bioRxiv Subject Collection: Neuroscience's Journal

Mapping Along-Tract White Matter Microstructural Differences in Autism
Previous diffusion magnetic resonance imaging (dMRI) research has indicated altered white matter microstructure in autism, but the implicated regions are highly inconsistent across studies. Such prior work has largely used conventional dMRI analysis methods, including the traditional microstructure model, based on diffusion tensor imaging (DTI). However, these methods are limited in their ability to precisely map microstructural differences and accurately resolve complex fiber configurations. In our study, we investigated white matter microstructure alterations in autism using the refined along-tract analytic approach, BUndle ANalytics (BUAN), and an advanced microstructure model, the tensor distribution function (TDF). We analyzed dMRI data from 365 autistic and neurotypical participants (5-24 years; 34% female) from 10 cohorts to examine commissural and association tracts. Autism was associated with lower fractional anisotropy and higher diffusivity in localized portions of nearly every commissural and association tract examined; these tracts inter-connected a wide range of brain regions, including frontal, temporal, parietal, and occipital. Taken together, BUAN and TDF allow robust and spatially precise mapping of microstructural properties in autism. Our findings rigorously demonstrate that white matter microstructure alterations in autism may be greater within specific regions of individual tracts, and that the implicated tracts are distributed across the brain.

Population activity of mossy fibre axon input to the cerebellar cortex during behaviours
The cerebellum gathers information from the neocortex via the cortico-ponto-cerebellar pathway, and forms sensorimotor associations for predicting movements and their sensory consequences. However, little is known about the functional properties of this major input to the cerebellar cortex. Recordings from individual cerebellar mossy fibre axons (MFAs) have shown that they convey sensory and motor information, but nothing is known about their population code. Here, we report that the population activity of pontine MFAs is heterogeneous, high-dimensional and that different subpopulations of MFAs are active during quiet and active behavioural states. Population activity occupied a substantial fraction of the state space and some MFAs are particularly informative about behaviour. Surprisingly, positively and negatively modulated MFAs are intermingled, suggesting granule cells integrate opposite-signed inputs to generate mixed bidirectional sensorimotor representations. Our results establish that neocortex and cerebellum can communicate with a low redundancy, high capacity, bidirectional population code, which is well-suited for forming sensorimotor associations.

A novel membrane contact site in vestibular hair cells
The mammalian vestibular system has two types of sensory receptor hair cells (HCs), each with different neurotransmission mechanisms. Type II HCs use ribbon synapses to transmit neurotransmitters like glutamate to afferent neurons. On the other hand, type I HCs are nearly engulfed by a calyceal afferent ending and also form ribbon synapses. These HCs regulate afferent activity through non-quantal transmission (NQT), which is faster than classic neurotransmitter release and may play a key role in stabilizing vision and balance during rapid head movements. Here, we describe a novel striated contact, present between the mouse type I HC and its calyceal afferent ending, and intimately associated with atypical plasma membrane-apposed (PMA) mitochondria. This distinctive arrangement has the potential to serve or modulate NQT.

'What' and 'where' brain-wide pathways are dominated by internal strategies
It is long thought that higher-order sensory processing is divided into two specialized cortical streams that encode in parallel either the identity of an object or its location (i.e., 'what' and 'where' streams). Here, using the mouse whisker system, we challenge this concept by demonstrating an existence of two alternating brain-wide (beyond cortex) subnetworks that are not primarily driven by external parameters, but rather by internal strategies. We combine simultaneous brain-wide neuronal recordings in mice trained to identify or locate a certain stimulus. We find that mice deploy either an active search or a passive sensation strategy during task performance. These strategies respectively drive two distinct and brain-wide subnetworks, frontal and posterior, regardless of the type of task performed. The posterior subnetwork encoded additional internal strategic parameters such as trial history, the first task of the day, and training history. A subgroup of trials that were not dominated by frontal cortex, contained meaningful task information in the posterior cortex and several thalamic areas. Integrated together, these two subnetworks may comprise normal cognitive function.

Estrous cycle stage gates the effect of stress on reward learning
Stress produces transient physiological responses that lead to long-lasting changes in cue-driven behavior. In particular, a single exposure to stress facilitates reward learning in male rats. Since stress can produce distinct behavioral phenotypes between males and females, it is critical to additionally determine how stress impacts reward learning in females. To address this, female rats were exposed to restraint stress immediately prior to training on an appetitive Pavlovian conditioning task with food rewards. Females were categorized based on their estrous cycle stage on the first day of Pavlovian conditioning. A single exposure to stress enhanced conditioned responding in non-estrus females but suppressed conditioned responding in estrus females. Therefore, a single stress experience produced opposing effects on cue-driven behavior depending upon the estrous cycle stage. In contrast, both estrus and non-estrus rats exposed to repeated prior stress exhibited an increase in conditioned responding relative to animals that underwent a single stress exposure. We further examined if the distal stress experience subsequently impacted extinction and the ability to learn a new cue-reward association. Prior stress did not affect extinction, though estrus and non-estrus rats exposed to repeated prior stress exhibited higher levels of conditioned responding to the novel cue-reward pairing. Taken together, our data demonstrate that the influence of stress on reward learning is impacted acutely by the estrous cycle as well as by prior history with stress.

Enhanced mGluR1 function causes motor deficits and region-specific Purkinje cell dysfunction
Spinocerebellar ataxias (SCAs) are autosomal dominantly inherited neurodegenerative disorders with no effective treatment. Aberrant signalling through the metabotropic glutamate receptor (mGluR1) has been implicated in several SCAs. However, whether disease is caused through decreased or increased mGluR1 signalling remains controversial. Here, we generate the first mouse model of enhanced mGluR1 function by introducing a gain-of-function mutation (p.Y792C) that causes SCA44 in the metabotropic glutamate receptor 1 (Grm1) gene. Grm1 mutant mice recapitulate key pathophysiological aspects of SCA, including progressive motor deficits, altered climbing fibre innervation and perturbed Purkinje cell spontaneous activity. We report that changes in synaptic innervation and intrinsic Purkinje cell activity upon overactive mGluR1 signalling manifest in a lobule- and disease-stage-specific manner. Our findings demonstrate that enhanced mGluR1 function is a direct and specific driver of Purkinje cell dysfunction and pathology and provide a mechanism for understanding the selective vulnerability of different Purkinje cell populations in SCA.

Aberrant preparation of hand movement in schizophrenia spectrum disorder: An fMRI study
Schizophrenia spectrum disorder (SSD) is linked to impaired self-other distinction and action feedback monitoring, largely stemming from sensory-motor predictive mechanisms. However, the neural correlates of these predictive processes during movement preparation are unknown. Here, we investigated whether patients with SSD exhibit aberrant sensory-motor predictive processes reflected in neural activation patterns prior to hand movement onset. Functional MRI data from patients with SSD (n = 20) and healthy controls (n = 20) were acquired during actively performed or passively induced hand movements. The task required participants to detect temporal delays between their movements and video feedback, which either displayed their own (self) or someone else's (other) hand moving in accordance with their own hand movements. Patients compared to healthy controls showed reduced preparatory blood-oxygen-level-dependent activation (active > passive) in clusters comprising the left putamen, left insula, left thalamus, and lobule VIII of the right cerebellum. Reduced activation in the left insula and putamen was specific to own-hand feedback. Additionally, patients with SSD revealed reduced suppression (passive > active) in bilateral and medial parietal (including the right angular gyrus) and occipital areas, the right postcentral gyrus, cerebellum crus I, as well as the left medial superior frontal gyrus. Ego-disturbances were negatively correlated with left insula and putamen activation during active conditions, and with right angular gyrus activation patterns during passive conditions when own-hand feedback was presented. These fMRI findings suggest that group differences are primarily evident during preparatory processes. Our results show that this preparatory neural activation is further linked to symptom severity, supporting the idea that the preparation of upcoming events as internal predictive mechanisms may underlie severe symptoms in patients with SSD. These findings could improve our understanding of other deficits in action planning, self-monitoring, and motor dysfunction in various psychiatric, neurological, and neurodegenerative disorders.

Distinct and complementary mechanisms of oscillatory and aperiodic alpha activity in visuospatial attention
Alpha oscillations are thought to play a key role in visuospatial attention, particularly through lateralisation mechanisms. However, whether this function is driven purely by oscillatory activity or also involves aperiodic neural components remains unclear, making it difficult to develop precise theoretical models of alpha function and attention. Using EEG and concurrent TMS-EEG, this study aimed to (1) disentangle the contributions of oscillatory and aperiodic alpha activity to visuospatial attention and (2) examine their causal roles by differentially modulating aperiodic and oscillatory components. First, across three independent EEG datasets, we found that both oscillatory and aperiodic responses in the alpha band contribute to spatial attention encoding and univariate lateralisation effects. The two signals were uncorrelated across electrodes and their combination yielded stronger effects than either signal separately, suggesting that they may play complementary roles. Then, we used concurrent TMS-EEG to modulate the two signals. Compared to arrhythmic TMS (ar-TMS), rhythmic TMS (rh-TMS), enhanced oscillatory alpha power, especially at the stimulated area, while decreasing aperiodic alpha power across the scalp. Despite these opposing effects, rh-TMS improved visuospatial attention representation carried by both oscillatory and aperiodic alpha signals, suggesting that both signals may support attentional processing through different mechanisms. Moreover, TMS-induced changes in oscillatory and aperiodic alpha decoding differentially predicted behavioural performance, with TMS-induced changes in oscillatory alpha decoding correlating with response errors and changes in aperiodic alpha decoding correlating with response speed. Together these findings reveal a functional dissociation between oscillatory and aperiodic activity in the alpha band. We suggest a dual mechanism for alpha band activity in supporting visuospatial attention, where the two components have distinct but complementary roles. Oscillatory components may primarily support attentional filtering and target prioritization, while aperiodic components may reflect overall neural excitability and cognitive efficiency. Both of these mechanisms contribute to successful visuospatial attention.

PhotoNeuro: A compact photodetector for synchronization of visual stimulus presentation during behavioral experiments in neuroscience.
Presenting visual stimuli in neuroscience experiments often requires the combination of analogue signals that carry information about the visual cue presented on the LCD display. Such signals are often sensed by photodetectors and recorded in analogue to digital converter (ADC) acquisition boards. The use of open-source visual programming languages such as Bonsai is becoming more and more popular. They are often used in combination with other open-source hardware such as Arduino development boards. These microcontroller-based boards can be used to automate behavioural experiments: e.g., actuate valves and motors and acquire analogue signals on their ADC channels. LCDs and other modern display allow fast presentation of arbitrary visual stimuli and are widely used for psychophysics and neuroscience experiments. However, most displays do not provide hardware timestamping options and are intrinsically nonlinear. Solving this limitation often requires a direct recording of the light emitted by the display with a photodiode. Such photodetectors are are often amplified at higher voltages and hard to integrate in most common recording systems that use microcontrollers. The other drawback commonly found by neuroscience researchers in commercial devices is the relatively big footprint that the sensor occupies on the screen which, ideally should be minimised so not to interfere with the stimuli presentation. In this paper we present a small footprint photodetector that can be easily replicated and operates at 5V making it suitable to use with common development boards and the visual programming language Bonsai that is commonly used for experiment creation and control. Additionally, we share a version that includes four photodiodes in small area (400 mm2).

