: experiences overlap in time and context, leading to neuronal activity patterns that share elements across episodes. While such overlap supports generalization and abstraction, it also increases interference and threatens representational stability. Here we introduce Homeostatic Binary Networks (HBNs), a minimal recurrent framework that combines binary activity, adjustable inhibition, Hebbian learning, and homeostatic plasticity to address these challenges. First, we formalize an Episode Generation Protocol (EGP) that creates compositional episodes with controllable overlap and noise, and define a corresponding semantic structure as conditional probabilities between concepts. We then show analytically and through simulations that recurrent synapses converge to conditional firing probabilities, thereby encoding asymmetric semantic relationships across concepts. These recurrent dynamics enable reliable recall and replay of overlapping episodes without representational collapse. Finally, by incorporating feed-forward plasticity with a neuronal maturity mechanism, output neurons form selective receptive fields in a one-shot manner and refine them through replay, yielding robust unsupervised classification of overlapping episodes. Together, our results demonstrate how simple principles such as neural and synaptic competition can support the stable representation and organization of overlapping memories, providing a mechanistic bridge between episodic and semantic structure in memory systems.

Adults up to 80 years old maintain effective movement planning when facing complex body dynamics
Aging can significantly impact motor performance, especially in highly complex tasks such as multi-joint movements where the nervous system needs to adequately coordinate mechanical interactions between joints. This coordination is inherently challenging for the brain. Effective coordination of multiple joints relies on intact feedforward control to predict movement dynamics in the initial phase of the movement, and on feedback control to fine-tune the execution in the final phase. However, the effect of aging on these specific control mechanisms remains controversial. In our experiment we investigated a pure elbow motion task using the KINARM exoskeleton. A group of 50 young (20-35 years old), 80 old (55-70 years old) and 30 older-old (80+ years old) healthy participants were recruited. Each participant performed 30deg elbow rotations while stabilizing the shoulder joint. Movements were directed toward two distinct targets in both flexion and extension directions. The task was performed under two controlled speed conditions to maximally challenge the motor system, as higher elbow velocities increase interaction torques at the shoulder, demanding greater neuromuscular effort for stabilization. The timing and magnitude of anticipatory EMG activity of the agonist shoulder muscle, necessary to counteract interaction torques, were preserved across all age groups. Moreover, increasing elbow velocity did not result in any performance differences between young and older old adults, indicating that shoulder stabilization during movement initiation remained intact with age. However, older adults exhibited reduced ability to stabilize the shoulder position until the end of the movement, leading to decreased reaching accuracy with older age. These results suggest that feedforward control, essential for movement planning, which is essential for shoulder stabilization during initiation, is preserved during healthy aging and remains resilient to increased motor demands, even in older old adults. In contrast, feedback control appears to deteriorate with age, potentially contributing to reduced movement precision in the final phase of the multi-joint movement.

Temporal Dynamics of Flexible Cognitive Control
In dynamic environments, flexible cognitive control adaptively adjusts processing through proactive mechanisms deployed in advance and reactive mechanisms engaged upon conflict. Previous studies have primarily focused on identifying neural networks supporting specific control components, while less is known about how multiple components interact over time to support adaptive control. To characterize these temporal dynamics, we combined EEG recordings with a face-word Stroop paradigm under changing conflict environment. A hierarchical Bayesian model was used to estimate trial-wise learning rate, predicted conflict level, and prediction error, providing computational indices of cognitive control flexibility. Neural correlation analysis revealed that these variables correlated with Theta, Alpha, and Beta oscillations in distinct brain regions. Connectivity analysis among these regions indicated enhanced cross-frequency directional interactions triggered by stimuli. Furthermore, connections reflecting updates to predicted conflict level prior to stimulus onset indexed individual strength in proactive control, while connections reflecting learning rate updates after stimulus onset indexed reactive control. These findings highlight how oscillatory dynamics coordinate multiple control components and provide new insight into how proactive and reactive control emerge as distinct modes within this interconnected neural architecture of flexible cognitive control.

