bioRxiv Subject Collection: Neuroscience's Journal

Towards individualized deep brain stimulation: A stereoencephalography-based workflow for unbiased neurostimulation target identification
BackgroundDeep-brain stimulation (DBS) is increasingly being used to treat a variety of neuropsychiatric conditions, many of which exhibit idiosyncratic symptom presentations and neural correlates across individuals.nnMethodsEleven patients (chronic pain=5, major depressive disorder=5, obsessive-compulsive disorder=1) underwent inpatient testing using stereoelectroencephalography (sEEG) and symptom monitoring to identify personalized stimulation targets for subsequent DBS implantation. We present a structured approach to this sEEG testing, integrating a Stimulation Testing Decision Tree with power analysis and effect size considerations to inform adequately powered results to detect therapeutic stimulation sites with statistical rigor.nnResultsEffect sizes (Cohens d) of stimulation-induced symptom score changes ranged from approximately -1.5 to +3.0. The standard deviation of sham trial responses was strongly correlated with the standard deviation of stimulation responses (r=0.86, p < 0.001). Power analysis (using a paired-t test) showed that, for large effect sizes (>=1.1), around 10 trials should be used per stimulation site. Furthermore, we show that 12-15 sham trials were needed to robustly estimate sham variability.nnConclusionsThe workflow presented is adaptable to any indication and is specifically designed to overcome key challenges experienced during stimulation site testing. Through incorporating sham trials, effect size calculations, and tolerability testing, the approach outlined can be used to find personalized, unbiased, and clinically efficacious stimulation sites.

Natural scene and object perception based on statistical image feature: psychophysics and EEG
Recent studies have suggested the importance of statistical image features in both natural scene and object recognition, while the spatial layout or shape information is still important. In the present study, to investigate the roles of low- and high-level statistical image features in natural scene and object recognition, we conducted categorization tasks using a wide variety of natural scene (250 images) and object (200 images) images, along with two types of synthesized images: Portilla-Simoncelli (PS) synthesized images, which preserve low-level statistical features, and style-synthesized (SS) images, which retain higher-level statistical features. Behavioral experiments revealed that observers could categorize style-synthesized version of natural scene and object images with high accuracy. Furthermore, we recorded visual evoked potentials (VEPs) for the original, SS, and PS images and decoded natural scene and object categories using a support vector machine (SVM). Consistent with the behavioral results, natural scene categories were decoded with high accuracy within 200 ms after the stimulus onset. In contrast, object categories were successfully decoded only from VEPs for original images at later latencies. Finally, we examined whether style features could classify natural scene and object categories. The classification accuracy for natural scene categories showed a similar trend to the behavioral data, whereas that for object categories did not align with the behavioral results. Taken together, these findings suggest that although natural scene and object categories can be recognized relatively easily even when layout information is disrupted, the extent to which statistical features contribute to categorization differs between natural scenes and objects.nnSignificance StatementHumans can reliably recognize complex natural scenes and objects. Recent studies have suggested that such recognition may rely on statistical image features, but the extent to which these features contribute to the recognition remains unclear. In the present study, we investigated how well statistical image features account for the perception of natural scenes and objects by conducting psychophysical categorization experiments and EEG decoding analyses. We found that natural scene categories could be reliably recognized based on statistical image features, and this recognition was consistent with neural responses. In contrast, although statistical image features also contributed to object category recognition, their effect appeared to be more limited. Together, these findings highlight the utility of statistical image features in visual perception.

Hippocampal ripples initiate cortical dimensionality expansion for memory retrieval
How are past experiences reconstructed from memory? Learning is thought to compress external inputs into low-dimensional hippocampal representations, later expanded into high-dimensional cortical activity during recall. Hippocampal ripples--brief high-frequency bursts linked to retrieval--may initiate this expansion. Analysing intracranial EEG data from patients with pharmaco-resistant epilepsy during an episodic memory task, we found that cortical dimensionality increased following ripple events during correct, but not incorrect, retrieval. This expansion correlated with faster reaction times and reinstatement of the target association. Crucially, hippocampal theta and cortical gamma phase-amplitude coupling emerged after ripples but before cortical expansion, suggesting a mechanism for ripple-driven communication. Ripple events also marked the separation of task-relevant variables in cortical state space, revealing how hippocampal output reshapes the geometry of memory representations to support successful recall.

Familial Alzheimer disease mutation identifies novel role of SORLA in release of neurotrophic exosomes
Sortilin-related receptor with A-type repeats (SORLA) is an intracellular sorting receptor that directs target proteins between endocytic and secretory compartments of cells. Mutations in SORL1, encoding SORLA, are common in individuals suffering from Alzheimer disease (AD) of unknown etiology. Conceptually, characterization of inheritable SORL1 variants associated with AD can provide important new information about functions of this receptor relevant for aging brain health. Here, we focused on elucidation of the AD-associated variant SORLA N1358S, carrying a mutation in the main ligand binding domain of the receptor. Using unbiased quantitative proteome screens, we identified major alterations in the mutant receptor interactome linked to biogenesis and secretion of exosomes. Using advanced biophysical, cell biological, as well as functional studies in stem cell-derived human cell models we corroborated impaired release and loss of neurotrophic action of exosomes from neurons and microglia expressing SORLAN1358S. An impaired neurotrophic potential was attributed to an altered exosomal content of RNA binding proteins and associated microRNAs, known to control neuronal growth and maturation. Our studies identified a so far unknown function for SORLA in controlling the quantity and trophic quality of extracellular vesicles secreted by cells, and they argue for impaired cellular cross talk through exosomes as a pathological trail contributing to the risk of AD seen with carriers of SORL1 variants.

Disentangling Arousal and Attentional Contributions to Pupil Size: Toward Simultaneous Estimation of Emotional and Cognitive States
Pupillary response serves as a noninvasive physiological marker of autonomic activity, modulated by both emotional arousal and the luminance of attended visual stimuli. However, these factors often co-occur, making it difficult to disentangle their individual contributions. This study investigated how auditory emotional stimuli and attention-guided changes in luminance independently influence pupil dynamics. Participants were instructed to direct their visual attention to either white or black moving dot patterns, and to shift their attention upon the onset of an emotional sound. Pupil responses were z-normalized on a per-trial basis, and optokinetic nystagmus (OKN) was recorded to verify attentional shifts. Results showed that emotional arousal robustly increased pupil size across conditions, while valence had no significant main effect. Pupil size was also modulated by the luminance of the attended stimulus, reflecting parasympathetic influences. No significant interaction between arousal and valence was observed, suggesting additive rather than interactive effects. These findings emphasize the methodological necessity of controlling attentional luminance in pupillometric studies and highlight the potential of pupil-based measures for emotion-aware system design. Crucially, because pupil dynamics reflect both luminance-guided attention and emotional arousal via distinct autonomic pathways, combining pupillometry with nonverbal indicators of attention--such as optokinetic nystagmus (OKN)--may enable the simultaneous estimation of attentional focus and emotional state in real time.

Multi-cohort, multi-sequence harmonisation for cerebrovascular brain age
IntroductionHigher brain-predicted age gaps (BAG), based on anatomical brain scans, have been associated with cognitive decline among elderly participants. Adding a cerebrovascular component, in the form of arterial spin labelling (ASL) perfusion MRI, can improve the BAG predictions and potentially increase sensitivity to cardiovascular health, a contributor to brain ageing and cognitive decline. ASL acquisition differences are likely to influence brain age estimations, and data harmonisation becomes indispensable for multi-cohort brain age studies including ASL. In this multi-cohort, multi-sequence study, we investigate harmonisation methods to improve the generalisability of cerebrovascular brain age.nnMethodsA multi-study dataset of 2608 participants was used, comprising structural T1-weighted (T1w), FLAIR, and ASL 3T MRI data. The single scanner training dataset consisted of 806 healthy participants, age 50{+/-}17, 18-95 years. The testing datasets comprised four cohorts (n=1802, age 67{+/-}8, 37-90 years). Image features included grey and white matter (GM/WM) volumes (T1w), WM hyperintensity volumes and counts (FLAIR), and ASL cerebral blood flow (CBF) and its spatial coefficient of variation (sCoV). Feature harmonisation was performed using NeuroComBat, CovBat, NeuroHarmonize, OPNested ComBat, AutoComBat, and RELIEF. ASL-only and T1w+FLAIR+ASL brain age models were trained using ExtraTrees. Model performance was assessed through the mean absolute error (MAE) and mean BAG.nnResultsASL feature differences between cohorts decreased after harmonisation for all methods (p<0.05), mostly for RELIEF. Negative associations between age and GM CBF (b=-0.37, R2=0.13, unharmonised) increased after harmonisation for all methods (b<-0.42, R2>0.12) but weakened for RELIEF (b=-0.28, R2=0.14). In the ASL-only model, MAE improved for all harmonisation methods from 11.1{+/-}7.5 years to less than 8.8{+/-}6.2 years (p<0.001), while BAGs changed from 0.6{+/-}13.4 years to less than -1.03{+/-}7.92 years (p<0.001).nnFor T1w+FLAIR+ASL, MAE (5.9{+/-}4.6 years, unharmonised) increased for all harmonisation methods non-significantly to above 6.0{+/-}4.9 years (p>0.42) and significantly for RELIEF (6.4{+/-}5.2 years, p=0.02), while BAGs non-significantly differed from -1.6{+/-}7.3 years to between -1.3{+/-}4.7 and -2.0{+/-}8.0 years (p>0.82). In general, the ASL-specific parameter harmonisation method AutoComBat performed nominally best.nnDiscussionHarmonisation of ASL features improves feature consistency between studies and also improves brain age estimations when only ASL features are used. ASL-specific parameter harmonisation methods perform nominally better than basic mean and scale adjustment or latent-factor approaches, suggesting that ASL acquisition parameters should be considered when harmonising ASL data. Although multi-modal brain age estimations were improved less by ASL-only harmonisation, possibly due to weaker associations between age and ASL features compared to T1w features feature importance, studies investigating pathological ASL-feature distributions might still benefit from harmonisation. These findings advocate for ASL-parameter specific harmonisation to explore associations between cardiovascular risk factors, brain ageing, and cognitive decline using multi-cohort ASL and cerebrovascular brain age studies.

Base exchange inhibitors of SARM1 form mononucleotide adducts and activate SARM1 in vivo
Activation of the NAD hydrolase SARM1 causes neuronal pathology. NAD binding to an allosteric site maintains SARM1 autoinhibition while NMN binding enables NADase activity. We evaluated SARM1 base exchange inhibitors (BEI) that exchange with nicotinamide in the SARM1 catalytic site to form inhibitor adducts. We found that BEI paradoxically activated SARM1 in some contexts, elevating both the SARM1 product cADPR and ratio to substrate, cADPR/NAD, in uninjured sciatic nerve and in healthy animals. Catalytically inactive E642A SARM1 knock-in mice were protected from elevated cADPR and cADPR/NAD in sciatic nerve after BEI dosing. Like the SARM1 activating forms of the neurotoxins Vacor and 3-acetylpyridine, BEI formed mononucleotide (MN) adducts in vivo. BEI also formed MN adducts in human THP-1 cells, as did the pyridine-containing drugs indinavir and chloroquine. These findings underscore the promiscuity of nicotinamide-related metabolism and potential for neurotoxicity arising from SARM1s susceptibility to activation by exogenous agents.

Repeated Binge-Like Alcohol Drinking Heightens Aggression in Mice
RationaleIn humans, alcohol drinking is a significant driver of violent behaviors such as assaults and homicides. While acute intoxication is known to produce heightened aggression, little is known about alcohols long-term effects. Emerging evidence, however, suggests that chronic alcohol intake can promote heightened aggression, including during abstinence and may also sensitize individuals to alcohols acute aggression-heightening effects.nnObjectivesThe goal of this study was to test the effects of chronic binge-like ethanol drinking on both alcohol-involved and alcohol-uninvolved aggression in male CFW mice. We aimed to model individual differences in binge drinking and assess changes in aggression during both acute and protracted abstinence.nnResultsAfter 5 weeks of Drinking in the Dark (DID), CFW mice that showed higher levels of EtOH drinking ( high drinkers, 1.33 g/kg/h) became more aggressive than low drinkers (0.45 g/kg/h) and H2O controls, as measured via frequency of attack bites during resident-intruder fighting. In the first aggressive encounter following 1 week of abstinence, animals with an alcohol drinking history initiate a fight more rapidly and with greater consistency than H2O controls. We also found that a single session of binge-like alcohol drinking acutely heightened aggression regardless of drinking history.nnConclusionsThese results suggest that repeated binge-like alcohol drinking causes escalations in alcohol-uninvolved aggression during acute (in high drinkers) and protracted abstinence (in all alcohol drinkers). However, chronic alcohol intake does not appear to sensitize animals to alcohol-involved aggression. These findings support the utility of genetically heterogeneous CFW mice for modeling individual variability in alcohol-related aggression.