Vertical Optokinetic Eye Movements in the Larval Zebrafish
The optokinetic response (OKR), a reflex enabling stable visual processing by minimizing retinal slip, has been well characterized in fish over the last decades, leading to insights and a better understanding of the underlying neuronal control and circuitries. However, only the horizontal component of the OKR has been investigated so far, although the optokinetic response is not limited to the horizontal plane, as it has also been observed vertically and even torsionally in other species. In this study, we characterize the vertical optokinetic response (vOKR) in larval zebrafish and compare it to the horizontal OKR (hOKR) and the vertical vestibulo-ocular reflex (vVOR). Two custom-built experimental setups, allowed for controlled vestibular stimulation alongside precise eye tracking and simultaneous recording of both horizontal and vertical eye movements during visual stimulation. Our findings reveal a distinct vOKR in larval zebrafish, but with a much smaller dynamic range compared to the hOKR and without any quick phases (resetting saccades). When presented with constant roll-rotating visual stimuli, zebrafish exhibit a brief initial vertical eye rotation in the direction of the stimulus, followed by a period with no further rotation but interspersed with only spontaneous saccades. This behavior contrasts sharply with the periodical occurrence of resetting saccades during hOKR. Despite its limited dynamic range, the initial vertical response is tuned to similar spatial frequencies and angular velocities as the hOKR. Intriguingly, zebrafish are capable of large vertical eye movements during the vVOR, suggesting that the restricted dynamic range of the vOKR is not due to inherent motor limitations. While it is unclear whether the observed differences in vertical versus horizontal optokinetic control have an adaptive value for zebrafish, the identified differences are drastic and informative for further studies on oculomotor circuits.

Scale-dependent brain age with higher-order statisticsfrom structural magnetic resonance imaging
Inferring chronological age from magnetic resonance imaging (MRI) brain data has become a valuable tool for the early detection of neurodegenerative diseases. We present a method inspired by cosmological techniques for analyzing galaxy surveys, utilizing higher-order summary statistics with multivariate two- and three-point analyses in 3D Fourier space. This method identifies outliers while offering physiological interpretability, allowing the detection of scales where brain anatomy differs across age groups and providing insights into brain aging processes. Similarly to the evolution of cosmic structures, the brain structure also evolves naturally but displays contrasting behaviors at different scales. On larger scales, structure loss occurs with age, possibly due to ventricular expansion, while smaller scales show increased structure, likely related to decreased cortical thickness and gray/white matter volume. Using MRI data from the OASIS-3 database for the complete sample of 864 sessions (reduced sample: 827 sessions), our method predicts chronological age with a Mean Absolute Error (MAE) of ~3.8 years (~3.6 years) for individuals aged ~40-100 (50-85), while providing information as a function of scale. A neural density posterior estimation shows that the 1-sigma uncertainty for each individual varies between ~3 and 7 years, suggesting that, beyond sample variance, complex genetic or lifestyle-related factors may influence brain aging. Applying this method to an independent database, Cam-CAN, validates our analysis, yielding a MAE of ~3.4 for the age range from 18 to 88 years. This work demonstrates the utility of interdisciplinary research, bridging cosmological methods and neuroscience.

Rapid and efficient optical tissue clearing for volumetric imaging of the intact and injured spinal cord in mice
Tissue clearing and 3D imaging have emerged as powerful techniques to assess the cellular and tissue-level architecture of the spinal cord. With the rapidly increasing variety and complexity of optical tissue clearing techniques, there is a critical need for optimization and streamlining of tissue-specific protocols, particularly when dealing with injury or disease states. We evaluated and combined multiple organic solvent-based techniques to develop sciDISCO: a spinal cord injury-optimized DISCO tissue clearing protocol. sciDISCO allows for the robust clearing, labeling, and 3D imaging of the intact spinal cord, as well as clearing around and through the lesion site formed after contusive spinal cord injury. In addition, we have identified alternatives for hazardous chemicals commonly used in organic solvent-based clearing including dichloromethane and dibenzyl ether. In this study, we demonstrate the compatibility of sciDISCO with multiple different labeling techniques to provide robust analysis of unique neuronal populations and morphologies in addition to cellular and tissue-level changes occurring following spinal cord injury.

Chromatic and Achromatic Contrast Sensitivity in the far Periphery
The contrast sensitivity function (CSF) has been studied extensively since the 1960s, however most studies to date have focused on the central region of the visual field. The current study aims to address two gaps in previous measurements: First, it provides a detailed measurement of the CSF for achromatic and, importantly, also chromatic stimuli in the far periphery of up to 90 degrees of visual angle. Second, we describe visual sensitivity around the monocular/binocular boundary that is naturally present in the far periphery. In the first experiment, the CSF was measured in 3 different conditions: Stimuli were either Achromatic (L+M), Red-Green (L-M) or and Yellow-Violet (S-(L+M)) gabor patches. Overall, results followed the expected patterns established in the near periphery, but achromatic sensitivity in the far periphery was mostly underestimated by current models of visual perception, the quick decay in sensitivity observed for red-green stimuli slows down in the periphery. The decay of sensitivity for yellow-violett stimuli roughly matches the decay for achromatic stimuli even up to the far periphery. For the second experiment, we compared binocular and monocular visual sensitivity at different locations in the visual field. We observed a consistent increase of visual sensitivity for binocular viewing in the central part of the visual field compared to monocular viewing, but this benefit already decreased within the binocular visual field in the periphery. Together, these data provide a detailed description of visual sensitivity in the far periphery. These measurements can help to improve current models of visual sensitivity and can be vital for applications in full-field visual displays in virtual and augmented reality.

Application of Down-Phase Targeted Auditory Stimulation During Sleep in a Home Setting: A Feasibility Study Across Seven Consecutive Nights
Introduction: Sleep deprivation, also known as "wake therapy", has long been recognized as a powerful antidepressant. Phase-targeted auditory stimulation (PTAS) has been suggested as an auspicious non-invasive nocturnal substitute for sleep deprivation. Down-PTAS with stimuli presentation during the down-phase of slow waves, in particular, may have therapeutic potential to improve mood by selectively reducing slow-wave activity (SWA). With down-PTAS being more nuanced than sleep deprivation, its effects presumably develop over multiple nights, thus necessitating transfer from sleep laboratory to home settings. Therefore, in this study, we investigated the technical feasibility, tolerability, and potential risks associated with a wearable device employed for down-PTAS in an unsupervised home setting. Methods: We recorded frontal EEG using the MHSL Sleepband Version 3 (MHSL-SB) in five healthy participants (23.8 +- 0.8 years, three women) over seven consecutive nights with (STIM) and without (SHAM) tone application at their homes. Tones were delivered shortly before the negative peak of slow waves during N2/N3 sleep, using alternating 10-s ON-OFF windows. Sleep staging followed American Academy of Sleep Medicine (AASM) guidelines. Of the 67 available sleep recordings, we excluded three due to parameter adjustments and another six for technical issues, leaving 58 sleep recordings (29 SHAM, 29 STIM) for further analyses. Low SWA (0.5-2 Hz, lSWA) was computed across the entire night, ON-OFF windows, and sleep cycles. Time-frequency analyses were performed time-locked to stimulus onset. We computed linear mixed effect models with condition (STIM vs. SHAM) as a fixed effect and random participant intercepts. Results: Data quality was sufficient for analyses in 87% of the available sleep recordings, with an average of over 1500 correctly delivered stimuli per recording. Down-PTAS did not affect sleep architecture, but it reduced lSWA primarily during the first sleep cycle when sleep pressure and lSWA were highest, and particularly in OFF windows. Additionally, stimulation elicited a K-complex-like auditory evoked response, aligning with previous laboratory findings. Conclusion: Our results demonstrate the successful implementation of down-PTAS in a home setting, confirming its feasibility for long-term, unsupervised use. The K-complex-like auditory evoked response may mask potential reductions in lSWA during ON windows, posing a scientific analytical challenge. Taken together, future clinical research should now assess the effects of down-PTAS in depressed patients, in whom reducing lSWA may partly mimic sleep deprivation.

Multimodal general expectancy effects elicited without influencing sensory representations
Predictive coding theories posit a reduction in error - signalling neural activity when incoming sensory input matches existing expectations - a phenomenon termed expectation suppression. While human neuroimaging studies have consistently reported reduced neural activity for expected events, it is uncertain whether this reduction arises from the sharpening or dampening of neurons selective for expected features. A further aspect of predictive coding that remains untested is how predictions are integrated across sensorimotor domains. To investigate these two questions, we employed a novel cross-domain probabilistic cueing paradigm, where participants were presented with both visual and motor cues within a single trial. These cues manipulated the orientation and temporal expectancy of target stimuli with 75% validity. Participants completed a reproduction task where they rotated a bar to match the orientation of the target stimulus while their neural and pupil responses were respectively measured via electroencephalography and eye tracking. Our results showed an effect of expectancy in the motor condition across multiple measures, while evidence in the visual condition was inconsistent. However, no differences in orientation fidelity were found in sensory representations between expected and violation trials for either domain. These findings show that violations of temporal expectancy produce prediction error signals that do not influence sensory representations. Further, the findings add to a growing body of work casting doubt on the effectiveness of probabilistic cueing paradigms for eliciting prediction errors. Due to null findings in the visual and representational analyses, we did not further investigate cross-domain prediction integration.

Meta plasticity and Continual Learning: Mechanisms sub serving Brain Computer Interface Proficiency
Objective: Brain Computer Interfaces (BCIs) require substantial cognitive flexibility to optimize control performance across diverse settings. Remarkably, learning this control is rapid, suggesting it might be mediated by neuroplasticity mechanisms operating on very short time scales. However, these mechanisms remain far from understood. Here, we propose a meta plasticity model of BCI learning and skill consolidation at the single cell and population levels comprised of three elements: a) behavioral time scale synaptic plasticity (BTSP), b) intrinsic plasticity (IP) and c) synaptic scaling (SS) operating at time scales from seconds to minutes to hours and days. Notably, the model is able to explain representational drift-a frequent and widespread phenomenon observed in multiple brain areas that adversely affects BCI control and continued use. Approach: We developed a closed loop all optical approach to characterize IP and BTSP with single cell resolution using two photon (2P) GCaMP7s imaging and the soma targeted ChRmineKv2.1 opsin in L2/3 of awake mice. We further trained mice on a 1-dimensional (1D) BCI control task and systematically characterized within session (seconds to minutes) learning as well as across sessions (days and weeks) with different neural ensembles. Main results: We found that on the time scale of seconds, substantial BTSP could be induced and was associated with significant IP over minutes. Over the time scale of days and weeks, these changes could accurately predict BCI control proficiency, suggesting that synaptic scaling may complement both BTSP and IP to stabilize and consolidate BCI control. Significance: Our results provide theoretical and early experimental support for an integrated meta plasticity model of continual BCI learning and skill consolidation. The model predictions may be used to design and calibrate neural decoders with complete autonomy while considering the temporal and spatial scales of plasticity mechanisms and their anticipated order of occurrence. With the power of modern-day machine learning (ML) and artificial Intelligence (AI), fully autonomous neural decoding and adaptation in BCIs might be achieved with minimal to no human intervention.