Dim light at night impacts circadian rhythms and Alzheimer's disease-like neuroinflammation and neuropathology in humanized APP SAA knock-in mice
Artificial light at night (light pollution) is widespread but understudied in the context of Alzheimer's disease (AD). Sleep and circadian disruption have been linked to amyloid-{beta} (A{beta}) accumulation and neuroinflammation, but whether dim light at night (dLAN) modifies these processes remains unclear. We tested whether chronic dLAN exposure (8 lux during the dark phase, 8 weeks) alters circadian rhythms, amyloid pathology, and neuroinflammation in 12-13 month-old humanized APP knock-in (KI) mice. hAPPSAA KI mice, which develop plaques, were compared with hAPPWT KI controls carrying only a humanized APP sequence. dLAN reduced circadian rhythm amplitude and stability while increasing fragmentation in both genotypes within two weeks. In hAPPSAA KI mice, dLAN modestly increased hippocampal plaque burden and soluble neocortical A{beta}. Astrocyte reactivity was elevated by genotype but not altered by nighttime light exposure. In contrast, microglial markers (CD45, MHCII) were increased with dLAN with CD45+ area elevated in hippocampus, and MHCII+ cell counts greater in the cortex and hippocampus of hAPPSAA KI mice. There were also distinct spatial responses between the microglia markers suggesting that dLAN primes microglia toward an antigen-presenting phenotype (MHCII) in the presence of A{beta}. Yet, the microglia/macrophage priming was not associated with amplified cytokine or chemokine levels at the 8-week dLAN exposure timepoint in the brain. These findings add to growing evidence that nighttime light exposure can disrupt circadian and immune regulation, and suggest that environmental light pollution should be further explored as a modifiable factor contributing to Alzheimer's disease progression.

Disrupted emotional resilience and neurovisceral integration in early small vessel disease
Background Cerebral small vessel disease (SVD) is a major cause of cognitive decline and late-life depression, yet its early affective markers are poorly understood. Ageing is typically associated with enhanced emotion regulation, including greater differentiation of affective states and a shift toward positivity. Whether SVD disrupts these resilience mechanisms before overt clinical impairment is unknown. Methods Eighty-two adults were studied: young (n=22) and middle-aged (n=23) adults without brain abnormalities, and middle-aged adults with early SVD (n=37). Participants completed an ecologically grounded social emotion fMRI paradigm and self-report questionnaires of interoceptive and emotional awareness. Group differences in emotional differentiation, positivity, and neurovisceral integration were analysed to assess the effects of healthy ageing and early SVD. Results Compared with young adults, middle-aged adults without SVD showed preserved emotional differentiation, positivity bias, and intact neurovisceral integration. In contrast, early SVD was associated with reduced emotional differentiation, loss of the age-related positivity effect, and altered insular encoding of arousal. Impaired neurovisceral integration translated into diminished heart rate adaptation during sustained emotional processing. Self-report alexithymia ratings and interoceptive profiles further indicated reduced emotional awareness and embodied self-regulation in adults with SVD. These effects persisted after adjustment for cognition, cardiovascular risk factors, depression, and anxiety. Conclusions Early SVD is associated with affective-interoceptive disintegration evident across behavioural, neural, and physiological levels. Altered embodied regulation of emotion may constitute an early marker of vascular brain injury and a target for preventative interventions.