Comparison of Neural Tracking and Spectral Entropy in Patients with Disorders of Consciousness
ObjectivesThis study aims to explore the brain responses of patients with disorders of consciousness (DoC) to natural speech. Specifically, it focuses on a key characteristic of natural speech: the speech envelope. To achieve this, we employed two distinct measures. The first evaluates how effectively the patients brain activity "tracks" the speech envelope, called neural tracking. The second assesses the complexity of the brains responses to the speech stimulus, measured through spectral entropy. These two measures are then compared in their association with the patients clinical diagnosis and their level of behavioral responsiveness, both of which were assessed using the Coma Recovery Scale-Revised (CRS-R).nnDesignFour patients with DoC participated in this study, during which their brain activity was recorded using electroen-cephalography (EEG). At the same time, they listened to a narrated story in both Dutch and Swedish. Additionally, EEG baseline recordings were collected. We employed a backward modeling approach to evaluate the speech envelopes neural tracking. This technique involves training a model to map the relationship between EEG signals and the corresponding speech envelope. Once the model is trained, it can use unseen EEG data to reconstruct the speech envelope, which is then compared to the original speech envelope to assess how effectively the patient processed the auditory stimulus. For the behavioral assessment, we recalculated the CRS-R score of each patient into the CSR-R index, a more meaningful score that utilizes all the information contained in the CRS-R instead of only the highest scores on each subscale.nnResultsOur findings revealed positive correlations between spectral entropy and the CRS-R index, which were more pronounced during the listening conditions than the baseline. While neural tracking of the speech envelope did not correlate with the CRS-R index, it did exhibit a positive association with CRS-R diagnoses, indicating that patients with better clinical diagnoses demonstrated higher levels of neural tracking. Additionally, we identified an interaction effect between spectral entropy and neural tracking. Specifically, higher levels of neural tracking were associated with a stronger positive relationship between spectral entropy and the CRS-R index. In contrast, when neural tracking was lower, this relationship disappeared.nnConclusionThis study demonstrated the potential of neural tracking and spectral entropy as complementary tools to investigate patients with DoC. Spectral entropy proved valuable for assessing behavioral responsiveness, while neural tracking shows promise in assessing the DoC diagnosis. Terms: disorders of consciousness (DoC), neural tracking, speech envelope, spectral entropy

Dynamic neural representations of scene beauty are relatively unaffected by stimulus timing and task
Understanding the neural correlates of aesthetic experiences in natural environments is a central question in neuroaesthetics. A previous EEG study (Kaiser, 2022) identified early and temporally sustained neural representations of visual scene beauty. These results were obtained with long presentation durations (1,450 ms) and with explicit beauty judgments, rendering it unclear how presentation time and task demands shape the neural correlates of scene beauty. In two EEG experiments, we replicated this study while varying presentation time and task. Experiment 1 tested whether reducing stimulus presentation time from 1,450 ms to 100 ms altered neural representations of beauty. Experiment 2 examined whether beauty-related representations prevailed when participants performed an orthogonal task instead of explicitly judging beauty. Representational similarity analysis revealed that beauty-related neural representations emerged early (within 150 - 200 ms post-stimulus) and were sustained over time, in line with previous findings. Critically, we found that neither reduced presentation time nor the absence of an explicit beauty judgment significantly altered beauty-related neural dynamics. These results suggest that the neural correlates of scene beauty are relatively robust to stimulus presentation and task regimes, providing a potential correlate of the spontaneous perception of beauty in natural environments.

Uncovering the Neural Fingerprint of Akinetic States in a Parkinsons Disease Rodent Model
Parkinsons Disease (PD) is characterized by complex motor deficits, including transient akinetic episodes during locomotion. Here, we investigated the neural correlates of akinesia in a 6-OHDA rat model of PD. We developed the open-source toolbox neurokin to analyse the kinematic and neural signal recorded during a runway task. First, we observed that compared to control, PD rats spent significantly more time in akinetic episodes, which were correlated with an increase in beta-band power. Next, we computed a set of temporally resolved kinematic and neural features capturing the evolution of locomotion states. We employed linear and non-linear machine learning models, to retrieve salient features that characterized akinetic episodes. Beyond confirming established associations with beta power, we identified Hjorth complexity and mobility as time-domain features modulated by akinetic onset. Our findings highlight novel, computationally lightweight biomarkers that might serve as targets for future state-adaptive neuromodulation therapies.

Heterochronic transcription factor expression drives cone-dominant retina development in 13-lined ground squirrels.
Evolutionary adaptation to diurnal vision in ground squirrels has led to the development of a cone-dominant retina, in stark contrast to the rod-dominant retinas of most mammals. The molecular mechanisms driving this shift remain largely unexplored. Here, we perform single-cell RNA sequencing (scRNA-Seq) and chromatin accessibility profiling (scATAC-Seq) across developmental retinal neurogenesis in the 13-lined ground squirrel (13LGS) to uncover the regulatory basis of this adaptation. We find that 13LGS cone photoreceptors arise not only from early-stage neurogenic progenitors, as seen in rod-dominant species like mice, but also from late-stage neurogenic progenitors. This extended period of cone generation is driven by a heterochronic shift in transcription factor expression, with cone-promoting factors such as Onecut2, Pou2f1, and Zic3 remaining active in late-stage progenitors, and factors that promote cone differentiation such as Thrb, Rxrg, and Mef2c expressed precociously in late-stage neurogenic progenitors. Functional analyses reveal that Zic3 and Mef2c are sufficient to promote cone photoreceptor and respress rod specification, and act through species-specific regulatory elements that drive their expression in late-stage progenitors. These results demonstrate that evolutionary modifications to gene regulatory networks underlie the development of cone-dominant retinas and provide insight into mechanisms of sensory adaptation and potential strategies for cone photoreceptor regeneration in vision disorders.

Alpha-synuclein phosphorylation is abundant in the non-synucleinopathy human brain
Phosphorylation of alpha-synuclein at serine 129 (PS129) has been strongly associated with aggregates and implicated in the synucleinopathy disease processes. Recent findings suggest that PS129 is abundant in the non-synucleinopathy mammalian brain, in a brain region-specific and context-dependent manner, raising important questions about the significance of PS129 for synucleinopathy disease processes. Here, we identified and described phosphatase labile physiological PS129 in the mammalian brain using a range of specimens from rodent to human surgically resected temporal lobectomy tissues. Results confirmed phosphatase-sensitive physiological PS129 in the non-synucleinopathy human temporal lobe and hippocampus when the post-mortem interval was eliminated (i.e., surgically resected human samples or perfusion-fixed animal brain). In the non-synucleinopathy mammalian brain, PS129 fluctuated between 2-45% of the total asyn pool in a case-specific and brain region-specific manner. In agreement with previous studies, physiological PS129 was abundantly distributed throughout the layers of the hippocampus and cortex. Physiological PS129 was not observed in PD brain, or non-synucleinopathy specimens of >2h post-mortem interval. Remarkably, in the PD brain, the PS129 to asyn ratio was similar ([~]5-40%) to that in the non-synucleinopathy brain. Despite physiological PS129 being associated with neuronal activity, physiological PS129 did not correlate with cFos expression. Conclusions: Physiological PS129 is abundant in the human brain, and apparent pathological enrichment, in part, can be explained by the enzymatic resistance of aggregates and not disease-driven phosphorylation events.

Fetal magnetoencephalography based on optically pumped magnetometers
The fetus in the third trimester of gestation has already the remarkable capacity to process external sensory information in utero. So far, investigations of fetal brain responses to sensory information have mostly relied on cryogenic magnetoencephalography (MEG), which is suitable to record fetal brain activity and is not much affected by layers of maternal tissues. Nevertheless, this solution is extremely expensive and limited to a couple of laboratories worldwide. In this work, we took advantage of the next generation cryogenic-free MEG, that is MEG based on optically pumped magnetometers (OPM), to develop a system that could record both fetal and newborn brain responses to auditory stimulation in a longitudinal design. Twenty-one pregnant women in their late third trimester of gestation (35-40 weeks of gestational age) were exposed to sequences of 500 Hz tones. Fetal brain activity was recorded using a wearable belt equipped with OPM sensors arranged on the womens abdomen based on fetal head position. Results revealed that fetal OPM-MEG successfully recorded significant evoked brain responses to auditory stimuli that peaked ~300 ms post-stimulus at the group level. A similar auditory paradigm was performed with on-scalp OPM-MEG in 14 one-month-old infants, with 9 participants common to both timepoints. Infant responses showed a significant latency decrease compared to the fetal ones in terms of magnetometers; a decrease that did not reach significance level for virtual gradiometers. This work demonstrates the ability of OPM-MEG to non-invasively record fetal brain responses to external sensory stimuli. It paves the way for a wider use of fetal MEG to investigate fetal cognition and positions OPM-MEG as the most promising lifespan-compliant solution for monitoring early brain development.

Alcohol Attenuates CRF-Induced Excitatory Effects from the Extended Amygdala to Dorsostriatal Cholinergic Interneurons
Alcohol relapse is linked to corticotropin-releasing factor (CRF) signaling and is caused by dysfunction within reward pathway circuitry, yet the underlying mechanisms guiding this process remain unclear. Here, we investigated how CRF modulates cholinergic interneurons (CINs) in the dorsal striatum, a region critical for mediating cognitive flexibility and action selection. Using monosynaptic and retrograde circuit tracing, we identified direct inputs from CRF-expressing (CRF) neurons in the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST) to dorsal striatal CINs. We showed that CINs express CRF receptor 1 (CRFR1) and established their functional connectivity with CeA/BNST CRF projections. Functional recordings revealed that CRF enhanced CIN excitability and promoted acetylcholine release in the dorsal striatum. However, acute alcohol exposure and withdrawal attenuated the excitatory effect of CRF on CIN firing, suggesting a mechanism by which alcohol disrupts CRF-dependent neuromodulation. These findings uncover a novel CRF-mediated circuit linking the extended amygdala to the dorsal striatum and provide insight into how CRF and alcohol interact to impair striatal function. This work highlights CRF signaling as a potential target for uncovering the mechanism of stress-induced changes to the reward pathway.nnHighlightsO_LIDorsal striatal CINs receive monosynaptic CRF+ inputs from CeA and BNST neurons.nC_LIO_LICRFR1 is expressed in striatal CINs, and CRF+ fibers are present in the dorsal striatum.nC_LIO_LICRF enhances dorsal striatal CIN activity via CRFR1 signaling.nC_LIO_LIAcute alcohol exposure impairs CRF-induced cholinergic activity.nC_LInnSignificance StatementThe dorsal striatum regulates goal-directed behavior and is implicated in alcohol use disorder (AUD). Within this region, cholinergic interneurons (CINs) support cognitive flexibility and receive input from limbic areas, including the central amygdala (CeA) and bed nucleus of the stria terminalis (BNST). In this study, we identified direct projections from CRF-producing neurons in the CeA and BNST to dorsal striatal CINs, a subset of which express CRF receptor 1 (CRFR1). Electrophysiological recordings confirmed these projections provide functional input that is disrupted by acute alcohol exposure. These findings lay the groundwork for future studies on how CRF and alcohol interact to impair striatal function.

Specialized parallel pathways for adaptive control of visual object pursuit
To pursue an unpredictably moving visual object, the brain must generate motor commands that continuously steer the object to the midline of the visual field via feedback. Behavior implies that visual pursuit relies on a feedback loop with flexible gain, but the mechanisms of this "adaptive control" are not well-understood. Here we show that adaptive control in the Drosophila pursuit system involves two parallel feedback loops. One serves to steer the object coarsely toward the midline; the properties of this pathway are relatively constant. The other functions to steer the object precisely to the midline, and its properties are flexible: gain increases when the object is moving away from the midline, when the pursuer is running fast, and during arousal. Genetically suppressing this flexible pathway decreases pursuit performance in aroused males. Our findings show how biological feedback systems can implement adaptive control to drive vigorous error correction while avoiding instability.nnHighlightsO_LIParallel pathways detect a visual object in the frontal versus lateral visual fieldnC_LIO_LISteering arises from combined ipsilateral excitation and contralateral inhibitionnC_LIO_LIThe circuit for frontal objects is direction-selective, for anticipatory steeringnC_LIO_LIThe circuit for frontal objects is also recruited during fast running and arousalnC_LI

GABAergic network from AVP neurons to VIP neurons in the suprachiasmatic nucleus sets the activity/rest time of the circadian behavior rhythm
The central circadian clock of the suprachiasmatic nucleus (SCN) is a network composed of multiple types of {gamma}-aminobutyric acid (GABA)-ergic neurons and glial cells. However, the precise role of GABAergic transmission in the SCN remains unclear. In this study, we investigated the GABAergic regulation from arginine vasopressin (AVP)-producing neurons in the SCN shell to vasoactive intestinal polypeptide (VIP)-producing neurons in the SCN core. Blocking GABA release from AVP neurons by a vesicular GABA transporter (Vgat) gene deletion lengthened the activity time (the interval between the onset and offset of locomotor activity) and shortened the duration of high Ca2+ activity in VIP neurons to match the behavioral rest time. Conversely, eliminating functional GABAA receptors (GABAAR) in VIP neurons by in vivo genome editing reduced locomotor activity level and the activity time, and lengthened the high Ca2+ duration in VIP neurons. Optogenetic activation of AVP neurons in vivo increased Ca2+ in VIP neurons during the night. A similar Ca2+ response of VIP neurons to AVP neuronal activation was also observed in SCN slices and was inhibited by a GABAAR antagonist, gabazine. Importantly, gabazine application alone raised the baseline Ca2+ in VIP neurons, suggesting a tonic depression of these neurons by GABA. Moreover, AVP neuronal activation decreased Ca2+ in non-AVP neurons located between AVP- and VIP-rich regions in the SCN. These results suggest that GABA from AVP neurons disinhibits VIP neurons indirectly by suppressing other intermediate GABA neurons to set the behavior activity/rest time precisely.

Logarithmic coding leads to adaptive stabilization in the presence of sensorimotor delays
Animals respond to sensory stimuli with motor actions, which in turn generate new sensory inputs. This sensorimotor loop is constrained by time delays that impose a trade-off between responsiveness and stability. Additionally, as the relationship between a motor command and the corresponding sensory feedback is context dependent, the response must be adapted in real time. It is generally believed that this adaptation process relies on an internal model that is continuously updated through prediction error minimization. Here, we experimentally reveal an alternative strategy based on a simpler feedback mechanism that does not require any internal model. We developed a virtual reality system for the miniature transparent fish Danionella cerebrum that enables in vivo brain-wide imaging during fictive navigation. By systematically manipulating the feedback parameters, we dissected the motor control process that allows the animal to stabilize its position using optic flow. The sensorimotor loop can be fully described by a single delay differential equation, whose solutions quantitatively capture the observed behavior across all experimental conditions. Both behavioral and neural data indicate that the observed adaptive response arises from the logarithmic nonlinearities at the sensory (Weber-Fechner law) and motor (Henneman's size principle) ends. These fundamental properties of the nervous system, conserved across species and sensory modalities, have traditionally been interpreted in terms of efficient coding. Our findings unveil a distinct functional role for such nonlinear transformations: ensuring stability in sensorimotor control despite inherent delays and sensory uncertainty.