LSD reconfigures the frequency-specific network landscape of the human brain
Lysergic acid diethylamide (LSD) and other psychedelic substances profoundly alter human consciousness. While several studies have demonstrated changes in brain function and connectivity associated with psychedelics, we still have a limited understanding of how LSD reshapes brain networks operating across different frequency bands. In this study, we applied the recently developed FREQ-NESS method to MEG data from 14 healthy participants who received LSD under four conditions: eyes-closed with or without music and eyes-open with or without a video stimulus. LSD significantly restructures canonical networks in the alpha and beta bands. Relative to broadband brain activity, it enhances the prominence of high alpha (12.1, 13.3 Hz) across all experimental conditions and high beta (25.3 Hz) in three conditions. Conversely, LSD decreases the prominence of low beta (18.1, 19.3 Hz) in both Open and Closed conditions and low alpha (8.5 Hz) in the latter. In addition, LSD substantially alters the spatial distributions or topographies of the networks. Under LSD, the low alpha (8.5 Hz) network shifts anteriorly toward the motor cortex, while high alpha (12.1, 13.3 Hz) becomes more localized to the visual cortex. Low beta (18.1, 19.3 Hz) expands over the temporal and occipital cortices, whereas high beta (25.3, 26.5 Hz) topographies remain unchanged. Our findings provide critical insights into the specific frequencies and spatial networks in which LSD modulates brain connectivity, adding nuance to prevailing theories about network disintegration under psychedelics.

Diurnal dynamics of multilayer brain networks predict cognitive trajectories in aging
Objectives. Resting-state functional connectivity (rsFC) is a highly dynamic process that varies across different times of the day within each individual. Although this variability was long considered to be noise, recent evidence suggests it may allow for an optimal adaptation to changes in the environment. However, the way rsFC is shaped on a circadian scale and its association with cognition are still unclear. Methods. We analyzed data from 90 late-middle-age participants from the Cognitive Fitness in Aging study (61 women; 50-69y). Participants completed five electroencephalographic (EEG) recordings of spontaneous resting-state activity spread over 20h of prolonged wakefulness. Using a temporal multilayer network approach, we characterized the diurnal variations of the dynamic recruitment and integration of resting-state brain networks. We focused on the theta and gamma frequency bands within the default mode network (DMN), central executive network (CEN), and salience network (SN). Additionally, we investigated the relationship recruitment and integration of these network with baseline cognitive performance and at 7-year longitudinal follow-up, as well as with positron emission tomography (PET) early neuropathological markers of Alzheimer disease such as B-amyloid and tau/neuroinflammation. Results. Diurnal changes in theta and gamma dynamics were associated with distinct cognitive aspects. Specifically, higher baseline memory performance was associated with higher theta dynamic integration of the SN and the CEN, as well as higher theta dynamic recruitment of the DMN. Moreover, lower longitudinal memory decline at 7-year was associated with higher theta dynamic integration of the SN, CEN, and DMN. In contrast, higher gamma diurnal dynamic integration of the SN and the CEN was associated with lower executive and attentional performance, as well as higher early B-amyloid accumulation, at baseline. Discussion. These findings suggest that maintaining a balance between network flexibility and stability throughout the diurnal phase of the circadian cycle may play a crucial role in cognitive aging, with stable theta-band connectivity supporting memory, whereas excessive gamma-band stability in the SN and CEN may contribute to executive decline and early amyloid accumulation. These insights highlight the importance of considering time-of-day in brain rsFC studies, calling for a temporal multilayer approach to capture these dynamic patterns more effectively.

Autoreactive IgG levels and Fc receptor γ subunit upregulation drive mechanical allodynia after nerve constriction or crush injury
B cells contribute to the development of pain after sciatic nerve chronic constriction injury (CCI) via binding of immunoglobulin G (IgG) to Fc gamma receptors (Fc{gamma}Rs) in the lumbar dorsal root ganglia (DRG) and spinal cord. Yet the contribution of B cells to pain after different types of peripheral nerve injury is uncertain. Using male and female mice, we demonstrate a divergent role for B cell-IgG-Fc{gamma}R signaling underlying mechanical allodynia between CCI, nerve crush (NC), spared nerve injury (SNI), and spinal nerve ligation (SNL). Depletion (monoclonal anti-CD20) or genetic deletion (muMT mice) of B cells prevented development of allodynia following NC and CCI, but not SNI or SNL. In apparent contradiction, circulating levels of autoreactive IgG and circulating immune complexes were increased in all models, though more prominent following NC and CCI. Passive transfer of IgG from SNI donor mice induced allodynia in CCI muMT recipient mice, demonstrating that IgG secreted after SNI is pronociceptive. To investigate why pronociceptive IgG did not contribute to mechanical allodynia after SNI, we evaluated levels of the Fc receptor {gamma} subunit. SNI or SNL did not increase {gamma} subunit levels in the DRG and spinal cord, whereas CCI and NC did, in agreement with B cell-dependent allodynia in these models. Together, the results suggest that traumatic peripheral nerve injury drives secretion of autoreactive IgG from B cells. However, levels of cognate Fc{gamma}Rs are increased following sciatic nerve constriction and crush, but not transection, to differentially regulate pain through the B cell-IgG-Fc{gamma}R axis.

PET-derived amyloid patterns in gray and white matter across Alzheimer's disease: A high-model-order ICA
Background: Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by gray matter (GM) changes, such as amyloid-beta (A{beta}) plaques and neurofibrillary tangles. While GM alterations are well-established, the fine-grained, spatially distinct patterns of homogeneous A{beta} uptake and their changes remain poorly understood. Additionally, white matter (WM) pathology is less explored. This study addresses these gaps by leveraging high-model-order independent component analysis (ICA) to identify spatially granular amyloid networks in both GM and WM. Methods: We analyzed [18F]Florbetapir (FBP) PET images from 716 participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), classified as cognitively normal (CN), mild cognitive impairment (MCI), or AD dementia. High-model-order ICA was applied to identify 80 GM and 13 WM FBP-related networks, which were labeled using terms from the Neuromark 2.2 Atlas. Statistical analyses assessed diagnostic effects and relationships between these networks and cognitive and neuropsychiatric variables. Results: Significant diagnostic differences were observed across GM and WM networks, revealing a continuous pattern of change from CN to MCI to AD. The analysis showed that the extended hippocampal, extended thalamic, basal ganglia, and frontal subdomains displayed an MCI profile closer to AD than to CN. In contrast, other subdomains exhibited a more mixed pattern, with MCI sometimes aligning more closely with CN and other times with AD. Notably, the hippocampal-entorhinal complex (HEC) within the extended hippocampal subdomain and the precuneus within the default mode subdomain were consistently associated with cognitive decline, highlighting their roles in disease progression. Additionally, WM networks, particularly the retrolenticular internal capsule (RICap), also demonstrated significant relationships with cognitive measures, suggesting that AD pathology extends beyond GM and disrupts broader network connectivity. These findings were validated in an independent replication dataset. Conclusion: High-model-order ICA effectively captures distinct fine-grained amyloid distributions, offering a network- level perspective that enhances our understanding of AD neurobiology. By decomposing complex PET signal patterns into distinct networks, this approach underscores the critical role of both GM and WM integrity in AD pathology. The consistent associations of the HEC, precuneus, and WM networks with cognitive decline highlight the widespread impact of AD-related pathology, emphasizing the value of this methodology in advancing AD research.

Endogenous auditory and motor brain rhythms predictindividual speech tracking
Slow, endogenous brain rhythms in auditory cortex are hypothesized to track acoustic amplitude modulations during speech comprehension. Temporal predictions from the motor system are thought to enhance this tracking. However, direct evidence for the involvement of endogenous auditory and motor brain rhythms is lacking. Combining magnetoencephalographic recordings with behavioral data, we here show that endogenous peak frequencies of individuals' resting-state theta rhythm in superior temporal gyrus predict speech tracking during comprehension. Importantly, endogenous rates of speech motor areas predicted auditory-cortical speech tracking only in individuals with high auditory-motor synchronization profiles. Higher rates in the supplementary motor area, and lower rates in inferior frontal gyrus, predicted stronger tracking. These findings align with participants' behavioral data and provide compelling support for oscillatory accounts of auditory-motor interactions during speech perception. Interestingly, working memory capacity predicted speech comprehension performance particularly in individuals with low auditory-motor synchronization profiles. The findings highlight two partially independent speech processing routes across individuals: an auditory-motor route, related to enhanced comprehension performance, and an auditory working-memory route.

Serotonin selectively modulates visual responses of object motion detection in Drosophila
Serotonin (5-HT) is a hormonal messenger that confers state-level changes upon the nervous system in both humans and flies. In Drosophila, lobula columnar (LC) cells are feature-detecting neurons that project from the optic lobe to the central brain, where each population forms an anatomically-distinct glomerulus with heterogeneous synaptic partners. Here, we investigated serotonin's effect on two LC populations with different 5-HT receptor expression profiles. Receptor expression does not predict neuromodulatory effects: LC15 expresses inhibitory 5-HT1A and 5-HT1B receptors, yet serotonin increases the amplitude of calcium responses to visual stimuli. LC12 expresses inhibitory 5-HT1A and excitatory 5-HT2A receptors, yet serotonin application does not influence visual responses. Serotonin targets select visual response properties, potentiating LC15 responses to a motion-defined bar and normalizing responses across bar velocity, but has no influence on contrast sensitivity. Serotonin does not significantly facilitate LC15 responses in postsynaptic dendrites, only in the presynaptic terminals of the glomerulus, which suggests that the neuromodulatory effects are strongest in the central brain. Connectomics confirms that LC12 and LC15 share neither presynaptic inputs nor postsynaptic outputs in the central brain. The wiring diagram shows no synaptic interactions between the LC15 circuit and major serotonergic 5-HTPLP neurons, nor to other serotonergic neurons of the central brain, suggesting that endogenous 5-HT acts via paracrine transmission on non-serotonergic pathways. Lobula- and glomerulus-specific GABAergic and glutamatergic inhibitory partners, positioned to filter visual stimuli, are putative 5-HT targets. These results provide a comparative framework for the neuromodulatory mechanisms involved in visual processing.

Electrical stimulation of the superior temporal gyrus evokes rapid responses in human visual cortex
Sounds produce rapid responses in human visual cortex. Animal research suggests that these responses are enabled by corticocortical projections from auditory to visual cortex. To test for the presence of such pathways in humans, we examined intracranial responses to direct electrical stimulation. Stimulation over auditory cortex elicited rapid responses in early visual cortex (particularly near the visual periphery), providing causal support for corticocortical transmission of cross-modal information.