Brain-derived neurotrophic factor supports pericyte and vascular homeostasis in the aging brain
Microvascular circulation in the brain is often impaired in connection with the loss of pericytes in old age. The neurotrophic factor BDNF also decreases in the aging brain. We hypothesized that BDNF regulates the homeostasis of cerebral pericytes and microvasculature. We used differently aged C57BL/6J mice, and C57BL6 mice with conditional knockout of Bdnf gene. Collagen IV-positive microvessels and PDGFR{beta}-positive pericytes in the brain were counted after immunological staining. Pericytes were also quantified by Western blot of PDGFR{beta} and CD13 in isolated cerebral microvessels. The level of BDNF and TrkB phosphorylation was determined in brain homogenates. To demonstrate the direct effect of BDNF on pericytes, TrkB and pericytes were co-stained in brain tissue, single-cell sequencing and transcriptomic analysis were used to identify and characterize Ntrk2-expressing pericytes, and TrkB was also detected in the pericyte cell line by Western blot. Cultured pericytes were further treated with recombinant BDNF in the presence and absence of an Akt inhibitor and examined for PDGFR{beta} expression. The length and branching of microvessels and pericytes decreased in conjunction with the reduction in mature BDNF and TrkB phosphorylation in aging brains. Deficiency of BDNF in neurons or astrocytes was sufficient to reduce cerebral microvessels, PDGFR{beta} and CD13 concentrations and Akt and Erk1/2 phosphorylation in isolated blood vessels. A subset of pericytes in the brain and cultured pericytes expressed TrkB. BDNF treatment increased PDGFR{beta} expression along with Akt and Erk1/2 phosphorylation in cultured cells. The effect of BDNF on PDGFR{beta} expression was abolished by treatment with Akt inhibitor. Therefore, BDNF induces the expression of PDGFR{beta} and CD13 by activating Akt signaling in pericytes, promoting the homeostasis of pericytes and microvasculature in the aging brain. Our study identified a BDNF-mediated mechanism that regulates microvascular integrity in the aged brain.

Improved interpretability in LFADS models using a learned, context-dependent per-trial bias
The computation-through-dynamics perspective argues that biological neural circuits process information via the continuous evolution of their internal states. Inspired by this perspective, Latent Factor Activity using Dynamical systems (LFADS, Pandarinath et al., 2018) identifies a generative model consistent with the neural activity recordings. LFADS models neural dynamics with a recurrent neural network (RNN) generator, which results in excellent fit to the data. However, it has been difficult to understand the dynamics of the LFADS generator. In this work, we show that this poor interpretability arises in part because the generator implements complex, multi-stable dynamics. We introduce a simple modification to LFADS that ameliorates issues with interpretability by providing an inferred per-trial bias (modeled as a constant input) to the RNN generator, enabling it to contextually adapt a simpler dynamical system to individual trials. In both simulated neural recordings from pendulum oscillations and real recordings during arm movements in nonhuman primates, we observed that the standard LFADS learned complex, multi-stable dynamics, whereas the modified LFADS learned easier-to-understand contextual dynamics. This enabled direct analysis of the generator, which reproduced at a single-trial level previous results shown only through more complex analyses at the trial average. Finally, we applied the per-trial inferred bias LFADS model to human intracortical brain computer interface recordings during attempted finger movements and speech. We show that modifying neural dynamics using linear operations of the per-trial bias addresses non-stationarity and identifies the extent of behavioral variability, problems known to plague BCI. We call our modification to LFADS as "contextual LFADS".

Hippocampal multi-layered RNAseq prioritizes oligodendrocyte dysfunction over immune-driven neuroinflammation in neurolupus pathogenesis
Neuropsychiatric systemic lupus erythematosus (NPSLE) is a severe manifestation of lupus marked by cognitive and mood disorders, yet its hippocampal molecular underpinnings remain poorly understood. Here, we provide a region-specific transcriptomic map of the hippocampus in MRL/Lpr mice --a validated NPSLE model-- compared to MRL+/+ controls. Bulk RNA-seq combined with integrative analyses (e.g. differential expression, GSEA, WGCNA, cell-type deconvolution) uncovered a robust disease-specific signature centered on oligodendrocyte dysfunction and myelination failure. Key myelin-related genes (Mbp, Plp1, Mog) and lineage-defining transcription factors (Sox10, Nkx6-2, Olig2) were repressed, while OPC markers remained unchanged, indicating a maturation blockade rather than lineage loss. Gene set enrichment highlighted widespread suppression of oligodendrocyte differentiation, axon ensheathment, and Wnt/retinoic acid signaling, alongside dysregulation of extracellular matrix components critical for axo-glial interactions. Co-expression network analysis revealed a disease-associated module enriched in myelination programs, with hub genes spanning structural, transcriptional, and adhesion-related functions. Deconvolution analysis confirmed a selective reduction of mature oligodendrocytes, contrasting with preserved neuronal populations and absence of classical astroglial or microglial activation signatures. RT-qPCR and Western blot validated the repression of myelination pathways at both mRNA and protein levels. Collectively, these findings challenge the inflammation-centric paradigm of NPSLE, revealing a cell-intrinsic vulnerability of the oligodendrocyte lineage. This conceptual shift --from immune-driven damage to impaired glial development-- redefines NPSLE pathogenesis and suggests novel therapeutic avenues targeting oligodendrocyte maturation and remyelination rather than focusing solely on immunosuppression.