Miniaturized and accessible functional ultrasound imaging system for freely moving mice
Functional ultrasound (fUS) imaging provides brain-wide activity maps with high spatiotemporal resolution and deep penetration, positioning it as a key technology for future non-invasive brain-computer interfaces (BCIs). Realizing this potential, particularly for chronic BCI applications requiring long-term monitoring in naturalistic settings, critically depends on significant system miniaturization to overcome the cost and complexity limitations of current platforms. Addressing this challenge, we present mini-fUS, a miniaturized, cost-effective fUS platform engineered for accessibility without compromising core performance for demanding neuroscience research. The system features a compact transmit-receiver, low-noise power supply, and high-speed data transfer, achieving pulse repetition frequencies up to 5 kHz with negligible jitter. Real-time GPU-accelerated beamforming and singular value decomposition (SVD) enable whole-brain activity mapping, demonstrated here in freely moving mice at up to 3.57 Hz with [~]100 {micro}m spatial resolution and 15 mm penetration depth. Validated through recordings of brain activity during sensory stimulation, anesthesia, and behavior, this design defines a practical hardware-software framework for fUS. By significantly improving accessibility and enabling robust monitoring in mobile subjects, this work advances the development of fUS for both fundamental research and future BCI technologies, while clarifying essential fUS operational principles.

Dysregulation of Multiple Solute Carrier genes and Metabolic Deficits in SLC1A4-Mutant Human iPSC-Derived Hippocampal Neurons
Mutations in SLC1A4, which encodes the neuronal amino acid transporter ASCT1, disrupt metabolic and synaptic homeostasis, contributing to neurodevelopmental deficits commonly observed in autism spectrum disorder (ASD). To investigate the underlying molecular mechanisms of SLC1A4-related disorders, we utilized human iPSC-derived hippocampal neurons and applied an integrated multi-omics approach, combining electrophysiology, calcium imaging, metabolomics, proteomics, and transcriptomics. Our findings reveal an initial phase of early neuronal hyperexcitability, driven by increased sodium and potassium currents, followed by a progressive decline in synaptic activity at later stages. Metabolomic analysis identified elevated glycine, serine, and glutamate levels during early differentiation, contributing to excitotoxicity, whereas later glutamate depletion and extracellular matrix (ECM) disruption were associated with synaptic dysfunction. Proteomics data further showed dysregulation in metabolic pathways, amino acid biosynthesis, and fatty acid metabolism pathways during early time points, and in later stage dysregulation in metabolic and ECM-receptor interactions. Additionally, transcriptomic analysis revealed dysregulation in calcium signaling, amino acid metabolism pathways such as valine, leucine and isoleucine degradation, tryptophan metabolism, and glycine, serine, and threonine metabolism. Further investigation of SLC-family transporter genes uncovered disruptions in glutamate and glycine transport, establishing a direct link between amino acid transport dysfunction and neuronal deficits. Collectively, our study demonstrates that SLC1A4 mutations lead to dysregulation of multiple solute carrier protein genes causing metabolic stress, excitability defects, and synaptic abnormalities, providing a molecular framework for understanding SLC1A4-related neurodevelopmental disorders and identifying potential therapeutic targets.

Maternal Immune Activation Disrupts Epigenomic and Functional Maturation of Cortical Excitatory Neurons
Elevated levels of maternal pro-inflammatory cytokines during gestation can disrupt offspring neural development, increasing the risk of neurodevelopmental disorders. We studied the effects of Poly(I:C)-induced maternal immune activation (PIC-MIA) during mid-gestation on developing cortical excitatory neurons' DNA methylation and transcriptome. PIC-MIA disrupted the developmental regulation of synapse-related genes and of genes implicated in autism spectrum disorders. Genomic regions that gain or lose DNA methylation during normal development were altered following PIC-MIA, including neurodevelopmental transcription factor binding sites. The DNA methylation and transcriptional changes were consistent with a delay in excitatory neuron maturation. Whole-cell recordings showed that PIC-MIA preferentially altered the physiological development of layer 5 excitatory neurons. Taken together, present results suggest that alterations in the epigenome, through the disruption of circuit formation, may drive the long-term consequences of maternal infection during gestation.

Cellular and molecular underpinnings of functional networks in the human brain
Understanding how cellular and molecular architecture underpins the large-scale organization of human brain function is a central challenge in neuroscience. By integrating transcriptomic (microarray data and single-nucleus RNA-sequencing [sn-RNA] data), molecular imaging, and neuroimaging datasets, we present converging evidence that the spatial distribution of diverse cell types, neurotransmitter systems, and mitochondrial phenotypes are systematically aligned with intrinsic connectivity networks (ICNs)-the macroscale scaffolding of brain function. These associations extend beyond local correspondence to reflect network-level structure: inter-ICN similarity networks derived from cellular and molecular profiles significantly recapitulate both static and dynamic patterns of functional network connectivity (FNC), mirroring the established division of ICNs into canonical functional domains. Importantly, these cellular and molecular profiles not only co-localize with ICNs and FNC but also appear to support their role as intermediaries linking microscale biological substrates to cognitive function. Mediation analyses reveal that specific ICNs statistically mediate the relationship between microscale cell-type architecture and domain-specific cognitive and behavioral processes. Moreover, dynamic FNC, particularly in specific transient states, captures the mediating pathways linking cell-type and neurotransmitter similarity networks to cognitive network organization. Taken together, our findings suggest that the brain's functional architecture is systematically aligned with cellular and molecular organization, which may act as a biological constraint guiding functional network formation and shaping the neural basis of cognition.

Resting State Functional Connectivity of the Marmoset Claustrum
The common marmoset (Callithrix jacchus) has been recently developed as a nonhuman primate model useful for studying behaviour, neurology, and higher-level cognitive processes considering their phylogenetic proximity to humans. Here, we investigated the resting state functional connectivity (RSFC) of the marmoset claustrum, a small, highly connected subcortical structure. Using an open resource of 234 functional MRI scans from awake marmosets, we found claustrum connectivity to the prefrontal cortex, posterior parietal cortex, temporal cortices, cingulate cortex, sensory cortices, limbic areas, basal ganglia, and cerebellum. We also found strong functional connectivity to regions and hubs involved in marmoset resting state networks. These findings demonstrate marmoset claustrum RSFC similar to previous human and rodent studies and validate the integration of marmosets into claustrum research.

Sharpened visual memory representations are reflected in inferotemporal cortex
Humans and other primates can robustly report whether they've seen specific images before, even when those images are extremely similar to ones they've previously seen. Multiple lines of evidence suggest that pattern separation computations in the hippocampus (HC) contribute to this behavior by shaping the fidelity of visual memory. However, unclear is whether HC uniquely determines memory fidelity or whether computations in other brain areas also contribute. To investigate, we recorded neural signals from inferotemporal cortex (ITC) and HC of two rhesus monkeys as they performed a memory task in which they judged whether images were novel or exactly repeated in the presence of visually similar lure images with a range of visual similarities. We found behavioral evidence for sharpening, reflected as memory performance that was nonlinearly transformed relative to a benchmark defined by visual representations in ITC. As expected, we found that behavioral sharpening aligned with visual memory representations in HC. Surprisingly, and unaccounted for by HC pattern separation proposals, we also found neural correlates of behavioral sharpening reflected in ITC. These results, coupled with further analysis of the data, suggest that ITC contributes to shaping the fidelity of visual memory in the transformation from visual processing to memory storage and signaling.

Ayahuasca Shifts Brain Dynamics Toward Higher Entropy: Persistent Elevation of Ising Temperature Correlates with Acute Subjective Effects
Serotonergic psychedelics profoundly alter high-order cognition, emotion, and sensory perception, creating dynamic, unpredictable brain states consistent with the entropic brain hypothesis. Although these acute effects are short-lived, users often experience lasting improvements in emotional and social functioning. Yet, few studies have quantitatively linked subjective experiences to neural dynamics. To bridge this gap, we investigate the acute and subacute effects of ayahuasca using fMRI data and the 2D Ising model, estimating the Ising brain temperature to quantify the shift from ordered to disordered resting state configurations and expose the critical transitions that characterize ayahuasca-induced brain dynamics. To complement our analysis, we investigated cortical functional connectivity changes through graph-theoretical metrics, quantifying how psychedelic ingestion alters functional network architecture in acute and subacute phases. Only the Ising temperature reliably differentiated the subacute phase. Applying a recently developed method that combines cortical connectivity analyses with Graph Neural Networks trained on Ising networks, our results robustly revealed significant Ising temperature increases during the acute (p < 0.001) and subacute (p < 0.05) phases compared with placebo, reflecting heightened brain entropy and a persistent shift toward a more disordered, paramagnetic state. To evaluate longer-term effects, the subacute temperature change correlated linearly with affective scores on the Hallucinogenic Rating Scale (HRS) captured during the acute session (p < 0.01), with HRS scores explaining substantially greater variance in the subacute group (adjusted R^2 = 0.58) than in the placebo group (adjusted R^2 = -0.05). These observations suggest that ayahuasca elevates system entropy and that the magnitude of lasting functional alterations scales with the intensity of the acute subjective experience.

Imaging traumatic brain injuries in mice with potassium channel PET tracer 3F4AP
ObjectiveTraumatic brain injury (TBI) can lead to secondary injury, including axon and myelin damage, which contributes to long-term neurological deficits. The PET tracer [18F]3F4AP, a fluorinated derivative of the FDA-approved drug 4-aminopyridine, selectively binds to voltage-gated potassium (KV) channels, offering a novel approach to assess TBI-related node of Ranvier disruption and demyelination. This study evaluates [18F]3F4AP PET in penetrating and non-penetrating TBI models.

MethodsEither controlled cortical impact (CCI, penetrating) or concussive (non-penetrating) TBI models were used to induce TBI in mice. Dynamic PET imaging with [18F]3F4AP was performed at time points of 0, 3, 7, 14, and/or 31 days post-injury (dpi), with quantitative analyses comparing tracer uptake in injured versus control regions. Luxol fast blue (LFB) staining was conducted to evaluate histological myelin loss.

ResultsIn the CCI model, [18F]3F4AP PET imaging demonstrated a 34% increase in tracer uptake at the injury site at 7 dpi, correlating with histological evidence of demyelination. Tracer uptake gradually declined over time, reflecting potential remyelination. The concussive TBI model showed a smaller and more diffuse increase in uptake at 7 dpi compared to CCI.

Conclusion[18F]3F4AP PET imaging effectively detects demyelination following TBI, with very high sensitivity in penetrating injuries. These findings highlight the potential of [18F]3F4AP as a valuable imaging biomarker for assessing TBI progression and/or therapeutic response. Further studies are warranted to explore its clinical applicability and comparison with other imaging modalities.

Spatiotemporal biases in localization and interception: common underlying mechanisms?
Human perception of space, time and motion is subject to several biases. Lab studies showed such effects in psychophysical judgements of location, but also in action-tasks, like predicting motion and intercepting. Given that similar underlying processes have been proposed for some of these biases, we tested for a shared mechanism by correlating them across observers. Using the classical implied motion sequence, participants either indicated the remembered location of an intermittently presented dot consistently "moving" from one location to the next, or intercepted a predicted future location of the same intermittently presented dot. We examined whether the errors in those tasks are associated by correlating i) the overall amount of overshooting, and ii) the effect of temporal manipulations of the "jump" duration on these biases across participants. We found two medium correlations indicating that these two biases are indeed related to each other. Participants who show a larger effect in one task also show a larger effect in the other task, and participants with larger proneness to temporal features show them consistently across both tasks. This suggests a shared underlying mechanism, and theoretical implications are discussed.

The Interplay of Bottom-Up Arousal and Attentional Capture during Auditory Scene Analysis: Evidence from Ocular Dynamics
The auditory system plays a crucial role as the brain's early warning system. Previous work has shown that the brain automatically monitors unfolding auditory scenes and rapidly detects new events. Here, we focus on understanding how automatic change detection interfaces with the networks that regulate arousal and attention, measuring pupil diameter (PD) as an indicator of listener arousal and microsaccades (MS) as an index of attentional sampling. Naive participants (N=36; both sexes) were exposed to artificial "scenes" comprised of multiple concurrent streams of pure tones while their ocular activity was monitored. The scenes were categorized as REG or RND, featuring isochronous (regular) or random temporal structures in the tone streams, respectively. Previous work showed that listeners are sensitive to predictable scene structure and use this information to facilitate change processing. Scene changes were introduced by either adding or removing a single tone stream. Results revealed distinct patterns in the recruitment of arousal and attention during auditory scene analysis. PD was greater in REG scenes compared to RND, indicating heightened arousal in unpredictable contexts. However, no differences in overall MS activity were observed between scene types, suggesting no differences in attentional engagement. Scene changes, though unattended, elicited both PD and MS suppression, consistent with automatic attentional capture and increased arousal. Notably, only MS responses were modulated by scene regularity. This suggests that changes within predictable environments more effectively recruit attentional resources. Together, these findings offer novel insights into how automatic auditory scene analysis interacts with neural systems governing arousal and attention.

Preclinical assay of the effects of lacosamide, pregabalin and tapentadol on the rat N1 spinal somatosensory evoked potential.
The high failure rate in translating novel analgesics into the clinic has highlighted the need for more translatable biomarkers of analgesic efficacy. The N13 component of spinal somatosensory evoked potential (SEP) has been proposed as a biomarker of spinal nociceptive processing in humans, but it is not known whether this can be back translated into rodents. Tapentadol, lacosamide and pregabalin were used as pharmacological probes to assess the sensitivity of spinal SEPs to drug action. In anaesthetised, naive rats (n=44), a multielectrode silicon probe was inserted into the L4 spinal cord to record SEPs from the dorsal horn following electrical stimulation of the sciatic nerve. At baseline, the N1 component (rodent equivalent of the human N13) had an amplitude of 1.33 +/- 0.07mV at a latency of 4.6 +/- 0.2ms following low-intensity stimulation, with an intensity-dependent amplitude increase into the noxious range. The N1 amplitude was significantly reduced by 10mg/Kg tapentadol (40.2 +/-12.5 % vs vehicle 96.2 +/-8.0 %) and 30mg/Kg lacosamide (46.3 +/-20.9 % lacosamide vs vehicle 115 +/-5.9 %) at 60 minutes after intraperitoneal administration. Tapentadol also reduced the N1 amplitude in the noxious range. Lacosamide increased the stimulus current required to evoke the half maximal N1 response (EC50), without reducing the maximum N1 amplitude in the noxious range. Pregabalin (at any dose up to 30mg/kg) did not modulate the N1 amplitude. These results show the spinal N1 is differentially modulated in a way that reflects distinct mechanisms of drug action consistent with it being a translatable biomarker of analgesic efficacy.