Understanding the mechanism of facilitation in hoverfly TSDNs
Many animals use visual motion cues to track and pursue small, fast-moving targets, for instance, prey or conspecifics. In target-pursuing insects, including dragonflies and hoverflies, Small Target Motion Detector (STMD) neurons are found in the optic lobes and are believed to be presynaptic to Target Selective Descending Neurons (TSDNs) that project to motor command centres. While STMDs respond robustly to target motion - even when displayed against moving backgrounds - TSDN target responses are modulated by background motion. Depending on whether the background motion is syn- or contra-directional to the target motion, the response of the TSDNs is either suppressed or facilitated (amplified). This suggests additional input from neurons tuned to background motion. However, the neural mechanism is not clearly understood. To explore the underlying circuitry, we developed three candidate models of the TSDN circuit - which combine input from STMDs and optic flow-sensitive Lobula Plate Tangential Cells (LPTCs) in different ways - and fitted them to published electrophysiology data from hoverfly TSDNs. We then tested the best-fitting models against new electrophysiological data using different background patterns. We found that the overall best model suggests simple inhibition from LPTCs with the same preferred direction as the STMDs feeding into the TSDN. This parsimonious mechanism can explain the facilitation and suppression of TSDN responses to small targets and may inform similar studies in other animals and open new avenues for bio-inspired robotics.

Light propofol anaesthesia for non-invasive auditory EEG recording in unrestrained non-human primates.
Non-invasive electroencephalographic (EEG) experiments have been instrumental in advancing our understanding of the brain mechanisms involved in the production and perception of sounds and human speech. Performing similar experiments in non-human primates (NHPs) would help further deepen our knowledge by allowing us to investigate the evolutionary roots of these processes. However, performing EEG on NHPs is a challenge, given its sensitivity to motion artefacts, device cost and durability, and animal training requirements. For these reasons, most attempts have used invasive intracranial recordings, which led us to develop an alternative that minimises stress and prioritises animal welfare. By using mild propofol sedation, neurophysiological experimentation can easily be integrated into the routine sanitary checks of captive animals and allows the optimisation of both EEG quality and animal welfare. To assess the influence of propofol on brain activity in NHPs, we sedated three olive baboons (Papio anubis), scored their sleep stages under different doses, and recorded auditory event-related potentials (ERP)in response to grunts. Analyses of the EEG recordings with regards to sleep stage and ERP components indicate that at low dose (< 0.1mg/kg/h), propofol induces a light sleep state conducive to recording stimulus-elicited auditory activity. Overall, this experiment confirms the use of propofol sedation as an appropriate technique to study auditory processes through unrestrained, non-invasive EEG in NHPs.

Seizure-like behavior and hyperactivity in napb knockout zebrafish as a model for autism and epilepsy
We identified N-ethylmaleimide-sensitive factor attachment protein beta (NAPB) as a potential risk gene for autism and epilepsy. Notably, Qatari monozygotic triplets with loss of function mutations in NAPB exhibit early onset epileptic encephalopathy and varying degrees of autism. In this study, we generated NAPB zebrafish model using CRISPR-Cas9-sgRNAs technology for gene editing of the two orthologs napba and napbb. We observed that napb crispants (CR) show shorter motor neuron axons length together with altered locomotion behavior, including significant increases in larvae total distance traveled, swimming velocity, and rotation frequency, indicating that these behavioral changes effectively mimic the human epileptic phenotype. We applied microelectrode array (MEA) technology to monitor neural activity and hyperexcitability in the zebrafish model. The napb CR shows hyperexcitability in the brain region. By combining behavioral tests with electrophysiological MEA assays, the established NAPB zebrafish model can be employed to study the pathophysiological mechanisms of ASD and epilepsy to screen potential therapeutic drugs.

Neural dynamics of induced vocal tract vibrations during vocal emotion recognition
Emotional prosody is defined as suprasegmental and segmental changes in voice and related acoustic parameters that can inform the listener about the emotional state of the speaker. Despite a large corpus of literature in psychological and brain mechanisms in emotional prosody perception, the perspective of embodied cognition in these mechanisms have been largely neglected. Here we investigated the influence of induced bodily vibrations in the categorization of ambiguous emotional vocalizations in an event-related potential study (N=24). The factorial design included Vocal emotion [anger and fear] and external Vibration [anger, fear, and none] as fixed factors. Emotional voices were morphed between a fearful expression with the speaker identity-matching angry expression, creating blends of emotions in each voice. Emotional congruent and incongruent vibrations were delivered on the skin through transducers placed close to the vocal cords. We hypothesized that induced bodily vibrations would constitute an interoceptive and proprioceptive feedbacks that would influence the perception of emotions, especially for more ambiguous voices as ambiguity would favour the processing of other available sensory information, here toward the tactile sensory modality. Behavioural results revealed that induced vibrations skewed the participants emotional ratings by biasing responses congruent with the vibration. Event-related potentials results indicated that N100 and P200 components subtending the early processing of emotional prosody were significantly modulated by induced vibrations in the congruent setting, which could be considered as a facilitation effect for emotion recognition at early stage of processing. A significant modulation of the late positive component was also observed in the incongruent setting, suggesting an error processing mechanism. EEG source reconstruction highlighted significant contrasts between vibration types in prefrontal, motor, somatosensory, and insular cortices. Altogether, our results suggest that voice-associated vibrations would play a significant role in vocal emotion perception and recognition through embodied mechanisms at both behavioral and neural levels.

Dependence of higher-order correlations and information compression on temporal resolution in neuronal data
Studying the higher order interactions in complex interacting systems based on limited data is a challenging task. Traditional methods rely on pre-defined assumptions on the connectivity structure of the underlying generative models. In this paper, the inference of the underlying structure in complex systems given a limited binary dataset is done by a novel approach ( Minimally complex models ) with minimal prior assumptions. Our results demonstrate that orders of interaction and the number of components required for encoding of information vary with the choice of temporal resolution that the data is studied or recorded in. This procedure accounts for optimal time resolution in which the presence of the higher order interaction is accompanied by maximal information compression. The model provides systematic framework for inferring interaction's orders and accurately comparing the significance of these type of interactions across different co-variates.

Neural Basis of Odometry in Drosophila
Path integration is a mode of navigation in which travel distance and direction are integrated to calculate position. Estimating travel distance, or odometry, requires the summation of translational vectors over time. Although neurons sensitive to translational velocity have been identified in numerous species, a definitive relationship between the activity of these translational velocity neurons and the subjective perception of distance has yet to be established. We developed a new memory-based assay to dissect the neural circuit of distance estimation. Flies can estimate distance by using self-motion, associate it with aversive stimulus onset, and use the PFN[->]h{Delta}B pathway to estimate it. Thus, we provide evidence for self-motion integration for distance estimation in flies and point to the neural basis of this integration.

Synaptotagmin-1 and complexin inhibit spontaneous vesicle fusion by masking PIP2, not by clamping SNARE assembly
Vesicle fusion underlies neurotransmitter release, enabling cellular communication. The rapid kinetics of vesicle fusion, tight docking to the plasma membrane, and coordination by multiple SNARE complexes suggest that SNARE complexes are already pre-assembled before fusion. Synaptotagmin-1 (Syt-1) and complexin (CPLX) have been proposed to clamp SNARE assembly and arrest fusion. However, these models are largely based on studies conducted under low ionic strength and structural analyses utilizing SNARE-Syt-1 chimera conjugates. We propose phosphatidylinositol 4,5-bisphosphate (PIP2) as a critical lipid catalyst that facilitates fusion through electrostatic dehydration. Here we show that neither the C2AB domain of Syt-1 nor CPLX-2 has clamping or inhibitory effect on SNARE assembly. Instead, the C2AB domain and CPLX-2 inhibit Ca2+-independent vesicle fusion by masking PIP2. Our data resolve the long-standing question of increased spontaneous neurotransmitter release in Syt-1 and CPLX knockout neurons, emphasizing PIP2 as an electrostatic lipid catalyst for fusion.

Distinct Roles of Somatostatin and Parvalbumin Interneurons in Regulating Predictive Actions and Emotional Responses During Trace Eyeblink Conditioning
Learning involves evaluating multiple dimensions of information and generating appropriate actions, yet how the brain assigns value to this information remains unclear. In this study, we show that two types of interneurons (INs) in the primary somatosensory cortex-somatostatin-expressing (SST-INs) and parvalbumin-expressing (PV-INs) neurons-differentially contribute to information evaluation during trace eyeblink conditioning (TEC). An air puff (unconditioned stimulus, US) delivered after a whisker stimulus (conditioned stimulus, CS) elicited both reflexive eye closure and stress-related locomotion. However, only self-initiated, anticipatory eye closure during the CS window, measured via electromyography (EMG), was directly relevant to learning performance. We found that SST-IN activity changes aligned with the learning induced changes of the anticipatory eye blinks during the CS period, correlated with the EMG changes across learning. In contrast, PV-IN activity was positively correlated with stress-related locomotion following the US and showed no learning related changes, suggesting a role in processing the emotional or aversive component of the task. Furthermore, cholinergic signaling via nicotinic receptors modulated both SST- and PV-IN activities, in a manner consistent with their distinctive roles, linking these interneurons to the regulation of learning-related actions and emotional responses, respectively. These findings demonstrate that distinct interneuron populations evaluate different dimensions of information-SST-INs for predictive, adaptive actions and PV-INs for stress-related emotional responses to guide learning and behavior.

Altered Interpersonal Neural Synchronization during Social Interaction After Shared Excluded Experiences in Depressed Adolescents
Background: Major depressive disorder (MDD) is common in adolescents, and the special development stage, during which adolescents' brain and neuroendocrine system develop intensively, makes it subtly difficult to develop prevention and treatment strategies for depressed adolescents compared with depressed adults. Meanwhile, public psychosocial stressors significantly influence adolescents' mental health and social interaction, rendering it essential to explore how a shared psychosocial stressor, i.e., shared excluded experiences, influences social interaction in depressed adolescents. Methods: We designed a 4-player cyberball game to probe adolescents' responses to shared excluded experiences and explore the underlying interpersonal neural synchronization (INS) with functional near-infrared spectroscopy (fNIRS). Results: We found that shared excluded experiences could enhance adolescents' social interaction preferences but decreased INS in each pair of excluded adolescents, which indicates a reduced willingness to interact with others after the exclusion. However, no significantly different behavioral responses to the shared excluded experiences were found in depressed adolescents compared to adolescents as healthy controls (HC). Further analyses revealed that adolescents with MDD experienced more negative feelings than HC after exclusion. Of note, adolescents with MDD demonstrated stronger INS than HC, indicating the potential empathic stress in depressed adolescents. In addition, there existed altered brain-behavioral association patterns in responses to shared excluded experiences in depressed adolescents. Conclusions: In summary, our study gives us deeper insights into how a shared psychosocial stressor impacts the INS in depressed adolescents, and it might be demonstrated that INS could be more sensitive than behavioral responses to detect social interaction deficits in depressed adolescents.