Common-specific edge-centric connectome across Four Episodes in Bipolar Disorder
Background: Bipolar disorder (BD) is a heterogeneous psychiatric illness marked by dynamic mood states, including manic (BipM), depressive (BipD), mixed (mBD), and remitted (rBD) episodes. These clinical fluctuations are accompanied by widespread functional disruptions in the brain. However, the shared and individual specific neural mechanisms across distinct episodes of BD remain poorly understood. Methods: We analyzed resting state fMRI data from 190 participants (BD patients in four episodes and healthy controls) using edge centric functional connectomes (eFC), which capture time resolved cofluctuations between brain regions. A common orthogonal basis extraction (COBE) algorithm was applied to decompose individual eFC matrices into shared and individual specific subspaces. We characterized the spatial topology, genetic relevance, and circuit level correlates of the shared component. Dynamic properties (entropy, identifiability) and symptom prediction models were assessed using entropy metrics, intraclass correlation coefficients, and support vector regression. Results: The shared eFC pattern was stable across participants, aligned with the sensory association gradient, and exhibited significant heritability and test retest reliability . Entropy of individual loadings increased with illness duration and was significantly elevated in BD, particularly in mBD. Microcircuit modeling revealed that this shared pattern was inversely related to external input strength , indicating intrinsic network dominance. mBD was associated with globally elevated eFC entropy and markedly reduced fingerprint stability. Symptom severity (HDRS, YMRS, HAMA) was significantly predicted from individual network topographies across BD phases, highlighting clinically meaningful dynamic signatures. Conclusion: Our findings demonstrate that BD episodes are underpinned by a conserved functional scaffold and distinct individual specific neural fingerprints. Edge centric dynamics especially those derived from individual specific decompositions offer robust biomarkers for mood state characterization and symptom severity, and may facilitate future personalized interventions in BD.

Spinal cord structural and functional architecture and its shared organization with the brain across the adult lifespan
The spinal cord connects the brain to peripheral systems. Yet its integration with cerebral networks remains a key neuroscience question. Capturing structural and functional central nervous system (CNS) changes throughout the lifespan is essential for characterizing healthy and pathological aging. Leveraging a unique multimodal dataset combining spinal and cerebrospinal imaging, we jointly mapped the spinal cord structural and functional architecture across adulthood. Our results revealed age-related changes across these modalities and identified organizational principles shared with the brain. These changes were most pronounced in the somatosensory pathway, with microstructural decline coupled to shifts in functional connectivity and local spontaneous activity as aging progresses. Extending analyses to the brain uncovered convergent CNS-wide aging mechanisms, including gray matter loss, functional dedifferentiation, and increased spontaneous activity, highlighting shared neural aging trajectories. Together, our findings provide a systems-level view of alterations with age and lay the groundwork for early biomarkers of sensorimotor decline.