Key genes and pathways in asparagine metabolism in Alzheimers Disease: a bioinformatics approach
Abstract Background: Asparagine (Asn) metabolism is essential for maintaining cellular homeostasis and supporting neuronal energy demands. Recent studies have suggested its dysregulation may contribute to Alzheimers disease (AD) pathogenesis; however, the specific genes and regulatory mechanisms involved remain incompletely understood. Methods: Four publicly available microarray datasets (GSE5281, GSE29378, GSE36980, and GSE138260) were utilized to investigate genes with differential expression between control and AD samples. Asparagine metabolism-related genes (AMGs) were retrieved from the GeneCards database, and their intersection with DEGs yielded candidate asparagine metabolism-related differentially expressed genes (AMG-DEGs). Functional enrichment analysis (Gene Set Enrichment Analysis, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes), protein-protein interaction (PPI) network analysis, and centrality scoring identified hub genes. Regulatory mechanisms were investigated through construction of competing endogenous RNA and transcription factor networks. Potential therapeutic compounds were predicted via drug-gene enrichment and evaluated using molecular docking simulations. Results: Thirty-nine AMG-DEGs were identified and found to be enriched in neurodevelopmental, synaptic transmission, and inflammatory signaling pathways. PPI analysis and centrality screening revealed seven hub genes (HPRT1, GAD2, TUBB3, GFAP, CD44, CCL2, and NFKBIA). Regulatory network analysis highlighted specific miRNAs, long non-coding RNAs, and transcription factors involved in their modulation. Drug screening and docking identified Bathocuproine disulfonate, DL-Mevalonic acid, and Phenethyl isothiocyanate as promising compounds with strong binding affinities to hub proteins. Conclusion: This study comprehensively maps the dysregulation of asparagine metabolism in Alzheimers disease and reveals a set of hub genes and regulatory elements potentially involved in disease progression. The predicted therapeutic compounds provide a foundation for further experimental validation and may contribute to the development of novel metabolism-targeted strategies for AD treatment.

Neuroinflammation driven by TLR7 activation in mice results in a global inflammatory response driving circuit-specific changes in neuronal gene expression
Interactions between the brain and immune system play a key role in the aetiology of brain disorders, with inflammation emerging as a potential causal factor in subsets of major depressive disorder, particularly those resistant to treatment. The causal mechanisms through which immune activation can drive depressive symptoms remain elusive, limiting the ability to develop new targeted therapies. Using a mouse model of neuroinflammation, involving a TLR7/8 agonist, we found central and systemic inflammation alongside anhedonia-like behaviours, altered thalamostriatal signalling and infiltration of peripheral immune cells into the brain. Here, we sought to use combined whole-brain transcriptome and spatial transcriptomics approaches to determine whether Aldara-driven neuroinflammation resulted in consistent immune and neurobiological changes throughout the brain. We found evidence of strong immune activation throughout the brain, with astrocytes displaying a strong inflammatory profile that was relatively uniform throughout. However, we found that this global inflammatory signal led to regionally-specific changes in gene expression, particularly reduced expression of genes associated with synaptic function in brain areas underlying mood and anxiety, such as ventral striatum and amygdala. Our data suggest potential mechanisms through which astrocytes regulate neuronal function in response to inflammation.

Central infusion of prostaglandin E2 reveals a unified representation of sickness in the mouse insular cortex
During infections, vertebrates develop stereotypic symptoms such as elevated body temperature, reduced appetite, and lethargy. These changes, collectively known as sickness syndrome, are orchestrated by the brain in response to immune mediators released during systemic inflammation. While the roles of subcortical regions, including the hypothalamus and brainstem nuclei, in regulating sickness symptoms are well established, the contribution of the neocortex to the encoding and modulation of the sick state remains less well understood. We examined the neuronal correlates of sickness in the neocortex of awake mice following a single intracerebroventricular (i.c.v.) injection of prostaglandin E2 (PGE2), a well-characterized mediator of sickness. Behavioral analysis revealed that PGE2 elicited a rapid and robust sickness response, characterized by fever, slower locomotion, quiescence, anorexia, and eye squinting. Whole-brain Fos mapping showed that PGE2 generates a distinct neural activation pattern encompassing much of the interoceptive network. Electrophysiological recordings using Neuropixel probes in awake mice revealed that neuronal population dynamics in the insular cortex (IC) and the primary somatosensory cortex (SSp), two regions involved in body state representation, encode sickness-related information, such as body temperature, walking velocity, grooming, and eye squinting. However, unlike SSp, ongoing neuronal activity in IC exhibited a better decoding performance for an integrated measure of sickness rather than individual symptoms. Together, these results suggest that PGE2 induces a coordinated physiological and behavioral response akin to a sick state, which is preferentially encoded in the IC.

Combined CSF1R Inhibition and Sensory Gamma Stimulation Provide Protective Effects in a Mouse Model of Alzheimers Disease
The CSF1R inhibitor Plx3397, an FDA-approved treatment for a rare cancer, has been shown to reduce microglia, lower inflammation, and improve synaptic integrity in several mouse models of Alzheimer's disease (AD). However, the effects of Plx3397 on synaptic and neural function in AD remain largely unknown. Here, we used the 5xFAD mouse model to characterize the effect of Plx3397 treatment. While Plx3397 administration increased synaptic density in 5xFAD mice, it also reduced the percentage of neurons phase-locked to gamma oscillations. This neural decoupling was closely associated with gene expression changes related to synapse organization. These observations prompted us to investigate whether gamma-frequency entrainment could counteract the neural circuit alterations induced by Plx3397 administration. We thus enhanced gamma phase-locking in neurons using non-invasive patterned sensory light stimulation. Remarkably, restoring gamma oscillations improved neural function, reshaped gene expression signatures, and improved learning and memory in Plx3397-treated 5xFAD mice. These findings suggest that CSF1R inhibitors like Plx3397 may benefit from a multimodal approach combining microglial targeting with non-invasive sensory stimulation to support neural physiology and improve cognitive function in AD.

Inferring macroscopic intrinsic neural timescales using optimal control theory
The temporal evolution of brain activity relies on complex interactions within and between brain regions that are mediated by neurobiology and connectivity. To understand these interactions, many large-scale efforts have measured structural connectivity, neural activity, gene expression, and cognition across multiple modalities and species. However, data-driven discovery of large-scale activity models remains difficult owing to the lack of flexible quantitative frameworks for estimating the interplay between brain structure and function while preserving biophysical realism. Here, we provide such a framework by integrating network control theory (NCT) with automatic differentiation to estimate model parameters with greater biophysical realism from data. Specifically, we estimate the structural form of regional self-inhibition---a quantity that is experimentally difficult to measure---from MRI data. Next, we demonstrate that the resulting model-based self-inhibition parameters correlate significantly with regions' intrinsic neural timescales (INTs), neurobiological measures of gene expression and cell-type densities, as well as behavioral measures of cognition. We demonstrate consistent results across multiple datasets and species. Finally, we demonstrate that our self-inhibition parameters enable the efficient control of brain dynamics from fewer brain regions. Taken together, our results provide a simple and flexible quantitative framework that more accurately captures the interplay between brain structure, function, and dynamics with greater biophysical realism.

Modelling Fragile X-Associated Neuropsychiatric Disorders in Young Inducible 90CGG Premutation Mice
Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder caused by a preCGG repeat expansion in the FMR1 gene. Individuals with the FMR1 premutation often exhibit neuropsychiatric symptoms before FXTAS onset, leading to the identification of fragile X-associated neuropsychiatric disorders (FXAND). Rodent models of FXTAS show motor impairments, pathological intranuclear inclusions, and heightened anxiety. However, the early onset of neuropsychiatric features and underlying mechanisms remain poorly understood. To address the above issues, we used the doxycycline (dox)-inducible 90CGG mouse model, with transgene activation at two developmental stages: adolescence and young adulthood. Mice were evaluated in a behavioural battery to assess anxiety-like behaviour, exploration, and motor coordination and learning. Next, we conducted a combination of ex vivo extracellular local field potential recordings to measure synaptic physiology and oscillatory activity in the limbic system, particularly in the basolateral amygdala (BLA) and ventral hippocampus (vH) regions. Parvalbumin interneurons and intranuclear inclusions in the amygdala and hippocampus were investigated by immunofluorescence, while mass spectrometry and gene set enrichment were used to identify differentially expressed proteins molecular pathways. Adolescent 90CGG mice displayed early-onset hyperactivity, transitioning to heightened anxiety in young adulthood, coinciding with the accumulation of intranuclear inclusions in the BLA and vH. Electrophysiological analysis revealed augmented gamma oscillations in the vH, emerging during adolescence and persisting in young adulthood. These changes correlated with a reduction in parvalbumin interneurons in these regions, and together likely contribute to enhanced BLA excitability and impaired vH plasticity. Finally, proteomic analysis of the vH revealed altered proteins linked to attention deficit hyperactivity disorder in adolescence and anxiety/depression in adulthood, aligning well with behavioural findings. Importantly, these behavioural, electrophysiological, and cellular alterations were reversible upon transgene inactivation. This study reveals a temporal progression of CGG premutation effects on behaviour, from hyperactivity to heightened anxiety to late onset motor dysfunction. Moreover, these findings provide altered network activity in the limbic system as a putative mechanism in neuropsychiatric features of premutation carriers.

Attractive and repulsive history effects in categorical and continuous estimates of orientation perception
Perceptual reports can be attracted towards or repulsed from previous stimuli and responses. We investigated the conditions in which attractive and repulsive history effects occur with oriented Gabors by manipulating response type and frequency, and stimulus duration. When subjects adjusted a continuous response cue to match orientation, we observed repulsion from the previous stimulus when the stimulus was presented for 50 ms and attraction from the previous stimulus and response when it was presented for 500 ms, regardless of whether responses were given to every stimulus or every other stimulus. With a categorical clockwise/counter-clockwise response, there was attraction to the previous response and repulsion from the previous stimulus. Attraction to the previous response was stronger with sequential responses and short relative orientations. Repulsion was constant across all stimulus durations and response frequencies, and increased with relative orientation. The overall history effect of the previous response and stimulus was repulsive with alternating categorical responses and attractive with sequential categorical responses. Our results replicate and synthesize seminal findings of the serial dependence and adaptation literature, and show independent history effects working with and against each other determined by whether the response is categorical or continuous.

Early Emergence of Perceptual Biases in Working Memory
Working memory (WM) is distributed across multiple cortical areas, suggesting that behaviors relying on WM arise from interactions between these regions. In a recent study, we found that during delayed comparison tasks, the first stimulus is not represented veridically in the prefrontal cortex (PFC), but instead is encoded in a systematically warped manner--biased toward the mean of the stimulus distribution. This neural distortion, which emerges already during the stimulus presentation and persists throughout the delay period, closely mirrors a contraction bias observed in behavior. Furthermore, the behavioral responses could be explained by a Bayesian observer model, in which the brain integrates prior expectations with noisy sensory inputs. These results suggest that the geometry of PFC neural trajectories embodies Bayesian estimates that underlie biased decisions. Here, we investigate whether the secondary somatosensory cortex (S2)--a lower-level sensory area also implicated in tactile WM--exhibits a similar encoding structure. Our analyses reveal that although WM-related signals in S2 are less robust than in PFC, the neural state space in S2 shares key geometric features with that of PFC, including a similarly warped representation of stimulus values. These findings suggest that perceptual biases may originate early in the cortical processing stream and are not exclusively shaped by higher-order associative areas. More broadly, our results support a distributed organization of WM, in which even sensory areas contribute to the formation of bias-prone representations that guide behavior.

Identification of a Thermogenic Target in the Dorsal Raphe Nucleus for Weight Management
Obesity emerges from a complex interplay of factors, including imbalanced interoception, genetic predisposition, and environmental cues, ultimately disrupting body weight homeostasis. While much research has concentrated on strategies to suppress appetite for sustained weight loss, insufficient attention has been given to counterregulatory mechanisms that promote energy expenditure. Here, we show that chronic inhibition of GABAergic neurons in the Dorsal Raphe Nucleus (DRNVGAT) reduces body weight in diet-induced obese (DIO) mice. In this study, molecular profiling and in-situ hybridization in rodent and human brains revealed that the constitutively activated orphan receptor GPR6 is selectively enriched in DRNVGAT neurons. We next developed and administered a potent and highly selective GPR6 inverse agonist, which significantly reduced weight gain in DIO mice by stimulating brown adipose tissue thermogenesis without affecting appetite. Altogether, this study transitions from transcriptomic profiling, high-throughput drug screening and metabolic phenotyping to successfully identify a novel candidate to treat obesity.

GABAergic neurons are major contributors of network inhibition in the neonatal hippocampus in-vivo
During development, neural network maturation is activity dependent. During the neonatal period, activity is provided by intermittent, spontaneous network activity patterns (SNAP) that occur independently of environment stimuli. Among the neurotransmitters that take part in neonatal development, the Gamma-amino-butyric acid (GABA) plays a pivotal role. GABAergic cells are the first to emerge the first to form functional synapses. GABA antagonists block hippocampal SNAPs in-vitro and alterations of GABAergic function dramatically impact cortical maturation. Based on these data, the traditional view is that the depolarizing action of GABA, a hallmark of immature networks in slice preparations, is at the core of developmental processes. However, in-vivo evidence for such depolarizing role is not clear, raising questions about the contribution of GABAergic neurons in-vivo. To address this issue we developed an in-vivo approach combining optogenetics and single-unit electrophysiology in non-anesthetized mice. This allowed us to both identify and manipulate hippocampal GABAergic cells while examining their influence on hippocampal SNAP. We found that, even during the first post-natal days, the net action of GABA is inhibitory, but not excitatory. This inhibitory action of GABA drastically increases after the second post-natal week.