Electrophysiological development and functional plasticity in dissociated human cerebral organoids across multiple cell lines
Microelectrode arrays (MEAs) are increasingly used to profile the development of synchronised activity in neural organoids, yet no organoid study has investigated the consistency of electrophysiological development across cell lines. Here, we used dissociated neural organoids derived from four cell lines on MEAs to characterise functional synapse development using multiple parameters across time. The dissociated organoids had increasing functional connectivity and network activity over time across all cell lines and plasticity in response to synaptic-like stimulation. Like the organoids they were derived from, dissociated organoid cultures contained a diverse mixture of cell types. Variability in activity parameters was associated with differences in cell type composition and regional identity, which in turn were affected by donor cell line and batch effects. These results demonstrate that dissociated cerebral organoids can generate functional neurons, akin to primary neuronal cultures from brain tissue, providing a scalable model for studies of neurodevelopment and synaptic function.

Chronic but not acute morphine exposure reversibly impairs spike generation and repetitive firing in a functionally distinct subpopulation of orexin neurons
Orexin (hypocretin) neuropeptides regulate numerous essential functions including sleep/wake state stability and reward processing. Orexin synthesizing neurons respond to drug cues and undergo structural changes following persistent drug exposure. Post-mortem brains from opioid users, and opioid-treated rodents have orexin somata that become ~20 % smaller and ~50% more numerous and are postulated to promote hyper-motivation for drug-seeking though increased orexin release. Biophysical considerations suggest that decreased soma size should increase cellular excitability, however the impact of chronic opioids on firing ability, which drives peptide release, has not been explored. To test this, we assessed the intrinsic electrophysiological properties of orexin neurons by whole-cell recordings in slices from male orexin-EGFP mice treated by daily morphine or saline injections for two weeks. Paradoxically, we found that while daily morphine decreased average soma size, it impaired excitability in a subpopulation of orexin neurons identified by electrophysiological criteria as H-type, while entirely sparing D-type neurons. This impairment was manifest by smaller, broader action potentials, variable firing and a downscaling of firing gain. These adaptations required more than a single morphine dose and recovered, along with soma size, after four weeks of passive withdrawal. Taken together, these observations indicate that daily opioid exposure differentially impacts H-type orexin neurons and predicts that the ability of these neurons to encode synaptic inputs into spike trains and to release neuropeptides becomes impaired in conjunction with opioid dependence.

Translating the Post-Mortem Brain Multi-Omics Molecular Taxonomy of Alzheimer's Dementia to Living Humans
Alzheimer's disease (AD) dementia is characterized by significant molecular and phenotypic heterogeneity, which confounds its mechanistic understanding, diagnosis, and effective treatment. In this study, we harness the most comprehensive dataset of paired ante-mortem blood omics, clinical, psychological, and post-mortem brain multi-omics data and neuroimaging to extensively characterize and translate the molecular taxonomy of AD dementia to living individuals. First, utilizing a comprehensive integration of eight complementary molecular layers from brain multi-omics data (N = 1,189), we identified three distinct molecular AD dementia subtypes exhibiting strong associations with cognitive decline, sex, psychological traits, brain morphology, and characterized by specific cellular and molecular drivers involving immune, vascular, and oligodendrocyte precursor cells. Next, in a significant translational effort, we developed predictive models to convert these advanced brain-derived molecular profiles (AD dementia pseudotimes and subtypes) into blood-, MRI- and psychological traits-based markers. The translation results underscore both the promise of these models and the opportunities for further enhancement. Our findings enhance the understanding of AD heterogeneity, underscore the value of multi-scale molecular approaches for elucidating causal mechanisms, and lay the groundwork for the development of novel therapies in living persons that target multi-level brain molecular subtypes of AD dementia.

A Prefrontal Cortex-Nucleus Accumbens Circuit Attenuates Cocaine-conditioned Place Preference Memories
The infralimbic (IL) subregion of the prefrontal cortex (PFC), via its descending projection to the nucleus accumbens (NAc), inhibits cue-induced drug seeking and reinstatement, but the underlying mechanisms are not fully understood. Here we show that the intrinsic membrane excitability of IL layer 5 pyramidal neurons projecting to the NAc shell (IL-NAcSh neurons) suppresses cocaine-associated memories. Following repeated cocaine exposures in a conditioned place preference paradigm, IL-NAcSh neurons anatomically traced by fluorescent retrobeads undergo prolonged decrease of membrane excitability, lasting for at least 15 days after cocaine withdrawal. This persistent IL-NAcSh neuron hypoexcitability was accompanied by an increase in the rheobase, an increase in the afterhyperpolarization potential, and a decrease in the membrane input resistance. This cocaine induced neuroadapation in intrinsic excitability was not observed in prelimibic cortex neurons projecting to the NAc core (PL-NAcCo neurons), a separate descending circuit thought to promote cue-triggered drug seeking. Chemogenetic restoration of IL-NAcSh neuron activity extinguishes both the acquisition and retention of cocaine conditioned place preference memories. Our results provide direct support for the notion that the IL-NAcSh circuit serves to extinct drug associated memories and restoring the drug impaired excitability of IL-NAcSh neurons has the potential to mitigate drug-cue association memories and drug seeking.

Multimodal social context modulates behavior in larval Drosophila
All animals need to navigate and make decisions in social environments. They influence each other's behavior, but how important this is and how they process and represent social information in their brain is less well understood. This includes fruit flies and fly larvae, which are usually not known as social insects. Using a Drosophila larva assay with reduced stimulation, we found that larval groups show enhanced dispersal and distance from each other in the absence of food. This social context-dependent modulation overrides responses to other external sensory cues and is shaped by developmental social experience. Leveraging the genetic toolbox available in Drosophila, we find that different sensory modalities are required for normal social context modulation. Our results show that even less social animals like fly larvae are affected by conspecifics and that they recognize each other through multimodal sensory cues. This study provides a tractable system for future dissection of the neural circuit mechanisms underlying social interactions.

Statistical Olfactory Learning in Honey Bees
Statistical learning is a key mechanism for detecting regularities in sensory inputs. Among its functions is the ability to extract regularities from sequences (of sounds, objects, odors, etc.), enabling species to predict future events and guide behavior. This capacity has been demonstrated in vertebrates, including human infants, non-human primates, and birds. However, the minimum computational architecture required for statistical learning remains unclear. To address this issue, we studied statistical learning in the honey bee (Apis mellifera), an invertebrate model for learning studies. We show that bees learn and recall the temporal structure of sequences of odorants, suggesting that statistical learning is a fundamental component of a conserved cognitive toolkit present even in invertebrates.

Cerebellin-2 positive (Cbln2+) Neurons in the Parafascicular Thalamic Nucleus Regulate Self-Grooming Behavior
Self-grooming represents a stereotyped repetitive behavior which is commonly observed in various neuropsychiatric disorders. Deep brain stimulation (DBS) targeting the centromedian / parafascicular complex (CM/PF) has been shown to alleviate obsessive-compulsive disorder/behavior (OCD/OCB) symptoms in human. However, little is known about the neural circuits of the PF that are involved in the regulation of self-grooming behavior in rodents. Here, we report that cerebellin-2 positive (Cbln2+) neurons in PF bidirectionally encode self-grooming. Chemogenetic activation of Cbln2+ PF neurons significantly reduces both physiological and pathological self-grooming, and chemogenetic inhibition of Cbln2+ PF neurons increases physiological self-grooming. Moreover, activating synaptic excitatory inputs to Cbln2+ PF neurons inhibits self-grooming, while synaptic inhibitory inputs enhance it. Cbln2+ PF neurons independently transmit neural signals to the dorsal and ventral striatum. Activation of PF-dorsal striatum and PF-ventral striatum pathways both inhibit self-grooming behavior. Together, these data reveal that Cbln2+ PF neurons are integral components of a brain network involved in self-grooming behavior.

A novel epifluorescence microscope design and soft-ware package to record naturalistic behaviour and cell activity in freely moving Caenorhabditis elegans.
Understanding how neural circuits drive behavior requires imaging methods that capture cellular dynamics in freely moving animals. Here, we introduce Wormspy, a compact, flexible, and cost-effective microscope system paired with an open-source software package, specifically designed for high-magnification epifluorescence imaging in Caenorhabditis elegans. By integrating dual channel fluorescence optics, off the shelf components, and a motorized stage, Wormspy enables simultaneous recording of neuronal activity and behavioral dynamics without restraining the animal. Our system incorporates both manual and automated tracking, including DeepLabCut based feature extraction, to maintain precise centering of the subject, even during complex locomotor behaviors. We demonstrate the utility of Wormspy across multiple paradigms: quantifying body wall muscle calcium transients during locomotion, capturing rapid sensory-evoked responses in the polymodal ASH neuron during aversive stimuli, and resolving food-related activity in the AWCON neuron. Notably, Wormspy further distinguishes subcellular calcium events in the RIA axonal compartments that correlate with head bending kinematics. This versatile platform not only reproduces known phenotypes, such as altered gait in gar-3 mutants, but also uncovers nuanced sensorimotor correlations previously inaccessible with conventional methods. Wormspy's modular design and open-source framework lower the technical and financial barriers to high-resolution, behaviorally relevant neural imaging. Our findings establish Wormspy as a robust tool for dissecting the neural underpinnings of behavior in freely moving organisms, with potential applications extending to other small model systems.

Goal learning, memory, and drift in the Drosophila head direction system
Selecting and memorizing goal direction are essential for navigation behavior. Heading information is represented in the head direction systems across species, including Drosophila. However, how navigation decisions are made and how goal memories are represented in these systems is little understood. Here, using a navigation learning assay for flies walking in virtual reality during two-photon imaging, we describe neural dynamics for direction selection and memory. We find that neurons which encode walking direction in the fan-shaped body, a navigation and learning related area in the center of the fly brain, show continuing autonomous activity or directional drift when the animal is at rest. Drift during rest centers around opposite directions to activity during walking, suggesting different computations between these two behavioral states. Targeted optogenetic activation of these neurons during rest is sufficient to induce a subsequent directional navigation preference. Learning leads to changes in drift distributions during rest depending on goal direction, revealing a memory in the network. The fly head direction system thus offers a compact architecture for direction selection, learning, and memory. Changes in neural representations due to goal learning and between rest and walking suggest similarities in navigation circuits across species.

Shared Neural Codes for Emotion Recognition in Emoji and Human Faces
Facial expressions are critical social signals, essential for human communication. This study used EEG to investigate the neural dynamics of the processing of emotional expressions in real and emoji faces, using a data-driven approach. Across two experiments with identical paradigms, two separate sets of participants viewed facial expressions (happy, angry, sad, neutral) in real faces (4 female and 4 male identities, n = 24) or emojis (6 platforms, n = 25) while performing a two-alternative forced-choice emotion recognition task. Time-resolved multivariate classification and spatio-temporal searchlight analyses revealed robust decoding of emotional expressions within and across experiments. Consistent effects emerged early and peaked between 145-160 ms over posterior-occipital and parietal regions. Notably, robust cross-classification between real and emoji faces demonstrated that face-like emoji stimuli evoke neural responses comparable to those elicited by real faces, with more sustained effects over right posterior sites. These findings suggest that the brain uses overlapping spatio-temporal codes for naturalistic and symbolic facial expressions, providing new insights into the neural coding of social signals and the representational overlap between natural and artificial emotional expressions.