Neural activity profiles reveal overlapping, intermingled subpopulations spanning area borders in mouse sensorimotor cortex
Cortical control of movement is a distributed computation spanning multiple densely-interconnected regions. Although we have rich anatomical atlases and a coarse understanding of how function maps to areas and subregions, we lack a detailed account of how behaviorally-relevant activity is organized across the cortical sheet. Here, we trained head-fixed mice to perform a 15-target reach-to-grasp task while we performed cellular-resolution, two-photon calcium imaging across five regions of sensorimotor cortex (>39,000 layer 2/3 neurons). We characterized each neurons trial-averaged peri-event activity with interpretable metrics and mapped these response properties across areas, revealing large-scale spatial structure. Neuronal response profiles often shifted abruptly at anatomical borders: motor areas showed sharper tuning and more linear relationships with target location, whereas somatosensory areas displayed more heterogeneous response patterns. Neural response properties also differed according to somatotopic representation. Nonlinear dimensionality reduction of the neural feature matrix revealed that areas varied in their average response profiles, but also that each area contained subpopulations. Neurons in each subpopulation had characteristic response profiles and were distributed across multiple cortical areas. The spatial distributions of the subpopulations overlapped, with neurons from different subpopulations salt-and-pepper intermingled in the overlap zones. Together, these results describe activity structure across sensorimotor cortex and identify several distinct but spatially-overlapping subpopulations with characteristic activity patterns during reach-to-grasp behavior.

N-terminally acetylated Met11-Tau: a new pathological truncated Tau species with functional relevance in Alzheimer Disease
Neurodegenerative diseases like Alzheimer disease (AD) are characterized by progressive accumulation of pathological Tau proteins. Among the diverse Tau species, truncated variants are emerging as key contributors, yet their identity remains elusive, particularly for the N-terminal truncated ones. The present study identifies and characterizes a novel N-terminally truncated and N-alpha-acetylated form of the Tau protein. Using a newly developed antibody specifically targeting this truncated variant, we demonstrate that this species accumulates early in degenerating neurons in both transgenic mouse models of AD-related Tau pathology and post-mortem brain tissues from AD patients. Importantly, in vivo functional experiments reveal that expression of this truncated Tau species exacerbates Tau pathology, whereas targeted immunotherapeutic with the specific antibody significantly reduces pathological Tau accumulation and prevents associated memory impairments. These findings position this newly identified Tau variant as both a marker of neurofibrillary degeneration and a pathogenic driver of neurodegeneration and supports its potential as a therapeutic target in Tau-related disorders, notably AD.

The impact of human brain geometry on the transport of an intrathecal tracer
Background: Intrathecal contrast-enhanced magnetic resonance imaging (MRI), utilizing the contrast agent gadobutrol as cerebrospinal fluid (CSF) tracer is emerging as a useful method to study glymphatic function in the human brain. A consistent finding with this technique is large inter-individual variability regarding tracer propagation. In this study, we outline an approach which predicts the distribution of tracer in the parenchyma based only on geometric information from brain tissue as captured by MRI, addressing one possible explanation for this variability. Methods: Registrations are computed from pre-injection MRI, and used to map images at 24 hours after tracer injection to perform predictions of tracer enrichment in the parenchyma in other patients. We apply the method to a dataset of human brain MRI of 134 patients examined for different tentative diagnoses including idiopathic normal pressure hydrocephalus, spontaneous intracranial hypotension and idiopathic intracranial hypertension, as well as a group of reference patients. Results: Tracer enrichment mapped between patients by image registration correlate strongly with actual observed enrichment. For patients in the reference group, the relative root mean squared error on our predictions is on average 26% in the gray matter, and 15% or less in other brain regions. Predictions are generally less reliable in the gray matter, and for patients with identified CSF leaks. Conclusion: We show that predictions made from purely geometrical considerations correlate strongly with actual MRI tracer enrichment for patients with similar diagnoses, thus quantifying the role of geometry in tracer enrichment.

fNIRS-Based Neurofeedback for Prefrontal Cortex Modulation: a Proof-of-Concept Study
Functional near-infrared spectroscopy (fNIRS) provides a non-invasive method for monitoring cortical hemodynamics. In this pilot study, we developed a simple neurofeedback system and tested whether participants could volitionally modulate prefrontal cortex blood flow using real-time fNIRS feedback. Preliminary results demonstrate the feasibility of this approach and highlight its potential for future applications in cognitive training and clinical interventions.