Spontaneously emerging patterns in human motor cortex code for somatotopic specific movements
The role of spontaneous brain activity remains a key question in neuroscience. While prior work shows sensory regions preferentially replay stimulus-specific patterns (e.g., faces in fusiform face area), we investigated whether motor cortex replays reflect somatotopic organization. Using fMRI, we compared resting-state activity to task-evoked patterns during specific movements (finger, toe, tongue). Spontaneous activity in each effector-specific motor subregion (hand, foot, mouth) exhibited greater similarity to task patterns of its corresponding movement than to non-preferred ones. For instance, hand movement patterns replayed more in hand regions than elsewhere. Positive rest-task correlations emerged for preferred movements, while negative correlations characterized non-preferred ones (except toe). This structured somatotopic organization suggests spontaneous activity encodes functional specialization, not just activation strength, mirroring task-evoked representations.

Reading ahead: Localized neural signatures of parafoveal word processing and skipping decisions
Visual reading proceeds fixation-by-fixation, with individual words recognized and integrated into evolving conceptual representations within only hundreds of milliseconds. This relies, in part, on interactions between cognitive and oculomotor systems, such that linguistic properties of words influence eye movements and fixation durations. When and where do these influences arise in the neural processing of an incoming word? To answer this, we combined magnetoencephalography (MEG) with eye-tracking in a natural story-reading paradigm. We replicated past findings that word frequency and predictability have additive influences on fixation durations. Next, we identified putative generators of these influences in localized brain activity time-locked to fixation onsets. Both properties independently influenced neural responses in left occipitotemporal and ventral temporal areas, at latencies early enough to influence subsequent saccade planning. These effects began in posterior areas (the left lingual gyrus, lateral occipital cortex) during parafoveal word processing, and shifted more anteriorly (the inferior temporal and parahippocampal gyri) when the word was fixated in foveal vision. Evidence for parallel processing of both parafoveal and foveal words was observed in the left posterior fusiform, which housed near-simultaneous effects of both the fixated and upcoming words' frequency and surprisal. We also found that parafoveal processing in this region, together with the left middle temporal gyrus, distinguished whether an upcoming word was skipped or fixated. These results suggest that during natural visual reading, word recognition and integration begin parafoveally, underpinned by a left-lateralized occipitotemporal system, where word processing rapidly exerts downstream influences on eye movement decisions.

Intrinsic rewards guide visual resource allocation via reinforcement learning
Humans and other animals prioritise visual processing of stimuli that signal rewards. While prior research has focused on tangible incentives (e.g., money or food), the effects of intrinsic incentives -- such as perceived competence -- are less well understood. Across a series of visual estimation experiments, we manipulated observers' subjective sense of confidence in their judgements using either deceptive trial-by-trial feedback or real discrepancies in stimulus reliability. We found that observers prioritised encoding of stimuli associated with lower uncertainty or error, benefiting performance for stimuli already estimated accurately, while further impairing performance for those estimated poorly. These reward-driven biases, while potentially adaptive, impaired overall accuracy in the present tasks by causing resource allocation to deviate from the error-minimizing strategy. To account for these findings, we supplemented a normalization model of neural resource allocation with a simple reinforcement learning rule. Intrinsic and extrinsic rewards cumulatively shaped the values assigned to different stimuli by the model, and the resulting discrepancies biased resource allocation and thereby estimation error, quantitatively matching the data. These findings reveal how intrinsic reward signals can shape resource allocation in ways that are both adaptive and counterproductive, offering a computational basis for the motivational biases underlying cognitive performance.

Head-Direction Cells in Postsubiculum Show Systematic Parallax Errors During Visual Anchoring
Spatial navigation relies on the head-direction (HD) system, which integrates angular head velocity (AHV) to track orientation. Since integration accumulates drift over time, visual landmarks provide corrective cues. However, whether the HD system explicitly accounts for the apparent shift in proximal objects' position when viewed from different angles remains unclear. These shifts are caused by the parallax effect, where closer objects move more strongly on the retina than distant ones. Here, we analyzed postsubicular HD cell activity in mice navigating with a single visual cue. We discovered a systematic parallax bias in the decoded HD, indicating that the HD system misinterprets the cue's position depending on the viewing angle. The observed error was smaller than predicted by a pure vision model, which can be explained by the combination of AHV integration with simple visual anchoring. Notably, each animal exhibited a unique anchoring angle - the direction at which the cue was associated with head direction - suggesting that the HD system maintains a relatively stable and possibly learned mapping between the cue angle from visual input (bearing) and head direction. These results provide evidence that the HD system, at least in simplified environments, does not perform explicit parallax correction but may instead attenuate errors passively through AHV integration and simple anchoring to multiple cues. This highlights a fundamental trade-off in neural coding between computational efficiency and positional accuracy, with implications for biological and artificial navigation systems.

More running causes more ocular dominance plasticity in mouse primary visual cortex: new gated running wheel setup allows to quantify individual running behaviour of group-housed mice
Environmental enrichment boosts neuronal plasticity in standard-cage raised (SC) mice. We previously showed that wheel running during 7 days of monocular deprivation (MD) can restore ocular dominance (OD)-plasticity in the primary visual cortex (V1) of adult SC-mice beyond postnatal day (P) 110 (P160). It remained - however - unknown whether individual wheel running parameters boost OD-plasticity differently and whether running for just 4 days would also boost OD-plasticity in younger mice aged 50-100 days (P70). To this end, we designed a gated running wheel setup (gRW) attached to the home cage, and tracked individual running wheel activity of group-housed mice. Mouse vision was checked by optometry and OD-plasticity in V1 was visualized using intrinsic signal optical imaging. As hypothesized, wheel running during MD boosted OD-plasticity in both P160 and P70 mice: after 4d/7d of MD (P70/P160), the OD-index, comparing ipsi- and contralateral eye induced V1-activation, dropped from 0.25{+/-}0.04 without MD to 0.12{+/-}0.03 with MD in P70 (t-test p<0.01), and from 0.24{+/-}0.04 to 0.05{+/-}0.04 in P160 mice (t-test p<0.01). Quantitative comparison of running parameters yielded that average running distance, running time and speed were similar in P70 and P160 mice, but P70 mice ran more bouts (P70/P160:19.5{+/-}3.3/17.0{+/-}3.3 bouts/d, t-test p<0.001) of shorter durations (P70/P160:2.9{+/-}0.5/5.0{+/-}0.5 min, t-test p<0.05). Most notably, individual running parameters correlated with individual OD-indices after MD: mice running longer distances, for longer time, at higher velocity and with longer bouts displayed a stronger OD-shift, i.e. animals showed more experience-dependent V1-plasticity (Pearson r2=0.42, p=0.022). The link between individual choices and brain physiology has become a rising topic in systems neuroscience. With our newly developed gated running wheel setup, we observed a striking correlation between individual running activity, and experience-dependent plasticity in mouse primary visual cortex. More running caused more plasticity: running speed, running distance, total running time, number of running bouts and bout duration all significantly correlated with a measure of visual cortical plasticity, the ocular dominance index. Thus, our observations add to the growing body of evidence that individual behavioural choices can strongly affect individual brain plasticity.

Isolating the Contribution of the Koniocellular Visual Pathway in Aversive Learning in Human Visual Cortex
The present study examined how the koniocellular retino-geniculate visual pathway contributes to the electrocortical amplification of threat cues in human visual cortex using a simple aversive conditioning task. The task involved S-cone isolating stimuli (Tritan condition) and achromatic luminance stimuli (luminance condition) that preferentially activated the koniocellular pathway and luminance channels, respectively. Steady-state visual evoked potential (ssVEPs) responses to the conditioned threat cues (CS+) and safety cues (CS-) in each condition were analyzed using a non-parametric Bayesian bootstrapped approach. The Tritan and luminance conditions exhibited greater ssVEP responses to the CS+ stimuli compared to the CS- stimuli in occipital sensors early into the trial (0 ms - 1000 ms; logBF10 > 2). In addition to these early conditioning effects, a late conditioning effect was observed (1500 ms - 2500 ms) in the Tritan condition that emerged over bilateral anterior sensors (logBF10 > 2). To further examine the koniocellular contribution to aversive learning, transitive Bayes factors were computed to compare the magnitude of the conditioning effects across conditions. Transitive Bayesian comparisons showed that the early conditioning effect was larger for the luminance condition than for the Tritan condition (logBF10 > 2). Furthermore, the late conditioning effect remained larger in the Tritan condition compared to the luminance condition (logBF10 > 2). Our results are consistent with previous work demonstrating that Tritan stimuli elicit enhanced electrocortical responses and with theoretical notions suggesting that the koniocellular pathway contributes to the representation of threat signals in human visual cortex.

One model to rule them all: unification of voltage-gated potassium channel models via deep non-linear mixed effects modelling
Ion channels are essential for signal processing and propagation in neural cells. Voltage-gated ion channels permeable to potassium Kv form one of the most prominent channel families. Techniques used to model the voltage-dependent gating of Kv channels date back to Hodgkin and Huxley (1952). Different Kv types can display radically different kinetic properties, requiring different mathematical models. However, the construction of Hodgkin-Huxley-like (HH-like) models is generally complex and time consuming due to the number of parameters, their tuning and having to choose functional forms to model gating. In addition to the between-Kv type heterogeneity, there can be significant within-Kv type kinetic heterogeneity between different cells with genetically identical channels. Since HH-like models do not account for such variability, extensions to it are necessary. We use scientific machine learning (SciML), the integration of machine learning methodologies with existing scientific models, and non-linear mixed effects (NLME) modelling to bypass the limitations of HH-like modelling. NLME is a modelling methodology that takes into account both within- and between-subject variability. These tools allowed us to complement the HH-like modelling and construct a unified SciML HH-like model that fits the recordings from 20 different Kv types. The unified SciML HH-like model produced closer fits to the data compared to a set of seven previous HH-like models and was able to represent the highly heterogeneous data from different cells. Our model may be the first step in producing a SciML foundation model for ion channels that would be capable of modelling the gating kinetics of any ion channel type.

Complement receptor C3ar1 deficiency does not alter brain structure or functional connectivity across early life development
Previous studies suggest that genetic deletion of the complement C3a anaphylatoxin chemotactic receptor (C3ar1), a key component of the innate immune response, influences behaviours associated with psychiatric symptomatology in mice but when and where C3ar1 is needed in the brain is not known. These questions are significant because, as a G-protein-coupled receptor (GPCR), human C3AR1 serves as a potential therapeutic target for disorders associated with complement dysregulation, such as schizophrenia. To provide a brain-wide assessment of developmental C3ar1 activity, we used longitudinal tensor-based morphometry (TBM), fractional anisotropy (FA) from diffusion-weighted magnetic resonance imaging (dMRI) and blood oxygen-level dependent functional MRI (BOLD fMRI) in male and female C3ar1-deficient mice and wild-type littermates, with behavioural assessment in adulthood. Unexpectedly, we did not find robust C3ar1-dependent phenotype in any of these measures. Therefore, our study does not support neurodevelopmental hypotheses for C3ar1 which will likely have implications for targeting this receptor in disease.

Neural microexons modulate arousal states via cAMP signalling in zebrafish
Arousal states, often dysregulated in neurodevelopmental disorders, shape how organisms perceive and respond to their environment. Here, we show that srrm3, a master regulator of neural microexons, is essential for normal arousal in zebrafish larvae. srrm3 mutants exhibit persistent hyperarousal, including sleep loss, sensory hypersensitivity, anxiety-like behaviour, and heightened neural and behavioural activity. Elevated cAMP signalling likely drives this hyperarousal, as pharmacologically reducing cAMP rescues mutant behaviour, while increasing cAMP in wild-type larvae phenocopies the mutant hyperaroused state. Pharmacological cAMP modulation also mimics and reverses srrm3-dependent transcriptional changes. These include immediate early gene downregulation, which, together with altered activity-dependent transcription factor motif occupancy, suggest adaptation to sustained neuronal hyperactivity. Additionally, srrm3 mutants show upregulation of microexon-containing genes, likely compensating for microexon loss. Together, these findings reveal a role for neural microexons in shaping arousal via cAMP signalling, providing insight into how splicing defects may underlie sensory and sleep disturbances.

Structural dynamics of mixed-subunit CaMKIIα/β heterododecamers filmed by high-speed AFM
CaMKII predominantly assembles into a 12-meric ring assembly, primarily consisting of CaMKII and CaMKII{beta} variants in the brain. Previous biochemical studies have reported varying ratios of these CaMKII variants across different brain regions and developmental stages. However, direct evidence for the formation of CaMKII/{beta} heterooligomers within a 12-meric ring assembly has been lacking at the single-molecule level. Here, we employed high-speed atomic force microscopy to visualize the conformational dynamics of forebrain-mimicked CaMKII/{beta} at a 3:1 ratio. Our findings revealed that the CaMKII and CaMKII{beta} subunits are intermixed within the 12-meric ring assembly, with more than 83% probability that CaMKII{beta} subunits adjacent to one another. Furthermore, in the activated state, CaMKII/{beta} heterooligomers form a stable kinase domain complex via interactions between adjacent CaMKII{beta} subunits, resulting in a long-lasting structure with an exposed target binding site. Collectively, our observations provide insights into the structural role of CaMKII{beta} subunits within the CaMKII/{beta} heterododecamer.