Dim Light at Night Disrupts the Sleep-Wake Cycle and Exacerbates Seizure Activity in Cntnap2 Knockout Mice: Implications for Autism Spectrum Disorders
Epilepsy is one of the most common comorbidities in individuals with autism spectrum disorders (ASDs). Many patients with epilepsy as well as ASD experience disruptions in their sleep-wake cycle and exhibit daily rhythms in expression of symptoms. Chronic exposure to light at nighttime can disrupt sleep and circadian rhythms. Contactin associated protein-like 2 knockout (Cntnap2 KO) mice, a model for autism spectrum disorder (ASD) and epilepsy, exhibit sleep and circadian disturbances and seizure-like events. This study examines how chronic dim light at night (DLaN) exposure affects sleep architecture, EEG power spectra, and seizure activity in Cntnap2 KO and wildtype (WT) mice. Using electroencephalography (EEG) recordings, male and female Cntnap2 KO and WT mice were exposed to DLaN for 2 or 6 weeks. EEG recordings were analyzed to assess sleep architecture, power spectrum, and seizure-like events. DLaN exposure delays the wake onset and disrupts sleep patterns in a sex-dependent manner, with females being more affected. DLaN significantly increased slow-wave activity (SWA) in both WT and KO mice, indicating increased sleep pressure. Finally, we found that DLaN dramatically increased the frequency of seizure-like events in the Cntnap2 KO mice and even increased the occurrence rate in the WT mice. Spectral analysis of seizure-like events revealed increased theta power, suggesting the involvement of hippocampus. Chronic DLaN exposure disrupts sleep and increases seizure-like events in Cntnap2 KO mice, with sex-specific differences. These findings emphasize the potential risks of nighttime light exposure for individuals with ASD and epilepsy, reinforcing the need to manage light exposure to improve sleep quality and reduce seizure risk.

High-Definition MEG Source Estimation using the Reciprocal Boundary Element Fast Multipole Method
Magnetoencephalographic (MEG) source estimation relies on the computation of the gain (lead-field) matrix, which embodies the linear relationship between the amplitudes of the sources and the recorded signals. However, with a realistic forward model, the calculation of the gain matrix in a "direct" fashion is a computationally expensive task because the number of dipolar sources in standard MEG pipelines is often limited to ~[1]0,000. We propose a fast approach based on the reciprocal relationship between MEG and transcranial magnetic stimulation (TMS). This approach couples naturally with the charge-based boundary element fast multipole method (BEM-FMM), which allows us to efficiently generate gain matrices for high-resolution multi-layer non-nested meshes involving source spaces of up to a ~1 million dipoles. We evaluate our approach by performing MEG source reconstruction against simulated data (at varying noise levels) obtained from the direct computation of MEG readings from 2000 different dipole positions over the cortical surface of 5 healthy subjects. Additionally, we test our methods with real MEG data from evoked somatosensory fields by right-hand median nerve stimulation in these same 5 subjects. We compare our experimental source reconstruction results against the standard MNE-Python source reconstruction pipeline.

The effects of mindfulness on working memory: a systematic review and meta-analysis
Objectives: Mindfulness is a promising health intervention, showing potential effects on cognitive functions like memory. Despite evidence suggesting mindfulness improves working memory, inconsistencies in results and methodologies prevent definitive conclusions. This meta-analysis examines the effects of mindfulness interventions on working memory across clinical and healthy populations, and various age groups. Methods: A systematic search for relevant English and Persian articles was conducted in WOS, Scopus, PsycINFO, and PubMed databases, along with nine meta-analyses up to February 2023. Included studies consisted of randomized controlled trials (RCTs), controlled trials (CTs), and single-group studies. Overall, 29 studies with 2076 participants aged 5-85 years were analyzed. Results: Mindfulness interventions demonstrated a medium effect size on working memory: RCT two-group studies (Hedges g = 0.438, p < 0.001), CT two-group studies (Hedges g = 0.385, p < 0.005), and single-group studies (Hedges g = 0.583, p < 0.001). These findings confirm the effectiveness of mindfulness interventions in improving working memory. Conclusions: Mindfulness interventions exhibit promising effects on working memory. However, further primary research, particularly rigorous RCTs, is needed to better understand their impacts on clinical versus healthy populations and across diverse age groups.

A universal power law optimizes energy and representation fidelity in visual adaptation
Sensory systems continuously adapt their responses based on the probability of encountering a given stimulus. In the mouse primary visual cortex (V1), the average population response is a power law of the prior probability of stimuli in the environment. For a given stimulus type (e.g., oriented gratings), this power law is universal, with the same exponent observed across different statistical environments, enabling predictions of average population responses to new environments. Here, we aim to provide a normative explanation for the power law behavior. We develop an efficient coding model where neurons adjust their firing rates through multi-objective optimization, hypothesizing that the neural population adapts to enhance stimulus detection and discrimination while minimizing overall neural activity. We show that a power law that matches the one observed experimentally can emerge from our model. We interpret the exponent as reflecting a balance between energy efficiency and representational fidelity in adaptation. Furthermore, we account for the invariance of the power law's exponent across environmental changes by linking it to the dependence of tuning curve modulation on stimulus probability. Finally, we explain that variations in the exponent with different stimulus types (e.g., natural movies) result from changes in the minimal distances between neural representations, in agreement with experimental findings. We conclude that a universal power law of adaptation can be explained as a trade-off between representation fidelity and energy cost.

A genome-wide in vivo CRISPR screen identifies neuroprotective strategies in the mouse and human retina
Retinitis pigmentosa (RP) is a genetically diverse blinding disorder lacking broadly effective therapies. We performed a genome-wide in vivo CRISPR knockout screen in mice carrying the P23H rhodopsin mutation (the most common cause of autosomal dominant RP in the United States) to systematically identify neuroprotective genes. We discovered multiple knockouts that accelerated rod photoreceptor loss, validated top candidates, and showed that overexpressing two genes-UFD1 and UXT-preserved rods and cones, maintained retinal function, and improved visual behaviors. To accelerate translation, we developed a human P23H RP model in adult retinal explants, recreating key disease features. UFD1 and UXT augmentation prevented photoreceptor loss in human P23H retinas. Our findings establish a pipeline for systematic identification and translational testing of neuroprotective genes in mouse and human RP models, provide a novel set of validated candidate genes, and underscore the therapeutic promise of UFD1 and UXT as mutation-agnostic strategies to preserve vision.

A post-mortem investigation of the locus coeruleus- noradrenergic system in resilience to childhood abuse
Childhood abuse (CA) is one of the strongest lifetime predictors of major depressive disorder (MDD) and suicide. However, some individuals exposed to CA are resilient, avoiding the development of psychopathology. Recently, the locus coeruleus-noradrenergic (LC-NE) system has been involved in resilience following stressful events at adulthood. We investigated how a history of CA affects the integrity of the LC-NE system at the molecular and cellular level in human post-mortem brain samples of depressed suicides, and whether differential neurobiological mechanisms can be revealed in resilient individuals. Anatomical analysis revealed that CA-induced MDD and suicide is associated with decrease in LC-NE neurons density. RNA sequencing of laser captured LC-NE neurons highlighted differentially expressed genes, principally in the RES-CA group. Resilience to CA involves specific neurobiological adaptations in the LC-NE system that potentially protect against the loss of LC-NE neurons and the negative long-term outcome of CA-induced depression and suicide. Our results provide insights into potential therapeutic targets for preventing or treating CA-induced MDD.

Contribution of CaV2.2 and GIRK1/2 channels to membrane excitability of rodent and human dorsal root ganglion neurons
Modulation of voltage-dependent calcium and potassium channels by G protein-coupled receptors (GPCRs) plays a key role in reducing nociceptive transmission. Specifically, baclofen and the analgesic peptide -conotoxin Vc1.1 activate GABAB receptors, resulting in the inhibition of CaV2.2 and CaV2.3 calcium channels, as well as the potentiation of GIRK1/2 potassium channels in mammalian primary afferent neurons. In this study, we examined the expression of these key ion channel targets in rodent and human dorsal root ganglion (DRG) neurons. We examined how CaV2.2 and GIRK channel antagonists, as well as a GIRK channel activator, influence the passive and active electrical properties of adult mouse DRG neurons. Additionally, we assessed the effects of -conotoxin Vc1.1 on neuronal excitability in the presence of the selective CaV2.2 antagonist {omega}-conotoxin CVIE and the GIRK channel activator ML297. Furthermore, we evaluated how the GIRK channel antagonist Tertiapin-Q affects the excitability of mouse colonic DRGs and colonic afferents and explored the role of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in regulating the membrane excitability of colonic DRGs. Our findings suggest that both CaV2.2 inhibition and GIRK channel potentiation contribute to the reduction of neuronal excitability in mouse DRGs, mediating the analgesic effects of Vc1.1 and baclofen observed in vivo. However, our findings indicate that GIRK channel potentiation may have a limited role in the mechanisms underlying Vc1.1 and baclofen action in colon-innervating DRGs and colonic afferents.

Intracortical bipolar stimulation allows selective activation of neuronal populations in the cortex
Intracortical electrical stimulation has emerged as a promising approach for sensory restoration, such as a cortical visual prosthesis, yet its effectiveness is limited by current spread and electrode density constraints. To determine whether intracortical bipolar current steering, via modulation of the return electrode position, can enhance neural activation selectivity compared to traditional monopolar stimulation, with the aim of improving spatial precision in sensory restoration. We applied intracortical stimulation and used two-photon calcium imaging on acute brain slices to directly visualize neural responses to bipolar stimulation. Biophysical computational modeling was used to complement the experimental results. The analysis included both cellular and population-level assessments to evaluate the impact of several stimulation patterns, such as current direction, electrode spacing and current amplitude, on recruitment patterns. Bipolar stimulation selectively activated distinct neural populations based on the direction of the current flow. This approach decreased the overlap between activated groups and increased the number of independently addressable neural clusters by up to 9-fold relative to monopolar stimulation. Moreover, the electrode configuration and spacing critically influenced the spatial spread of activation. Intracortical bipolar current steering enhances neural activation selectivity by engaging independent neural populations through current directionality. These findings suggest that this strategy may improve the spatial precision of neural prosthetics and sensory restoration without the need for an increased electrode density.

The cellular and behavioral blueprints of chordate rheotaxis.
The oceans are filled with life-forms exhibiting complex adaptations to help navigate fluid environments and take advantage of fluid motion to locomote and disperse. However, the neuronal and behavioral underpinnings of navigating in fluid environments outside vertebrates are poorly understood. We present behavioral and computational modelling-based evidence that the pre-vertebrate chordate Ciona intestinalis actively modulates its heading and angular velocities to counter oncoming flows and perform positive rheotaxis. We demonstrate that a distributed network of ciliated peripheral sensory neurons is responsible for sensing hydrodynamic information such as flow velocity and direction. Pharmacological removal of sensory cilia impedes rheotactic behavior and reduces stimulus evoked neuronal activity. Whole-brain calcium imaging experiments reveal that the central nervous system of Ciona can encode the onset and offset of flow, flow direction, and flow velocity, suggesting that miniature chordate brain is capable of surprisingly sophisticated computations.