Increased HCN1 activity in human excitatory neurons drives excessive network bursting in Dravet syndrome
Dravet syndrome (DS) is a severe childhood epilepsy caused by mutations of the sodium channel NaV1.1. These mutations are thought to compromise the ability of inhibitory interneurons to regulate network activity, leading to seizure events. However, standard treatments to restore inhibition have limited efficacy, suggesting the existence of additional pathological mechanisms. Here, we use hiPSC-derived neuronal networks containing both excitatory and inhibitory neurons to show that excessive bursting activity in DS cultures is driven by excitatory neurons. This rise in bursting frequency is caused by the increased expression of HCN1 pacemaker channels in excitatory neurons, and bursting activity can be normalised using a channel blocker. With this work, we propose a new pathophysiological mechanism in DS and identify HCN1 as a novel therapeutic target.

Toothy: an interactive platform for dentate spike curation
Dentate spikes (DSs) are hippocampal population events that occur during low-arousal states, defined by large-amplitude positive voltage peaks recorded in the hilus of the dentate gyrus (DG). DSs can be classified into two types (DS1 and DS2), with DS2 linked to transient increases in arousal, brain-wide neural activation, and functional relevance for memory encoding. Despite growing interest in their physiological and functional properties, no standardized framework exists for detecting and classifying DSs. We present Toothy, an open-source tool for DS detection and classification in large-scale electrophysiological recordings. Toothy offers a modular and interactive workflow comprising three key steps: (1) ingestion and preprocessing of local field potential (LFP) recordings, (2) detection of hippocampal population events, and (3) classification of DS types using peri-event current source density (CSD) profiles. To support both flexibility and reproducibility, features include compatibility with multiple recording formats, customizable processing parameters, interactive event review tools, and comprehensive logging of event detection and classification parameters. In addition to DS detection, Toothy can also detect sharp wave-ripples (SPW-Rs; an oscillatory population event recorded in the CA1 region), enabling comparative analysis between DSs and SPW-Rs. Toothy provides a standardized, reproducible pipeline for DS detection and classification, advancing broader efforts towards investigating hippocampal dynamics across diverse settings.

Characterisation of cold-selective lamina I spinal projection neurons
Skin cooling is detected by primary afferents that express the Trpm8 channel, but how this information is conveyed to the brain remains poorly understood. We have previously identified a population of lamina I projection neurons belonging to the anterolateral system (ALS) that receive numerous contacts from Trpm8-expressing primary afferents. Here, using a semi-intact somatosensory preparation, we show that these cells correspond to the cold-selective ALS neurons identified in previous physiological studies. We also confirm the presence of synapses from Trpm8 afferents onto these cells at the ultrastructural level. Based on our previous transcriptomic findings, we identify calbindin as a molecular marker, and show that this can be used to target the cold-selective ALS neurons for anterograde tracing studies. We provide evidence that they project to 3 brain regions that are associated with thermosensation: the rostralmost part of the lateral parabrachial area, the caudal part of the periaqueductal grey matter, and the ventral posterolateral nucleus of the thalamus. Our findings provide important insights into the organisation of neuronal circuits that underlie thermoregulation and the perception of cold stimuli applied to the skin.

Shedding light on left hippocampal mGlu5 in Alzheimer's disease
Metabotropic glutamate receptor 5 (mGlu5) plays a central role in synaptic plasticity and memory, and has emerged as a potential therapeutic target in Alzheimer's disease (AD). While asymmetries in hippocampal function have been observed in AD patients, the lateralized contribution of mGlu5 signaling to cognitive decline remains unclear. Here, we show the presence of a physiological left-right asymmetry in mGlu5 expression in the hippocampus of wild-type mice, with higher levels in the left hemisphere, consistent with previous observations. Importantly, we reveal that this asymmetry is lost in J20 AD model mice due to a selective reduction of mGlu5 in the left hippocampus. Then, using the light-controllable negative allosteric modulator Alloswitch-1, we demonstrate that selective inhibition of mGlu5 in the left, but not right, hippocampus is both necessary and sufficient to restore working and short-term memory in J20 mice. This left-specific modulation also reverses downstream pathological signaling, including aberrant Pyk2 and GSK3-{beta} activation and tau hyperphosphorylation, in both hippocampi. Our findings identify a functional lateralization of mGlu5 in hippocampal circuits and highlight the potential of spatially targeted photopharmacology for precise intervention in early AD pathology.