Shape-Shifting Conotoxins Reveal Divergent Pore-Targeting Mechanisms in Nicotinic Receptors
The neuronal 7 nicotinic acetylcholine receptor (7-nAChR) and muscle-type nicotinic acetylcholine receptor (mt-nAChR) are pivotal in synaptic signaling within the brain and the neuromuscular junction respectively. Additionally, they are both targets of a wide range of drugs and toxins. Here, we utilize cryoEM to delineate structures of these nAChRs in complex with the conotoxins ImI and ImII from Conus imperialis. Despite nominal sequence divergence, ImI and ImII exhibit discrete binding preferences and adopt drastically different conformational states upon binding. ImI engages the orthosteric sites of the 7-nAChR, while ImII forms distinct pore-bound complexes with both the 7-nAChR and mt-nAChR. Strikingly, ImII adopts a compact globular conformation that binds as a monomer to the 7-nAChR pore and as an oblate dimer to the mt-nAChR pore. These structural characterizations advance our understanding of nAChR-ligand interactions as well as the subtle sequence variations that result in dramatically altered functional outcomes in small peptide toxins. Importantly, these results further elucidate the broad nature of cone snail toxin activities and highlight how targeted molecular evolution can give rise to functionally similar activities with surprisingly diverse mechanisms of action.

The Infraslow Fluctuation of Sigma Power During Sleep in Young Individuals with Schizophrenia
A reduction in sleep spindles, a major electrophysiological characteristic of Non-Rapid Eye Movement sleep, has been suggested as a potential biomarker of schizophrenia. While research has primarily focused on the spindle quantity, recent studies have begun to explore their temporal dynamics throughout the night. In healthy individuals, sleep spindles fluctuate on an infraslow [~]50-second timescale, alternating between phases of high and low spindle activity. This fluctuation is referred to as the infraslow fluctuation of sigma power (ISFS), which is modulated by noradrenergic activity from the locus coeruleus and linked to the organization of arousal and memory reactivation processes during sleep. Given the known deficit in sleep spindles, dysregulation of noradrenergic activity, and impairments in sleep maintenance and memory in schizophrenia, this study investigates the ISFS in sleep electroencephalography data from individuals with either Childhood-Onset Schizophrenia (COS; N = 17) or Early-Onset Schizophrenia (EOS; N = 11), aged 9 to 21 years, alongside age- and sex-matched healthy controls (N = 56). The presence and strength of the ISFS were reduced in both COS and EOS groups compared to controls, particularly in central-parietal electrodes. No significant differences in these features of the ISFS were found between the two clinical groups, despite group differences in sleep spindle density and clinical characteristics. These findings suggest that the ISFS is observable but reduced in young patients with schizophrenia and support the notion that the timing of sleep spindles may inform pathomechanistic models of the disorder, as well as future diagnostic approaches and interventions.

PIBE: Parallel ion beam etching of sections collected on wafer for ultra large-scale connectomics
We have developed a parallel ion beam thinning device with low incident ion beam energy, enabling simultaneous 20nm thickness reduction for biological sections which are collected on 4-inch wafer. Together with SEM imaging and volume stitchingit is trustworthy and efficient to achieve three-dimensional electron microscopy imaging of millimeter-scale samples for ultra large scale connectomics.

Cardiac interoception impacts behavior and brain-wide neuronal dynamics
We sought to explore the question as to whether an animal's behavior can be modified by internal physiological changes. We focused on the optomotor response, in which an animal moves in response to visual gratings, because it is quantitative, robust, and evolutionarily conserved. Using larval zebrafish, we demonstrate that engagement in the optomotor response is inversely related to heart rate. We modulate heart rate by external threat, activation or blockade of the sympathetic nervous system, pharmacological blockade of the cardiac pacemaker channel, and direct optogenetic pacing of the heart, and find that the correlation persists through all perturbations. We find neurons in the primary sensory ganglia and several regions of the brain whose activity reflects changes in heart rate, some more active during bradycardia and some during tachycardia. Specifically, we show that the area postrema, known to be a center of cardiovascular integration, shows particularly strong encoding of heart rate, both following threat and during optogenetic cardiac pacing. We suggest that there may be neural mechanisms to assess heart rate changes over time, and that this interoceptive measurement is used to regulate other neural circuits and behavioral output.

Achieving cell-type specific transduction with adeno-associated viral vectors in pigeons
Birds are valuable models for studying learning, cognition, song, and vision, yet tools for controlling and recording brain activity with millisecond precision remain underutilized in avian research. Advances in methods such as chemogenetics, optogenetics, and in vivo imaging have transformed rodent studies but require gene delivery techniques, like adeno-associated viruses (AAVs), in non-transgenic species. This study validates AAV tools for precise gene expression in pigeons. We identified AAV8 as a highly effective vector, demonstrating strong neuronal tropism and anterograde/retrograde transgene expression, while AAVretro was ineffective. The CaMKII promoter and mDLX enhancer enabled cell-type-specific expression, targeting predominantly excitatory and inhibitory neurons, respectively. Additionally, we established proof of concept for the expression of NpHR (a chloride pump) and demonstrated the functionality of conditional gene expression systems, including Cre/loxP and Tet-On/Tet-Off. These advancements expand the genetic toolkit for pigeons, facilitating precise manipulation of neural circuits and enabling future studies on complex avian behaviors and brain functions. By bridging molecular tools and avian neuroscience, this work paves the way for comparative and translational research, offering insights into the neural basis of cognition and sensory processing in birds.

Early visual experience elicits cellular and functional plasticity in the retina and alters behaviour
Our interaction with the surrounding environment shapes how our brain processes sensory information and drives adaptive behaviour. This plasticity allows the brain to rewire in response to specific sensory experiences. For instance, early manipulation of visual inputs profoundly impacts brain plasticity, which is crucial for functions like size perception, object recognition, and visuospatial processing. While neuronal plasticity has been detected in visual target structures such as the colliculus, thalamus, and cortex, it remains unclear if the retina, the primary sensory organ, undergoes significant plasticity. Here, we show that the zebrafish retina demonstrates pronounced plastic transformations in response to alterations of the visual environment during development, which ultimately modifies the detection of oriented visual stimuli. We demonstrate that orientation-selective amacrine cells undergo profound morphological changes in animals exposed to distinct visual environments during development. We further find that the functional orientation-selective output from the retina is altered in a manner consistent with the visual environment in which the animals are raised and that these changes are persistent. Finally, animals tested in a virtual reality system show that early exposure to different visual environments changes their innate preference for specifically oriented patterns. Our findings unveil a unique developmental form of sensory organ plasticity with continuing structural and functional consequences.

Brainstem sensing of multiple body signals during food consumption
Studies of body-to-brain communication often examine one stimulus or organ at a time, yet the brain must integrate many body signals during behavior. For example, food consumption generates diverse oral and post-oral chemical and mechanical signals transduced by well-characterized peripheral neuronal pathways. Far less is known about how these and other bodily signals are integrated and organized in the brainstem lateral parabrachial nucleus (LPBN), a key interoceptive sensory hub. We established methods to image the activity of 1000s of neurons throughout a large region of mouse LPBN. Food consumption drove a seconds-long wave of activity across LPBN, with dynamics mirroring the movement of food through the upper gastrointestinal tract observed using X-ray fluoroscopy. By imaging the same neurons across days, we found that spatially clustered subsets of neurons encoded oral signals, stomach filling, visceral malaise, arousal, and/or body movement. Moreover, only certain subsets were modulated by cortical input. Together, these experiments reveal a functional specialization in the LPBN that integrates contextual information from the body to guide behavior.

Continuous theta-burst stimulation of the prefrontal cortex in the macaque monkey: no evidence for within-target inhibition or cross-hemisphere disinhibition of neural activity
Continuous theta-burst stimulation (cTBS) can perturb neural activity and behavior by inducing effects that persist beyond the relatively short stimulation period. Although widely used in basic research and clinical settings, there lacks an understanding of the neurophysiological and behavioural effects of cTBS. Two assumptions motivating the use of cTBS are that it will i) inhibit neural activity in the targeted area, and ii) consequently disinhibit neural activity in the mirroring region in the contralateral cortex. Here, we test these assumptions in the oculomotor system of the rhesus macaque. In two macaques, we delivered cTBS between blocks of trials where they performed a delayed pro-/anti-saccade task, delivered cTBS to the right PFC (areas 8Ar and 46, which includes the frontal eye fields; 32 cTBS-PFC sessions), to the air as a SHAM control (27 cTBS-SHAM sessions), or to the nearby primary motor cortex as a brain control (21 cTBS-M1 sessions). Across these different types of sessions, we compared changes in oculomotor behavior (reaction times, error rates, peak saccade velocity), and changes in neural activity recorded from the left, contralateral PFC. Despite multiple lines of evidence consistent with TMS influencing neural activity in the cTBS-PFC and cTBS-M1 sessions, we found no behavioral evidence for inhibition of the right PFC in the cTBS-PFC sessions, nor any evidence for contralateral disinhibition in the left PFC. Our results call into question some of the fundamental assumptions underlying the application of cTBS.

Backpropagation through time training of an unrolled Hodgkin Huxley model for automatic conductance estimation
Precise estimation of biophysical parameters such as ion channel conductances in single neurons is essential for understanding neuronal excitability and for building accurate computational models. However, inferring these parameters from experimental data is challenging, often requiring extensive voltage-clamp measurements or laborious manual tuning. Here we present a novel approach that leverages backpropagation through time (BPTT) to automatically fit a Hodgkin--Huxley (HH) conductance-based model to observed voltage traces. We unroll the HH model dynamics in time and treat the unknown maximum conductances as learnable parameters in a differentiable simulation. By optimizing the model to minimize the mean squared error between simulated and observed membrane voltage, our method directly recovers the underlying conductances (for sodium gNa, potassium gK, and leak gL) from a single voltage response. In simulations, the BPTT-trained model accurately identified conductance values across different neuron types and remained robust to typical levels of measurement noise. Even with a single current-clamp recording as training data, the approach achieved precise fits, highlighting its efficiency. This work demonstrates a powerful automated strategy for biophysical system identification, opening the door to rapid, high-fidelity neuron model customization from electrophysiological recordings. The code is availible at https://github.com/skysky2333/HH_BPTT.

Representational dynamics during extinction of fear memories in the human brain
Extinction learning - the suppression of a previously acquired fear response - is critical for adaptive behavior and core for understanding the etiology and treatment of anxiety disorders. Electrophysiological studies in rodents have revealed critical roles of theta (4-12Hz) oscillations in amygdala and hippocampus during both fear learning and extinction, and engram research has shown that extinction relies on the formation of novel, highly context-dependent memory traces that suppress the initial fear memories. Whether similar processes occur in humans and how they relate to previously described neural mechanisms of episodic memory formation and retrieval remains unknown. Intracranial EEG (iEEG) recordings in epilepsy patients provide direct access to the deep brain structures of the fear and extinction network, while representational similarity analysis (RSA) allows characterizing the memory traces of specific cues and contexts. Here we combined these methods to show that amygdala theta oscillations during extinction learning signal safety rather than threat and that extinction memory traces are characterized by stable and context-specific neural representations that are coordinated across the extinction network. We further demonstrate that context specificity during extinction learning predicts the reoccurrence of fear memory traces during a subsequent test period, while reoccurrence of extinction memory traces predicts safety responses. Our results reveal the neurophysiological mechanisms and representational characteristics of context-dependent extinction learning in the human brain. In addition, they show that the mutual competition of fear and extinction memory traces provides a mechanistic basis for clinically important phenomena such as fear renewal and extinction retrieval.

A New Serological Autoantibody Signature Associated with Multiple Sclerosis
The role of autoantibodies in the pathogenesis of Multiple Sclerosis (MS) remains incompletely understood. In this study, we analyzed serum samples from a cohort of MS patients in Qatar using high-throughput KoRectly Expressed (KREX) immunome protein-array technology. Compared to healthy controls, MS patients showed significantly altered autoantibody responses to 129 proteins, with a notable enrichment in autoantibodies targeting antiviral immune response-related proteins. Machine learning analysis identified a distinct molecular signature comprising 17 differentially expressed autoantibodies, including those against MX1, ISG20, MAX, SUFU, NR1H2, HMGN5, and EPHA10. Among these, autoantibodies against MX1-a key effector in the interferon-alpha/beta signaling pathway-showed the most pronounced increase, with nearly a threefold elevation in MS patients. While MX1 has previously been implicated in MS, this is the first report of autoantibody reactivity against the protein, suggesting a potential role in disease onset and progression. These findings support a link between antiviral immune responses and MS pathophysiology and offer a promising blood-based autoantibody signature that could inform future diagnostic and therapeutic strategies.

Excitation-Inhibition Balance and Fronto-Limbic Connectivity Drive TMS Treatment Outcomes in Refractory Depression
Depression affects over 350 million people worldwide, with treatment resistance occurring in up to 30% of cases. Intermittent theta burst stimulation (iTBS) targeting the left dorsolateral prefrontal cortex (DLPFC) has emerged as a promising intervention, yet the neurophysiological mechanisms determining which patients will respond remain poorly understood. Here, we combined transcranial magnetic stimulation with electroencephalography and whole-brain computational modeling to uncover the mechanistic basis of treatment efficacy in 90 patients with treatment-resistant depression. We identified two distinct neurophysiological signatures that differentiate responders from non-responders: (1) post-treatment shifts in excitation-inhibition balance toward greater inhibitory control, and (2) a pre-treatment brain state characterized by anticorrelated dynamics between subgenual anterior cingulate cortex and DLPFC. These features were significantly correlated with clinical improvement and could not be explained by non-specific factors. Our findings provide a neurophysiologically-informed framework for developing personalized and optimized neuromodulation approaches in treatment-resistant depression.

Early visual signatures and benefits of intra-saccadic motion streaks
Eye movements routinely induce motion streaks as they shift visual projections across the retina at high speeds. To investigate the visual consequences of intra-saccadic motion streaks, we co-registered eye tracking and EEG while gaze-contingently shifting target objects during saccades, presenting either continuous, streaky or apparent, step-like motion in four directions. We found significant reductions of secondary saccade latency, as well as improved decoding of the post-saccadic target location from the EEG signal when motion streaks were available. These signals arose as early as 50 ms after saccade offset and had a clear occipital topography. Using a physiologically plausible visual processing model, we provide evidence that the targets motion trajectory is coded in orientation-selective channels and that speed of gaze correction was linked to the visual dynamics arising from the combination of saccadic and target motion, providing a parsimonious explanation of the behavioral benefits of intra-saccadic motion streaks.