Spatial task instructions and global activation trends influence functional modularity in the cortical reach network
Humans can be instructed to ignore visual cues or use them as landmarks for aiming movements (Musa et al. 2024), but it is not known how such allocentric cues interact with egocentric target codes and general planning activity to influence cortical network properties. To answer these questions, we applied graph theory analysis (GTA) to a previously described fMRI dataset (Chen et al. 2014). Participants were instructed to reach toward targets defined in egocentric or landmark-centered (allocentric) coordinates. During Egocentric pointing, cortical nodes clustered into four bilateral modules with correlated BOLD signals: a superior occipital-parietal / somatomotor module, an inferior parietal / lateral frontal module, a superior temporal / inferior frontal module, and an inferior occipital-temporal / prefrontal module. The Allocentric task showed only three modules, in part because inferior occipital nodes were incorporated into the superior occipital-parietal / somatomotor module. Both tasks engaged local (within module) and global (between module) cortical hubs, but the Allocentric task recruited additional hubs associated with allocentric visual codes and ego-allocentric integration. Removing reach-related activation trends reduced global synchrony and increased clustering, specifically diminishing dorsoventral coupling in the allocentric task. Cross-validated decoding confirmed that modularity provided the best predicter of task type and suggest that temporal / parietal modules spanning prefrontal cortex play an important role in task instruction. These results demonstrate that activation trends related to motor plans influence global network integration, whereas task instructions influence intermediate / local network properties, such as the modular integration and hub recruitment observed in our Allocentric task.

Simultaneous zero echo time fMRI of rat brain and spinal cord
Purpose: Functional assessments of the central nervous system (CNS) are essential for many areas of research. Functional MRI (fMRI) typically targets either the brain or the spinal cord, but usually not both, due to the obstacles associated with simultaneous image acquisitions from distant fields of view (FOVs) with conventional MRI. In this work, we establish a novel MRI approach that enables artefact-free, quiet, simultaneous fMRI of both brain and spinal cord, avoiding the need for dynamic shimming procedures. Methods: We utilized zero echo time (TE) Multi-Band-SWeep Imaging with Fourier Transformation (MB-SWIFT) technique at 9.4T in a simultaneous dual-FOV configuration and two separate radio frequency (RF) transmit-receive surface coils. The first coil covered the rat brain, while the second was positioned approximately at the T13-L1 level of the rat's spinal cord with copper shielding to minimize the coupling between the RF coils. Eight Sprague-Dawley rats were used for hindlimb stimulation fMRI studies. Results: Robust and specific activations were detected in both the brain and spinal cord during hind paw stimulation at individual and group levels. The results established the feasibility of the novel approach for simultaneous functional assessment of the lumbar spinal cord and brain in rats. Conclusion: This study demonstrated the feasibility of a novel dual-FOV fMRI approach based on zero-TE MB-SWIFT and set the stage for translation to humans. The methodology enables comprehensive functional CNS evaluations of great value in different conditions such as pain, spinal cord injury, neurodegenerative diseases, and aging.

cAMP-related second messenger pathways modulate hearing function in Aedes aegypti mosquitoes
The powerful ears of male Aedes aegypti mosquitoes facilitate identification and localization of mating partners via detection of female flight tones. Male hearing function is modulated by the efferent release of neurotransmitters, though the secondary mechanisms underlying this modulation remain unclear. Here, we investigated these mechanisms using octopamine as a model, as octopamine modulates hearing function and the erection status of fibrillar hairs lining male ears. We found that pharmacological interference with octopamine receptors alters hearing function at multiple levels and identified the second messenger cAMP as likely mediating these changes. Furthermore, the erection status of male ear fibrillar hairs could be altered by targeting specific sub-types of octopamine receptors, but these changes were not linked to changes in ear frequency tuning. Finally, we suggest that octopamine 2 receptors linked to fibrillar hair erection may not always produce functional proteins across species, with downstream implications for hearing behaviors.

Improving retention time of Indocyanine Green for in vivo two-photon microscopy using liposomal encapsulation
We propose a technique for improving the retention time of Indocyanine Green (ICG), an FDA-approved, widely available, near infrared (NIR) probe for in vivo imaging of the cerebrovascular structure in rodents. We present a synthesis process for liposomal nanoparticles that, when used to encapsulate ICG, significantly increase the circulation time of the vascular label. Further, we conduct in vivo imaging experiments with unencapsuated (free) ICG and liposomal ICG (L-ICG) and compare the retention of ICG in the vascular network. Our work tackles one of the most fundamental limitations in using ICG i.e. rapid clearance, for the purpose of two-photon microscopy.

American ginseng (Panax quinquefolius L.) extracts (G1899) reverse stress-induced behavioral abnormalities in mice
Stress affects brain functions, which leads to the development of mental disorders like anxiety, depression, cognitive decline, and social dysfunction. There is increasing focus on the role of nutritional, herbal and nutraceutical compounds on mental and cognitive functioning. Interestingly, studies suggest that American ginseng (Panax quinquefolius L.) extracts (G1899) improve cognition. We thus examined whether G1899 showed protective effects on stress-induced behavioral changes in animals. 200 mg/kg G1899 was orally administered daily for 4 weeks to 2-3-month-old female and male mice before inducing stress. To induce acute stress in animals, we intraperitoneally injected a low dose of lipopolysaccharides (LPS) (10 g/kg), and saline was used as a control. We also used chronic restraint stress (CRS) as a chronic stress model in mice. After LPS injection or CRS, multiple behavioral assays were carried out - a sucrose preference test, an open filed test, reciprocal social interaction, contextual fear conditioning, and a tail suspension test - to determine whether acute or chronic stress affected animals' behaviors and whether G1899 had protective effects against stress-induced behavioral dysfunction. We found that both LPS injection and CRS induced stress-related behavioral dysfunction, including depression-like behavior, anhedonia, social dysfunction, and fear memory impairments in both females and males. However, G1899 treatment was sufficient to reverse stress-induced behavioral abnormalities in animals. Our data further suggested that G1899 reduced the activity of hippocampal neurons by suppressing glutamatergic activity. Our study suggests that G1899 supplements can be protective against both acute and chronic stress in mice by suppressing neuronal and synaptic activity.

In vivo reconstruction of Duvernoy's postmortem vasculature images
Non-invasive measurement of the human brain's angioarchitecture is critical for understanding the basis of functional neuroimaging signals, diagnosing cerebrovascular diseases, and tracking neurodegeneration. Ultra-high-field magnetic resonance imaging (MRI) has opened a new window for mesoscopic (<0.5 mm) imaging of angioarchitecture, revealing fine vascular details that were previously inaccessible in vivo. However, current mesoscopic MRI methods for imaging of the angioarchitecture face two major limitations. First, acquisition times are prohibitively long -often exceeding 40 minutes -making integration into everyday clinical practice and research projects impractical. Second, even with data successfully acquired, conventional data visualization methods- such as 2D slice browsing and 3D vessel segmentation renders- are rudimentary and have limited effectiveness for navigating and interpreting the complex vascular network. In this paper, we present a fast whole-brain MRI protocol that provides robust images of the brain's venous network at 0.35 mm resolution in under seven minutes. Additionally, we introduce novel data processing and visualization techniques that enable identification of specific vessel types and more informative navigation of the complex vascular network. We demonstrate that, with these advancements, we can reproduce the seminal postmortem vasculature images of Duvernoy and Vannson (1999) in vivo. Furthermore, leveraging the fact that MRI allows coverage of the entire brain, we achieve, for the first time, whole-brain intracortical mesoscopic vein maps in humans. Our acquisition and post-processing methods lay the groundwork for detailed examinations of vascular organization across individuals, brain regions, and cortical layers. More generally, these methods make mesoscopic imaging of angioarchitecture viable for broad neuroscientific and clinical applications.

Comprehensive profiling of anaesthetised brain dynamics across phylogeny
The intrinsic dynamics of neuronal circuits shape information processing and cognitive function. Combining non-invasive neuroimaging with anaesthetic-induced suppression of information processing provides a unique opportunity to understand how local dynamics mediate the link between neurobiology and the organism's functional repertoire. To address this question, we compile a unique dataset of multi-scale neural activity during wakefulness and anesthesia encompassing human, macaque, marmoset, mouse and nematode. We then apply massive feature extraction to comprehensively characterize local neural dynamics across >6,000 time-series features. Using dynamics as a common space for comparison across species, we identify a phylogenetically conserved dynamical profile of anaesthesia that encompasses multiple features, including reductions in intrinsic timescales. This dynamical signature has an evolutionarily conserved spatial layout, covarying with transcriptional profiles of excitatory and inhibitory neurotransmission across human, macaque and mouse cortex. At the network level, anesthetic-induced changes in local dynamics manifest as reductions in inter-regional synchrony. This relationship between local dynamics and global connectivity can be recapitulated in silico using a connectome-based computational model. Finally, this dynamical regime of anaesthesia is experimentally reversed in vivo by deep-brain stimulation of the centromedian thalamus in the macaque, resulting in restored arousal and behavioural responsiveness. Altogether, omprehensive dynamical phenotyping reveals that spatiotemporal isolation of local neural activity during anesthesia is conserved across species and anesthetics.

Feeding-fasting cycle of obesogenic food determines glucocorticoid neuromodulation of cortico-hippocampal activities sustaining long-term memory
BackgroundHighly caloric food consumed around the clock perturbs the metabolism and cognitive functioning. We hypothesized that obesogenic food could alter neuronal representations of memory depending on the feeding-fasting cycle.

MethodsWe tracked memory performance, dendritic spine dynamics and neuronal representations of memory in C57Bl6J mice fed obesogenic food ad libitum from peri-adolescence. We aimed to correct energy rich diet-induced plasticity deficits and cognitive impairment with time-restricted feeding in males and females. We further used chemogenetics, pharmacology and knock-in mice to investigate functional correlates underlying diet-induced neurocognitive impairments.

ResultsWe find that changes in the feeding-fasting cycle reverted the effects of ad libitum obesogenic food on memory impairment in both sexes (n=55, p=0.003). Concurrently, it also corrected the increased dendritic spine maintenance and neuroactivity in hippocampus and the decreased spine maintenance and activity in parietal cortex (n=48, p<0.005). Bi-directional effects in cortex and hippocampus mediated by glucocorticoid signalling are causal to behavioural changes (n=91, p=0.0008), and scaling hippocampal with cortical activities restored memory in mice fed obesogenic food (n=44, p=0.02).

ConclusionThese results indicate that meal scheduling is a promising approach to confront glucocorticoid signalling bias and memory deficits caused by obesogenic food.

Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWhat and when we eat contributes to our health. This is particularly worrisome for kids and adolescents because of the lifelong effects that unrestricted snacking on highly caloric food could cause on brain maturation. A variety of school policies and nutritional programs have emerged to prevent poor nutritional habits. But obesity is on the rise and a major cause of neurological disabilities difficult to detect and treat. Human studies are limited by the size and duration of sampling with low resolution metrics to prove causality between nutritional habits and cognitive health trajectory. Animal studies showed that all-day snacking on highly caloric food disrupts innate biological rhythms that influence hormonal secretions, neuronal structure and function in brain regions that encode, store and retrieve memories. It isnt known if, like adipocytes and hepatocytes, the brain in obesity can develop glucocorticoid resistance -a state that would prevent the robust but complex effects of this hormone on memory- to the point that researchers still question whether glucocorticoids are a cause or solution to obesity related-brain comorbidities.

Added value of this studyLongitudinal sampling of several metrics at multiple timepoints in mice fed highly caloric food since peri-adolescence up to adulthood showed that the trajectory of obesity-related brain comorbidities is corrected when reinstating the feeding/fasting cycle, albeit consuming highly caloric food. Glucocorticoid resistance -manifesting as receptor phosphorylation deficits impeding coincidence detection between glucocorticoid and neuronal activities -was reversible when reinstating the feeding/fasting cycle, albeit consuming highly caloric food. Studies in receptor mutant mice lacking a phosphorylation site-independent of glucocorticoids showed it is required to reinstate neuroplasticity to changes of feeding/fasting cycle, albeit consuming highly caloric food. Fos-trapping experiments showed less engagement of pyramidal neurons in the cortex when activity-dependent phosphorylation of glucocorticoid receptor was low, and more in the hippocampus of mice fed obesogenic diet, which reinstating the feeding/fasting cycle reverted, albeit consuming highly caloric food. Finally, chemogenetic experiments confirmed the requirement for the co-engagement of cortical and hippocampal pyramidal neurons to fully remember, despite poor nutritional habits.

Implications of all the available evidenceThe cortico-hippocampal activities necessary for remembering are uncoupled by obesogenic food consumed ad libitum but not on meal scheduling, extending neuroimaging correlation studies in obese adolescents. Poor nutritional habits cause glucocorticoid resistance in the brain as previously suggested, with altered neuronal representation of memory that meal scheduling corrected. This result should transform school policies and familial nutritional habits to promote cognitive health. Future research will develop allosteric ligands targeting phosphorylation motifs in the glucocorticoid receptor as more specific alternative to orthosteric ligands for the treatment of obesity-related brain comorbidities.

BAND: Behavior-Aligned Neural Dynamics is all you need to capture motor corrections
Neural activity in motor cortical areas is well-explained by latent neural population dynamics: the motor preparation phase sets the initial condition for the movement while the dynamics that unfold during the motor execution phase orchestrate the sequence of muscle activations. While preparatory activity explains a large fraction of both neural and behavior variability during the execution of a planned movement, it cannot account for corrections and adjustments during movements as this requires sensory feedback not available during planning. Therefore, accounting for unplanned, sensoryguided movement requires knowledge of relevant inputs to the motor cortex from other brain areas. Here, we provide evidence that these inputs cause transient deviations from an autonomous neural population trajectory, and show that these dynamics cannot be found by unsupervised inference methods. We introduce the new Behavior-Aligned Neural Dynamics (BAND) model, which exploits semi-supervised learning to predict both planned and unplanned movements from neural activity in the motor cortex that can be missed by unsupervised inference methods. Our analysis using BAND suggests that 1) transient motor corrections are encoded in small neural variability; 2) motor corrections are encoded in a sparse sub-population of primary motor cortex neurons (M1); and 3) combining latent dynamical modeling with behavior supervision allows for capturing both the movement plan and corrections.

SummaryMotor cortical neural activity is commonly viewed as a low-dimensional dynamics evolving from the movement preparation state, which explains the most of both neural and behavioral variability. We found that movement corrections to unexpected behavior perturbations do not follow the same pattern, with only a small fraction of neural variability explaining large changes in behavior. We show that capturing both movement planning and corrections requires models that incorporate dynamics and weak behavior supervision. We characterize the bidirectional relationships between motor cortical activity and behavior, identifying neural code for both feedforward and feedback-driven motor control.

Reduced neural sensitivity to musical tempo despite enhanced neural tracking of musical features in older adults
A substantial body of prior research has focused on how older adults process and comprehend speech, whereas less attention has been devoted to how older adults encode and perceive naturalistic music. In the current study, we investigated whether the neural tracking of different musical features in naturalistic music differs between age groups. Younger and older adults (both sexes) listened to the excerpts of naturalistic music with different tempi (1-4 Hz) while electroencephalography (EEG) was recorded. The results show an age-related enhancement of neural responses to sound onsets, suggesting a loss of inhibition in the aged auditory cortex. Neural tracking of different musical features, including the amplitude envelope, amplitude onset, and spectral flux, were also enhanced in older adults, indicating that the hyperresponsiveness generalizes to features of naturalistic music. However, our results show that, despite enhanced neural responses, older adults exhibit reduced neural sensitivity of early sensory responses to music pieces with different tempi. Moreover, spectral flux mostly effectively predicted the changes in EEG activity due to differences in musical tempo, but this was reduced in older adults compared to younger adults. The current findings suggest that hyperresponsiveness in auditory cortex of older adults is accompanied by a lack of sensitivity to the tempo in music. The results highlight the complex changes in the aged auditory system that affect the processing of naturalistic sounds.

Reward Network Activations of Win versus Loss in a Monetary Gambling Task
Reward processing is a vital function for health and survival and is impaired in various psychiatric and neurological disorders. Using a monetary gambling task, the current study aims to elucidate neural substrates in the reward network underlying evaluation of win versus loss outcomes, and their association with behavioral characteristics, such as impulsivity and task performance, and neuropsychological functioning. Functional MRI was recorded in thirty healthy, male community volunteers (mean age = 27.4 years) while they performed a monetary gambling task in which they bet with either 10 or 50 tokens and received feedback of whether they won or lost the bet amount. Results showed that a set of key brain structures in the reward network, including putamen, caudate nucleus, superior and inferior parietal lobule, angular gyrus, and Rolandic operculum, had greater blood oxygenation level dependent (BOLD) signal during win relative to loss trials, and the BOLD signals in most of these regions were highly correlated with one another. Further, exploratory bivariate analyses between these reward related regions and behavioral and neuropsychological domains showed significant correlations with moderate effect sizes, including: (i) negative correlations between non-planning impulsivity and activations in putamen and caudate regions, (ii) positive correlations between risky bets and right putamen activation, (iii) negative correlations between safer bets and right putamen activation, (iv) a negative correlation between short-term memory capacity and right putamen activity, and (v) a negative correlation between poor planning skills and left inferior occipital cortex activation. These findings contribute to our understanding of the neural underpinnings of monetary reward processing and their relationships to aspects of behavior and cognitive function. Future studies may confirm these findings with larger samples of healthy controls and extend these findings by investigating various clinical groups with impaired reward processing.

Cocaine Blocks Cholinergic Activity in the Medial Habenula Prior to But Not After Induced Preference for the Drug
Descending projections from the medial habenula potently influence brainstem systems associated with reward and mood. Relatedly, the ventral, cholinergic segment of the nucleus has been linked to nicotine and cocaine addiction. Here we report that cocaine has no effect on baseline firing in the ventral medial habenula but entirely blocks the self-sustained activity initiated by endogenous acetylcholine. This effect was not altered by antagonists to dopamine receptors and thus presumably reflects a direct action on cholinergic receptors. Remarkably, cocaine had no effect on endogenous cholinergic activity in mice that had been extinguished from an induced cocaine preference. In all, the drug has potent effects, albeit through an exotic mode of action, on the medial habenula and these are eliminated by prior experience with the drug. These results describe a novel target for cocaine that is plausibly related to the psychological effects of the drug, and an unexpected consequence of earlier use.

Glutamate indicators with increased sensitivity and tailored deactivation rates
Identifying the input-output operations of neurons requires measurements of synaptic transmission simultaneously at many of a neurons thousands of inputs in the intact brain. To facilitate this goal, we engineered and screened 3365 variants of the fluorescent protein glutamate indicator iGluSnFR3 in neuron culture, and selected variants in the mouse visual cortex. Two variants have high sensitivity, fast activation (< 2 ms) and deactivation times tailored for recording large populations of synapses (iGluSnFR4s, 153 ms) or rapid dynamics (iGluSnFR4f, 26 ms). By imaging action-potential evoked signals on axons and visually-evoked signals on dendritic spines, we show that iGluSnFR4s/4f primarily detect local synaptic glutamate with single-vesicle sensitivity. The indicators detect a wide range of naturalistic synaptic transmission, including in the vibrissal cortex layer 4 and in hippocampal CA1 dendrites. iGluSnFR4 increases the sensitivity and scale (4s) or speed (4f) of tracking information flow in neural networks in vivo.

Soluble Immune Factor Profiles in Blood and CSF Associated with LRRK2 Mutations and Parkinson's Disease
Background and Objectives: Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene are one of the most common genetic causes of Parkinson's disease (PD) and are linked to immune dysregulation in both the central nervous system and periphery. However, peripheral and central profiles of soluble immune factors associated with LRRK2 mutations and PD have not been comprehensively characterized. Using serum and CSF samples from the LRRK2 Cohort Consortium (LCC), this study aimed to probe a broad range of soluble immune biomarkers associated with LRRK2 mutations and PD. Methods: We investigated the levels of soluble immune regulators in the serum (n=651) and cerebrospinal fluid (CSF, n=129) of LRRK2 mutation carriers and non-carriers, both with and without PD. A total of 65 cytokines, chemokines, growth factors, and soluble receptors were assessed by Luminex immunoassay. A multivariable robust linear model was used to determine levels associated with LRRK2 mutations and PD status, adjusting for age, sex, and sample cohort. Correlations were assessed using the Spearman correlation coefficient. LRRK2 G2019S knock-in mice were used to validate the associations identified in the LCC. Results: In this extensive discovery cohort, we identified several elevated serum immune regulatory factors associated with LRRK2 mutations. In particular, serum stromal cell-derived factor-1 alpha (SDF-1 alpha) levels, as supported by findings in LRRK2 G2019S knock-in mice, and tumor necrosis factor receptor II (TNF-RII) were significantly increased after multiple comparison adjustment. In contrast, LRRK2 mutations were associated with reduced soluble immune markers, including BAFF, CD40-Ligand, I-TAC, MIP-3 alpha, NGF beta, and IL-27 in CSF. Those with clinically diagnosed PD, with or without LRRK2 mutations, did not show strong signals in serum but reduced inflammatory analytes in CSF, including MIF, MMP-1, CD30, Tweak, and SDF-1 alpha. In addition, we found that the serum levels of these soluble immune factors display varied correlations with their corresponding CSF levels. Discussion: This study highlights distinct immune profiles associated with LRRK2 mutations and PD in the periphery and CNS. Serum levels of SDF-1alpha and TNF-RII were elevated in LRRK2 mutation carriers, while CSF immune markers were reduced. In PD, irrespective of LRRK2 status, reduced CSF inflammatory analytes and weak serum signals were observed. These results provide insight into immune dysregulation linked to LRRK2 mutations. If replicable in independent datasets, they offer potential avenues for biomarker and therapeutic exploration