GlialCAM Cytoplasmic Signaling in Oligodendrocytes and Astrocytes is Essential for White Matter Homeostasis in the Brain
Glial cell adhesion molecule (GlialCAM) is an astrocyte- and oligodendrocyte-expressed transmembrane protein with two extracellular IgG-like domains and a cytoplasmic tail with putative signaling functions. While numerous studies have explored functions for the GlialCAM IgG-like domains in brain development and physiology, functions for its cytoplasmic signaling tail remain largely unknown. Therefore, we developed a mutant mouse model that expresses a truncated GlialCAM construct (GlialCAM -CT) that contains intact extracellular and transmembrane domains but lacks the cytoplasmic tail. Deletion of the GlialCAM cytoplasmic domain in glial cells of the brain results in vacuolization within white matter regions without disrupting neurovascular barrier integrity. Consequently, mutant mice exhibited selective deficits in motor coordination, muscular strength, and memory. Single cell transcriptome sequencing identifies GlialCAM-dependent defects in ECM remodeling pathways in white matter tracts. In situ spatial profiling revealed robust activation of astrocytes and microglia in the mutant brain. Proteomic analysis identified GlialCAM cytoplasmic tail interactors with links to MAPK signaling and cytoskeletal regulatory networks. These data reveal important functions for the GlialCAM cytoplasmic tail in homeostasis of white matter tracts in the adult murine brain. The GlialCAM -CT model may also be useful for studying the pathogenesis and possible treatment of neurological diseases linked to white matter degeneration.

Distributed neural computation and the evolution of the first brains
Brains likely evolved from diffuse nerve nets in the pre-Cambrian, but we do not know what the first brains looked like or how they were organized. Acoel worms, the sister lineage to all other animals with brains, offer a window into this transition. We studied the three-banded panther worm Hofstenia miamia, whose brain is diffuse and unlike any previously described: it shows little anatomical or functional regionalization or stereotypy. Worms forage successfully even after large portions of the brain are removed, suggesting most regions can perform most computations. Neural cell type markers are also distributed across the brain with little regionalization. High-resolution studies of hunting reveal that more brain tissue improves performance, but no specific brain region is required. These results lead us to propose that H. miamia's brain is built from computationally pluripotent 'tiles', whose interactions generate coherent behavior. This architecture suggests that early brains arose by condensation of diffuse nerve nets into unregionalized brains, with regionalization evolving secondarily.

Neural signatures of harm aversion predict later willingness to exert effort for others rewards
Prosocial behaviours, actions that incur personal costs to benefit others, are central to human social life. Two key domains are moral harm aversion, where individuals forgo personal gains to prevent harming others, and prosocial effort, which involves exerting effort to benefit others. Although previous studies suggest a relationship between these behaviours, it remains unclear whether neural responses in one domain can predict prosocial motivation in another. Here, we tested whether neural sensitivity to morally salient information in harm aversion could predict prosocial effort later. Participants completed two tasks: a harm aversion task during fMRI, in which they traded off monetary profit against delivering electric shocks to another person; and, one week later, a prosocial effort task outside the scanner, in which they decided whether rewards for others were worth the required physical effort. We focused on three regions implicated in cost-benefit decision-making and social cognition: the anterior cingulate cortex (ACC), anterior insula (AI), and temporoparietal junction (TPJ). Behaviourally, greater harm aversion was associated with increased prosocial effort. Neurally, AI responses to others harm predicted sensitivity to others rewards in the effort task, consistent with a role in representing others outcomes across positive and negative valences. By contrast, TPJ responses to profit from harming others predicted decreased sensitivity to others rewards, suggesting a role in context-dependent valuation that may constrain prosocial behaviour. These findings demonstrate that neural responses to morally salient information in one context correlate with prosocial motivation in another, highlighting mechanisms that bridge moral sensitivity and effortful prosociality.