Characterization of the functional and clinical impacts of CACNA1A missense variants found in neurodevelopmental disorders
CACNA1A encodes the P/Q-type CaV2.1 calcium channels whose function underlies neuronal excitability, presynaptic neurotransmitter release, and Ca2+ signaling in neurons. Pathogenic variants in CACNA1A have been found in individuals with various neurological conditions, including hemiplegic migraine, epilepsy, developmental delay, and ataxia. Clinical presentations can vary significantly between patients, with limited information known about the underlying neurobiology of these different clinical patterns. Adding further complication, prior work on pathogenic missense variants has demonstrated variable impacts on CaV2.1 channel function, sometimes in opposite directions. As such, the relationships between specific coding variants, electrophysiological properties, and clinical phenotypes remain elusive. In this study, we determined the biophysical properties of an allelic series of 42 de novo missense CACNA1A variants discovered in a neurodevelopmental disorder cohort of more than 31,000 individuals, together with the most common eight coding variants found in the general population. We found that all but one de novo variant altered at least one aspect of the channel properties examined, and the majority (70%) of the variants reduced the channel current density. In addition, for variants that encode human CaV2.1 channels (hCaV2.1) with detectable currents, nearly 50% altered how channels respond to membrane potential, while common variations did not significantly change any channel biophysical properties. Coupled with our functional analyses and AlphaMissense prediction, we showed that CaV2.1 missense variants significantly underlie the risk of developmental epileptic encephalopathy. Subsequently, we examined the physiological impact of variant hCaV2.1 using NEURON simulations as an omnibus output of neuronal function and found that abnormal biophysical channel properties have a profound impact on Purkinje cell excitability. Most interestingly, we correlated the clinical phenotype with molecular consequences of missense variants provided by our comprehensive functional analyses and found that distinct CaV2.1 channel molecular function is significantly associated with different clinical outcomes. By analyzing an entire allelic series of CACNA1A de novo changes in a large cohort of individuals with neurodevelopmental disorders, we provide a powerful approach to dissecting the role of missense variants in CACNA1A channelopathy, which in turn may help pave the way for future precision medicine initiatives.

Bridging Stem Cell Models and Medicine: Integrated 3D Human Cerebral Organoids and Pediatric Serum Reveal Mechanisms and Biomarkers of Anesthetic-Induced Neurotoxicity
BackgroundGeneral anesthetics have been shown to cause acute pathological changes in the developing brain, including neuronal cell death. These effects contribute to long-term cognitive and behavioral impairments observed in animal models. Epidemiological and prospective clinical studies have also reported associations between early-life exposure to anesthesia and neurodevelopmental deficits in children, raising significant concerns about pediatric anesthesia and highlighting the urgent need to understand the molecular mechanisms and biomarkers of anesthetic-induced developmental neurotoxicity (AIDN) using human-relevant models.

MethodsThis study employed human induced pluripotent stem cell-derived cerebral organoids that were exposed to varying doses of anesthetic propofol for 1 to 6 hours, including single and repeated exposures. In parallel, serum samples were collected pre- and post-surgery from pediatric patients under 4 years old (n = 10 per group) who underwent either short (<1 hour) or prolonged anesthesia (>3 hours) at the Childrens Hospital of Wisconsin between September 2018 and October 2019. Pathological changes in organoids were assessed using chemical assays, electron microscopy, and western blotting. Brain injury-related proteins in patient serum were quantified via ELISA. Genome-wide expression profiling was conducted on 18,855 mRNAs and 27,427 lncRNAs in organoids and serum using microarray and bioinformatics.

ResultsHigher doses, longer duration, and repeated exposures to propofol led to increased apoptosis in organoids. Six-hour exposure induced autophagy as evidenced by LC3-II elevation and led to dysregulation of 553 mRNAs and 792 lncRNAs in organoids, along with their co-expressed signaling networks, affecting pathways related to synaptic integrity, mitochondrial function, and inflammation. ELISA and serum analysis of pediatric patients (<4 years old) exposed to anesthesia (>3 hours) demonstrated elevated brain cell injury-associated proteins (e.g., increased NSE) and brain cell type-specific gene expression changes. Serum findings corroborated organoid data, identifying 21 mRNAs and 12 lncRNAs that were dysregulated in both models and associated with cell injury, neuronal development, inflammation, and learning deficits.

ConclusionsThis study represents the first integrative transcriptomic analysis of AIDN using both 3D human cerebral organoids and pediatric patient serum--two complementary, human-relevant models. By identifying consistently dysregulated coding and non-coding RNAs across both platforms, we provide compelling evidence of shared molecular signatures linked to neuronal injury, inflammation, and neurodevelopmental disruption. These findings offer not only mechanistic insights but also lay the groundwork for the development of minimally invasive biomarkers and future therapeutic strategies. This dual-model approach bridges experimental discovery with clinical relevance, advancing the translational understanding of pediatric anesthetic neurotoxicity and supporting efforts to improve long-term neurological outcomes in vulnerable patient populations.

In Utero Exposure to Anti-Caspr2 Antibody Disrupts Parvalbumin Interneuron Function in the Hippocampus
Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition characterized by deficits in communication and social interaction and may stem from an imbalance between excitatory and inhibitory (E/I) signaling in neural circuits. Parvalbumin-expressing (PV+) interneurons are crucial for maintaining E/I balance and regulating network oscillations. Alterations in the number of PV+ interneurons or reductions in PV expression have been observed in both the postmortem brains of individuals with ASD and in animal models, including those induced by in utero exposure to maternal brain-reactive antibodies. In this study, we investigate the impact of in utero exposure to maternal anti-Caspr2 IgG on PV+ interneuron development and function in the hippocampus. Our results demonstrate a selective reduction in PV+ interneurons and perisomatic inhibitory synapses in the hippocampal CA1 region of juvenile and adult male offspring exposed in utero to anti-Caspr2 antibodies compared to controls. Additionally, local field potential (LFP) recordings from these mice show increased gamma power and altered neuronal firing patterns during social interactions, indicating functional impairments in inhibitory circuitry. These findings highlight the consequences of exposure to maternal anti-Caspr2 antibodies on PV+ interneuron development and function, providing insights into the neurobiological mechanisms underlying ASD associated behavioral phenotypes.

Estimating fMRI Timescale Maps
Brain activity unfolds over hierarchical timescales that reflect how brain regions integrate and process information, linking functional and structural organization. While timescale studies are prevalent, existing estimation methods rely on the restrictive assumption of exponentially decaying autocorrelation and only provide point estimates without standard errors, limiting statistical inference. In this paper, we formalize and evaluate two methods for mapping timescales in resting-state fMRI: a time-domain fit of an autoregressive (AR1) model and an autocorrelation-domain fit of an exponential decay model. Rather than assuming exponential autocorrelation decay, we define timescales by projecting the fMRI time series onto these approximating models, requiring only stationarity and mixing conditions while incorporating robust standard errors to account for model misspecification. We introduce theoretical properties of timescale estimators and show parameter recovery in realistic simulations, as well as applications to fMRI from the Human Connectome Project. Comparatively, the time-domain method produces more accurate estimates under model misspecification, remains computationally efficient for high-dimensional fMRI data, and yields maps aligned with known functional brain organization. In this work we show valid statistical inference on fMRI timescale maps, and provide Python implementations of all methods.

Pitfalls of mapping functional and molecular human brain imaging data from separate cohorts
It has become increasingly common to probe correlations between human brain imaging measures of receptor/protein binding and function using population-level brain maps drawn from independent cohorts, estimating correlations across regions. This strategy raises issues of interpretation that we highlight here with a multimodal brain imaging dataset and simulation studies. Twenty-four healthy participants completed neuroimaging with both [11C]Cimbi-36 positron emission tomography and magnetic resonance imaging scans to estimate receptor binding potential (BP) and cerebral blood flow (CBF), respectively, in 18 cortical/subcortical regions. Correlations between BP and CBF were estimated in three ways: 1) Pearson correlation across regions of mean regional BP and CBF ({rho}l), to mimic studies using data from independent cohorts; 2) Pearson correlation between BP and CBF across participants in each region ({rho}2); or 3) the correlation between BP and CBF across participants across all regions within a single linear mixed effects model ({rho}3). We observed a significant positive correlation across regions ([Formula]l = 0.672; p = 0.0023). Region-specific correlations across participants were substantively lower and not statistically significant ([Formula]2: mean = 0.140, range = -0.112 to 0.336; all p > 0.10), nor when estimated simultaneously within a linear mixed model ([Formula]3 = 0.138, p = 0.26). Our simulation study illustrated that regional differences in BP or CBF mean and variance can bias across regions correlations by 1000% or create a type-1 error of 100%. Our observations that both the estimated correlation and the statistical significance can differ greatly highlights that inferring across region correlation as evidence for correlation across participants is erroneous. Without validated methods that limit confounding and other biases, we discourage future studies from inferring across region correlation of population-level brain maps from independent cohorts in this manner.

Stochastic activity in low-rank recurrent neural networks
The geometrical and statistical properties of brain activity depend on the way neurons connect together to form recurrent circuits. How the structure of connectivity shapes the emergent activity remains however not fully understood. We investigate this question in recurrent neural networks with linear additive stochastic dynamics. We assume that the synaptic connectivity can be expressed in a low-rank form, parameterized by a handful of connectivity vectors, and and examine how the geometry of emergent activity relates to these vectors. Our findings reveal that this relationship critically depends on the dimensionality of the external stochastic inputs. When inputs are low-dimensional, activity is confined to a low-dimensional subspace spanned by a subset of the connectivity vectors, whose dimensionality matches the rank of the connectivity matrix, along with the external inputs. Conversely, when inputs are high-dimensional, activity is generally high-dimensional; recurrent dynamics shape activity within a subspace spanned by all connectivity vectors, with a dimensionality equal to twice the rank of the connectivity matrix. Applying our formalism to excitatory-inhibitory circuits, we discuss how inputs geometry also play a crucial role in determining the amount of input amplification generated by non-normal dynamics. Our work provides a foundation for studying activity in structured brain circuits under realistic noise conditions, and offers a framework for interpreting stochastic models inferred from experimental data.

Telmisartan and Lisinopril Show Potential Benefits in Rescuing Cognitive-Behavioral Function Despite Limited Improvements in Neuropathological Outcomes in Tg-SwDI Mice
Cerebral amyloid angiopathy (CAA) is a cerebrovascular disease that results from beta-amyloid (A{beta}) accumulation in the vessel walls that is associated with cognitive impairment and other neurological pathologies. There are currently no medications approved to treat CAA. This study investigated whether renin-angiotensin system (RAS)-targeting drugs, commonly prescribed to treat hypertension, can be repurposed to treat CAA, and whether their effects differ by sex. Male and female Tg-SwDI mice were treated for 5 months with sub-depressor doses of either telmisartan [angiotensin II receptor blocker (ARB)] or lisinopril [angiotensin-converting enzyme (ACE) inhibitor] starting at 3 months of age. Blood pressure monitoring was performed 2 and 4 months after the start of treatment, followed by behavior testing at 7 months of age. Histochemical analyses were conducted to determine vasculopathy, A{beta} pathology, and neuroinflammation (microgliosis and astrogliosis). Outcomes in drug-treated and untreated Tg-SwDI mice were compared to each other and with wild-type (C57BL/6J) controls. Overall, both drugs were able to rescue some cognitive-behavioral functions; however, no reductions in A{beta} levels were observed, and only limited improvements in vascular density and neuroinflammatory markers were detected. Notably, some treatment effects varied with sex, the specific behavioral task, and the brain region analyzed. These findings support the hypothesis that RAS-targeting drugs exert neuroprotective effects through mechanisms beyond blood pressure control offering a promising therapeutic avenue for CAA.

Cell type-specific contributions to impaired blood-brain barrier and cerebral metabolism in presymptomatic 5XFAD mice
Altered cerebral metabolism and blood-brain barrier (BBB) dysfunction are emerging as critical contributors to the preclinical phase of Alzheimers disease (AD), underscoring their role in early pathogenesis. To identify sensitive biomarkers before irreversible neuronal loss and cognitive decline, we examined 5XFAD mice at 3 months of age by applying multiple advanced MRI techniques. Arterial spin tagging based MRI revealed increased BBB permeability and water extraction fraction, indicating compromised BBB integrity at the early stage of pathogenesis in 5xFAD mice. Despite preserved cerebral blood flow, a decreased unit mass cerebral metabolic rate of oxygen (CMRO2) was evident in the same cohorts of 5XFAD mice. Interestingly, a region-specific decrease of tissue pH values was detected in the hippocampus of these 5XFAD mice by creatine chemical exchange saturation transfer MRI. Elevated neuronal H4K12 lactylation in the hippocampus supports the reduced pH values. To further dissect the cellular and molecular mechanisms underlying these MRI-detectable changes in 5XFAD mice, we conducted single-nucleus RNA sequencing (snRNA-Seq) with optimized blood vessel enrichment protocols. Our results revealed cell type-specific transcriptomic changes in the hippocampus of 3-month-old 5XFAD mice, including downregulation of synaptogenesis and synaptic transmission genes in the CA1 and dentate gyrus excitatory neurons, impaired endothelial gene expression linked to brain barrier function and angiogenesis, altered innate immune response genes in astrocytes, as well as upregulation of cholesterol biosynthesis and metabolism genes in the CA1 excitatory neurons. These findings underlie the intricate interplay between BBB disruption and metabolic dysregulation before the onset of cognitive decline in AD. Our study demonstrates that BBB dysfunction and cerebral metabolic alterations preceded brain hypoperfusion and cognitive decline, emphasizing potential molecular pathways for early intervention. These findings, once validated in human studies, could significantly enhance early diagnosis and inform novel therapeutic strategies targeting early AD pathogenesis.

Survival of Transplanted Retinal Ganglion Cell in Human Donor Eyes under Elevated Pressure
Glaucoma is a group of optic neuropathies characterized by visual field loss, classically due to increased intraocular pressure (IOP) and retinal ganglion cell (RGC) degeneration. Current treatment options reduce IOP, but progressive RGC degeneration persists. The ability to reprogram de novo RGCs from human corneal keratocytes provides a valuable tool to potentially restore vision in patients with late-stage disease when most RGCs are irreversibly damaged. We investigate the survival of these human induced pluripotent stem cell (hiPSC) derived RGCs after culturing them in human donor eyes under conditions of elevated and normal IOP using the pressurized ocular translaminar autonomous system (TAS) chamber. The hiPSCs were generated by reprogramming human donor keratocytes using Sendai viral vectors with Yamanaka factors. The hiPSCs were then differentiated into retinal organoids (ROs) from which RGCs were obtained. The RGCs were transduced with AAV2-CBA-EGFP (Adeno-Associated Virus serotype 2- Chicken Beta Actin- Enhanced Green Fluorescent Protein) and successfully transplanted into donor human eyes obtained from individuals having non-ocular history. They were pressurized for 5-7 days, with the left eye maintained at normal IOP and right eye at high IOP. Viability was measured by expression levels of pro-survival pathways via qRT-PCR, immunohistochemistry staining, and electroretinography (ERG) for retinal function. After RGC transplantation, increased expression of pro-survival and decreased inflammatory and apoptotic markers were identified in normal IOP conditions compared to high IOP. In conclusion, survival of RGCs was more conducive under normal IOP conditions with significantly increased degeneration observed at high IOP. Thus, suggesting that elevated IOP could potentially create a microenvironment that would significantly inhibit successful transplantation of de novo RGCs.

Quantum Magnetization Exchange through Transient Hydrogen Bond Matrix Defines Magnetic Resonance Signal Relaxation and Anisotropy in Central Nervous System
The integrity of cellular membranes (lipid bilayers) and myelin sheaths covering axons is a crucial feature controlling normal brain structural and functional networks. Yet, in vivo evaluation of this integrity at the nanoscale level of the cellular membranes organization is challenging.

Herein we explore the dual property of biological water in Central Nervous System (CNS), as one of the major stabilizing factors of cellular membranes, and the major source of MRI signal. We introduce the Basic Transient Hydrogen Bond (THB) model of the MR signal relaxation due to the quantum spin/magnetization exchanges within the THB Matrix encompassing water molecules and membrane-forming macromolecules.

Our data show the existence of two THB Matrix components with distinct lifetimes - one in a few nano-second range, and another in the range of tens nanoseconds. Importantly, the former component facilitates longitudinal relaxation of MR signal, the latter contributes to its transverse relaxation and causes the anisotropy of MR signal relaxation. These distinct features offer opportunity to study nanoscale level microstructure of cellular membranes. Furthermore, the ability to differentiate distinct THB Matrix components based on their MR signal relaxation properties can be fundamental to identifying pathological changes and enhancing disease visibility on MRI scans.

Organization of brainwide inputs to discrete lateral septum projection populations
The lateral septum (LS) is anatomically positioned to play a critical role in directing information from the hippocampus and cortex to downstream subcortical structures, such as the hypothalamus. In fact, early anatomical tracing studies investigated the organization of hippocampal inputs to the LS and its hypothalamic outputs to begin to understand how its structure might relate to its function. These studies also characterized the cellular anatomy of the LS and the organization of different molecular markers within it. However, relatively little is known about the organization of other, non-hypothalamic projection populations within the LS and what types of input these different projection populations receive. Here, we used retrograde tracing to determine the organization of LS projections to six different brain regions that mediate various social behaviors. We found that these projection populations occupy discrete anatomical compartments within the LS. We then used a monosynaptic rabies tracing strategy to map brainwide inputs to these six discrete LS projection populations and examine how different brain regions innervate them. We identified unique region-dependent patterns of inputs to individual LS projection populations. In particular, we observed differences in cortical, hippocampal and thalamic innervation of the six different LS projection populations, while the hypothalamic inputs were largely similar across projection populations. Thus, this study provides insight into the anatomical connectivity that may underlie the functional heterogeneity of the LS.

Spatiotemporal Analysis of Remyelination Reveals a Concerted Interferon-Responsive Glial State That Coordinates Immune Infiltration
Remyelination, the process by which axons are re-encased in myelin after injury, is a critical step in restoring brain function, yet the dynamics from initial injury to repair remain poorly characterized. Here, we combined optimized single-nucleus RNA-seq with Slide-seqv2, a high-resolution spatial transcriptomics technology, to densely reconstruct the cellular processes that coordinate remyelination after a focal demyelinating injury. This revealed several findings: First, we found extensive transcriptional diversity of glia and monocyte-derived macrophages from demyelination to repair. Second, we identified a population of infiltrating peripheral lymphocytes--predominantly CD8 T-cells and natural killer cells--that are enriched specifically during remyelination. Third, we identified a concerted interferon-response gene signature that is shared across several cell types--microglia, astrocytes, and the oligodendrocyte lineage--just prior to reestablishment of myelin. These interferon-responsive glia (IRG) form clusters around remyelinating white matter and their formation is solely dependent on the type I interferon receptor. Functionally, we found that IRG secrete the cytokine CXCL10 which mediates infiltration of peripheral lymphocytes into the repairing white matter. Depletion of the most abundant infiltrating lymphocyte, CD8 T-cells, attenuated the differentiation of mature oligodendrocytes during remyelination. Together, our data reveals the diversity of glial-immune interactions that orchestrate white matter repair and a type I-dependent glial state that drives lymphocyte influx into damaged white matter to modulate oligodendrocyte differentiation.

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Hypothalamic deiodinase type-3 establishes the period of circannual interval timing in mammals
Animals respond to environmental cues to time phenological events, but the intrinsic mechanism of circannual timing remains elusive. We used transcriptomic sequencing and frequent sampling, during three distinct phases (induction, maintenance and recovery) of circannual interval timing for Djungarian hamster energy balance, to investigate the molecular architecture of a neuroendocrine seasonal clock. Our study identified three distinct phases of transcript changes, with deiodinase type-3 (Dio3) expression activated during the early induction phase. Subsequent work demonstrated that targeted mutation of Dio3 resulted in a shorter period for circannual interval timing. Hamsters that exhibit naturally disrupted Dio3 expression do not show any change in body mass or pelage. Our work demonstrates that changes in Dio3 induction is essential for setting the period of circannual interval timing.

Heparan sulfate glycosaminoglycans mediate CXCL4 (PF4) transport across the blood-brain barrier and effects on neurogenesis
CXCL4 (PF4) is a chemokine stored in platelets that has pleiotropic effects across biological settings. These effects include driving of inflammation and fibrosis as well as reversal of the effects of ageing. We have recently demonstrated that CXCL4 function is driven, independently of known chemokine receptors, through binding to glycosaminoglycan (GAG) side chains on proteoglycans within the cell surface glycocalyx. In this study, we have used intravital imaging and radioactive tracer studies, in combination with an exogenous inhibitor and a GAG-binding CXCL4 mutant, to demonstrate that CXCL4 can enter the brain parenchyma of mice by binding to proteoglycans within the cell surface of the endothelial glycocalyx of the blood-brain barrier (BBB). Furthermore, we have also demonstrated that CXCL4 directly promotes neurogenesis in vitro, which is mediated by its ability to oligomerise and bind to GAGs. These findings provide a molecular mechanism for CXCL4 uptake and function within the brain. Furthermore, these data have important implications for understanding CXCL4 during health and disease that may enable development of CXCL4-related therapeutics for inflammatory diseases and ageing.

Non-duality in brain and experience of advanced meditators - Key role for Intrinsic Neural Timescales
Distinguishing between self (internal) and environment (external) is fundamental to human experience, with ordinary waking consciousness structured around this duality. However, contemplative traditions describe non-dual states where this distinction dissolves. Despite its significance, the neural basis of non-duality remains underexplored. Using psychological questionnaires for non-duality experience and EEG-based intrinsic neural timescales as measured by the autocorrelation window (ACW), we studied non-duality in advanced meditators, novice meditators, and controls. All subjects underwent breath-watching meditation (internal attention) and a visual oddball cognitive task (external attention); this allowed us to conceptualize non-duality as a lack of distinction between internal and external attention. Our key findings include: (a) advanced meditators report greater experience of non-duality during breath-watching (psychological scales), (b) EEG-based ACW is longer during internal attention (breath watch) than external attention (oddball task) in all subjects taken together, (c) advanced meditators show no such distinction with equal duration of their ACW during both internal and external attention (we replicated this finding in another dataset of expert meditators); (d) the advanced meditators internal-external ACW difference correlated with their experience of the degree of non-duality (psychological scales) during internal attention. Together, these findings suggest that the brains intrinsic neural timescales during internal and external attention play a key role in mediating the experience of non-duality in advanced meditators.

Effect of Transcranial Light Stimulation on the Neurovascular Unit in the Human Brain
Transcranial light stimulation (tLS) is emerging as a non-invasive approach for enhancing brain function and treating neurological disorders; however, its impact on the human neurovascular unit (NVU) remains poorly understood. Herein, we combined photon transport modeling with multimodal neuroimaging to reveal how light influences vascular and neuronal responses in the human brain. Simulations of photon propagation through transcranial tissue captured key scattering and attenuation patterns, guiding the localization of light effects in vivo. Using simultaneous functional magnetic resonance imaging and arterial spin labeling, we showed that tLS significantly increased blood oxygenation level-dependent signals and cerebral blood flow in the light-affected regions. These hemodynamic changes co-occurred with a reduction in cortical excitability, as revealed by electroencephalographic source reconstruction and transcranial magnetic stimulation-evoked potentials. To probe the underlying mechanism, we incorporated inhibitory neural inputs into the computational NVU model. The model predicted that tLS enhances inhibitory neuronal activity and nitric oxide release, driving vasodilation and elevating metabolic support. These findings revealed that transcranial photons can differentially modulate neuronal and vascular components of the NVU--suppressing excitability while promoting perfusion--thereby suggesting a novel therapeutic avenue for targeting neurovascular dynamics in cognitive and clinical applications.

Characterizing semantic compositions in the brain: A model-driven fMRI re-analysis
Semantic composition allows us to construct complex meanings (e.g., "dog house", "house dog") from simpler constituents ("dog", "house"). So far, neuroimaging studies have mostly relied on high-level contrasts (e.g., meaningful > non-meaningful phrases) to identify brain regions sensitive to semantic composition. However, such an approach is less apt at addressing how composition is carried out, namely what functions best characterize the integration of constituent concepts. To address this limitation, we rely on simple computational models to explicitly characterize alternative compositional operations, and use representational similarity analysis to compare the representations of models to those of target regions of interest within the general semantic network. To better target composition beyond specific task demands, we re-analyze fMRI data aggregated from four published studies (N = 85), all employing two-word combinations but differing in task requirements. Converging evidence from confirmatory and exploratory analyses reveals compositional representations in the pars triangularis of the left inferior frontal gyrus (BA45), even when analyses are restricted to a subset where the task did not require participants to actively engage in semantic processing. These results suggest that BA45 represents combinatorial information automatically across task demands, and further characterize these combinatorial representations as resulting from the (symmetric) intersection of constituent features. Additionally, a cluster of compositional representations emerges in the left middle superior temporal sulcus, while semantic, but not compositional, representations are observed in the left angular gyrus. Overall, our work clarifies which brain regions represent semantic information compositionally across different contexts and task demands, and qualifies which operations best describe composition.

Thalamic NRXN1-Mediated Input to Human Cortical Progenitors Drives Upper Layer Neurogenesis
According to the protocortex hypothesis, extrinsic thalamic signaling is necessary for refining cortical areas and cell types, but the mechanism by which these inputs shape the development and expansion of the human cortex remains largely unexplored. We fuse cortical and thalamic organoids to study this process. Using single-nuclei RNA-sequencing and cellular imaging, we discover that thalamic signals during a critical period promote human cortical upper-layer neurogenesis. In assembloid models and human primary cortex, we find NRXN1 mediates thalamic axon contact with primate-enriched outer radial glia, driving developmental gene expression changes. Genetic perturbation of NRXN1 in thalamic neurons reduces these contacts and attenuates cortical upper-layer neurogenesis. These findings in human developmental models suggest a novel role for thalamic regulation of primate outer radial glia cell fate.

Degraded mapping of disparity tuning in visual cortex explains deficits in binocular depth perception
Sensory cortex is highly organized, but understanding why remains elusive. Here we demonstrate that depriving juvenile mice of vision in one eye during the critical period for the development of binocularity (monocular deprivation) caused enduring deficits in binocular depth perception. This deprivation of binocular vision severely degraded retinotopic mapping of binocular disparity tuning, despite no detectable differences in the range or selectivity of disparity tuning by populations of neurons. Disparity tuning was strongest in the central portion of the visual field and transitioned from representing nearer to farther depths from the lower to upper visual field, respectively. Monocular deprivation caused greater uniformity in disparity across visual space and an overall shift to nearer disparities. We propose that this disruption to the organization of disparity tuning explains impaired binocular depth perception.

Type I interferons enhance human dorsal root ganglion nociceptor excitability and induce TRPV1 sensitization
Type I interferons (IFNs) are critical cytokines for antiviral defense and are linked to painful inflammatory diseases like rheumatoid arthritis and neuropathic pain in humans. Studies in rodent models demonstrate a direct action on sensory neurons in the dorsal root ganglion (DRG) to promote hyperexcitability but rodent behavioral results are conflicting with some reports of pro-nociceptive actions and others of anti-nociception. Given the role of type I IFNs in human disease, we sought to clarify the action of action of IFN- and IFN-{beta} on human DRG (hDRG) nociceptors. We found that IFN receptor subunits IFNAR1 and IFNAR2 are functionally expressed by these neurons and their engagement induces canonical STAT1 signaling and non-canonical MAPK activation as measured by increased phosphorylation of the cap-binding protein eIF4E by MNK1/2 kinases. Using patch clamp electrophysiology, Ca2+-imaging, and multi-electrode arrays we demonstrate that IFN- and -{beta} increase the excitability of hDRG neurons with short (30 min) and long-term (24-48 h) exposure and prolong the duration of capsaicin responses, an effect that is blocked by inhibition of MNK1/2 with eFT508, a specific inhibitor of these kinases. Our studies support the conclusion that type I IFNs are pronociceptive when they interact with hDRG nociceptors in the periphery.