Localization of Fascin to Dendritic Protrusions Regulates Postsynaptic Plasticity
The Fascin family of actin-bundling proteins organizes actin filaments (F-actin) into tightly packed bundles that drive dynamic membrane protrusions such as filopodia. In neurons, fascin has been thought to primarily function in axons, as previous studies reported its absence from dendritic filopodia and spines. Here, we demonstrate that fascin is both present and functionally important in dendritic compartments. Using optimized immunocytochemistry and CRISPR-based endogenous tagging of fascin1 in cultured hippocampal neurons, we show that fascin localizes to developing dendritic filopodia and is enriched in mature dendritic spines. Super-resolution imaging further reveals that fascin is organized into discrete nanoscale foci within spine heads, but not the spine neck. Finally, we show that CRISPR-mediated knockout of fascin1 in mature hippocampal neurons impairs synaptic potentiation, without affecting baseline excitatory synaptic transmission. Together, our findings uncover a previously overlooked aspect of actin organization in dendritic spines and establish fascin as a critical regulator of postsynaptic plasticity.

A GPCR signaling pathway in insect odor detection
Odor detection differs fundamentally in vertebrates, which use G protein-coupled receptors (GPCRs), and insects, which employ ion channels. Here, we report the first evidence for a GPCR defining tuning properties of insect olfactory sensory neurons. Single-cell transcriptomics of the Drosophila melanogaster antenna identified selective expression of the G{gamma}30A subunit in acid-sensing Ir64a-DC4 neurons. G{gamma}30A is essential for broadening responses to long-chain acids, acting with Gs, G{beta}13F, adenylate cyclase Ac13E and the Cngl channel. We further discovered that Cirl, a latrophilin-family GPCR, is broadly-transcribed in the antenna but the protein is localized only in Ir64a-DC4 sensory cilia, dependent upon G{gamma}30A, but not Ir64a. Importantly, loss of Cirl also narrows Ir64a-DC4 tuning properties. Homologous neurons in Drosophila sechellia naturally exhibit narrow acid tuning, despite functional conservation of Ir64a; these differences correlate instead with lower expression of metabotropic components. Our findings reveal unexpected roles for GPCR/metabotropic signaling in olfactory detection and divergence in insects.

Differential effects of aging and Alzheimer's disease on microemboli clearance in a mouse model of microinfarction
Background: Cerebral microinfarcts often occur as a result of microvessel occlusion and are prevalent among dementia patients and the aging population. Detailed studies on the timecourse of microvascular occlusions indicate that endogenous mechanisms exist to re-canalize occluded vessels. One recently discovered mechanism is angiophagy, where vessels engulf and expel microemboli, thus mitigating damage caused by micro-occlusions. While several previous studies have shown that angiophagy occurs in rodent models, the frequency and timing of this process is not well characterized. In addition, there is limited data on the impact of aging on angiophagy, or the occurrence of this process in clinically relevant diseases such as Alzheimer's disease. Methods: To further study the timecourse of angiophagy, we induced micro-occlusions in young, aged and 3xTg Alzheimer's mice via injection of 20um microspheres into the carotid artery. Mice were sacrificed on day 3, 7 or 14 and the brains were processed for brain-wide localization of microspheres and quantification of angiophagy. Results: We found the largest number of microspheres in the neocortex, yet when accounting for region size, microspheres were more evenly distributed across brain regions. When quantifying angiophagy in young non-diseased mice, we found that approximately 43% of microspheres had extravasated from the vessel by day 14. This process was delayed in aged mice, with only 10% of microspheres extravasated by day 14. Moreover, in young 3xTg Alzheimer's mice, we found the rate of angiophagy to be more efficient at day 14 compared to non-transgenic controls, with 47% and 43% of microspheres extravasated, respectively. A similar trend was observed in aged Alzheimer?s mice, in which 38% of microspheres were extravasated by day 14 in 3xTg mice, compared to only 30% in non-transgenic controls. Conclusions: Taken together, we find that while aging impairs the process of angiophagy, Alzheimer's mice exhibit a paradoxical increase in the rate of microsphere extravasation.