bioRxiv Subject Collection: Neuroscience's Journal

Test-retest reliability of resting-state EEG intrinsic neural timescales
Intrinsic neural timescales (INTs), which reflect the duration of neural information storage within local brain regions and capacity for information integration, are typically measured using autocorrelation windows (ACWs). Extraction of INTs from resting-state brain activity has been extensively applied in psychiatric disease research. Given the potential of INTs as a neural marker for psychiatric disorders, investigating their reliability is crucial. This study, using an open-source database, aimed to evaluate the test-retest reliability of ACW-0 and ACW-50 under both eyes-open and eyes-closed conditions across three sessions. The intraclass correlation coefficients (ICCs) were employed to quantify the reliability of the INTs. Our results showed that INTs exhibited good reliability (ICC > 0.6) at the whole-brain level across different index types and eye states. Spatially, except for the right temporal region in the eyes-open condition, all other regions showed moderate-to-high ICCs. Over 60% of the electrodes demonstrated moderate-to-high INT ICCs under both eyes-open and eyes-closed conditions, with ACW-0 being more stable than ACW-50. This present study comprehensively assessed the reliability of INT under various conditions, providing robust evidence for their stability in neuroscience and psychiatry.

In vivo quantification of creatine kinase kinetics in mouse brain using 31P-MRS at 7 Tesla
31P-MRS is a method of choice for studying neuroenergetics in vivo, but its application in the mouse brain have been limited, often restricted to ultra-high field (>7 Tesla) MRI scanners. Establishing its feasibility on more readily available preclinical 7 Tesla (T) scanners would create new opportunities to study metabolism and physiology in murine models of brain disorders. Here, we demonstrate that the apparent forward rate constant (kf) of creatine kinase (CK) can be accurately quantified using a progressive saturation-transfer approach in the mouse brain at 7T. We also find that a reduction of approximately 20% in the breathing rate of anesthetized mice can lead to a 36% increase in kf attributable to a drop in intracellular pH and mitochondrial ATP production. To achieve this, we used a test-retest analysis to assess the reliability and repeatability of 31P-MRS acquisition, analysis and experimental design protocols. We report that most 31P-containing metabolites can be reliably measured using a localized 3D-ISIS sequence, which showed highest SNR amplitude, SNR consistency and minimal T2 relaxation signal loss. Using this protocol, our study identifies, for the first time, key physiological factors influencing mouse brain energy homeostasis in vivo and provides a methodological basis that will guide future studies interested in implementing 31P-MRS on preclinical 7T scanners.

Understanding The Myelin g ratio From First Principles, Its Derivation, Uses And Artifacts
In light of the increasing importance for measuring myelin g ratios - the ratio of axon-to-fiber (axon + myelin) diameters in myelin internodes - to understand normal physiology, disease states, repair mechanisms and myelin plasticity, there is urgent need to minimize processing and statistical artifacts in current methodologies. Unfortunately, many contemporary studies fall prey to a variety of artifacts, which reduce study outcome robustness and slow development of novel therapeutics. Underlying causes stem from a lack of understanding of the myelin g ratio, which has persisted more than a century. An extended exploratory data analysis from first principles (the axon-fiber diameter relation) is presented herein and has major consequences for interpreting published g ratio studies. Indeed, a model of the myelin internode naturally emerges because of (1) the strong positive correlation between axon and fiber diameters and (2) the demonstration that the relation between these variables is one of direct proportionality. From this model, a robust framework for data analysis, interpretation and understanding allows specific predictions about myelin internode structure under normal physiological conditions. Further, the model establishes that a regression fit to g ratio plots has zero slope, and it identifies the underlying causes of several data processing artifacts that can be mitigated by plotting g ratios against fiber diameter (not axon diameter). Hypothesis testing can then be used for extending the model and evaluating myelin internodal properties under pathophysiological conditions (accompanying article). For without a statistical model as anchor, hypothesis testing is aimless like a rudderless ship on the ocean.

Functional separation of long-range inputs by intrinsic dynamics of dorsal raphe 5-HT neurons
The serotonergic dorsal raphe nucleus (DRN) receives diverse long-range synaptic inputs, yet the processing rules governing their contribution to DRN output spiking patterns are largely unknown. Here, we use electrophysiological, optogenetic and computational approaches to compare electrophysiological features of two major excitatory inputs onto DRN 5-HT neurons - the lateral habenula (LHb) and medial prefrontal cortex (mPFC). Dual-color opsin strategies revealed that a population of 5-HT neurons receive inputs from both mPFC and LHb. Subthreshold excitatory postsynaptic potentials triggered by both inputs were largely indistinguishable, yet suprathreshold spiking behavior exhibited input-specific latencies and dispersion statistics. A support vector machine classifier demonstrated that input identity can be accurately decoded from spike timing, but not subthreshold events, of under ten 5-HT neurons. Upon examining the intrinsic cellular mechanisms in 5-HT neurons that couple EPSPs to spiking dynamics, we uncovered two likely candidate mechanisms: a low-threshold calcium conductance that selectively boosts slow excitatory inputs, and a subthreshold, voltage-dependent membrane noise that generates variation of spike latency and jitter. Stochastic simulations suggest that these two intrinsic properties of 5-HT neurons are sufficient to transform LHb and mPFC inputs into distinct output spiking patterns. These results reveal that hub-like networks like the DRN can segregate distinct informational streams by a cell-intrinsic mechanism. The resulting emergent population spike synchrony code provides a means for the DRN to widely broadcast these streams as a multiplexed signals.

Respiration shapes response speed and accuracy with a systematic time lag
Sensory-cognitive functions are intertwined with physiological processes such as the heart beat or respiration. For example, we tend to align our respiratory cycle to expected events or actions. This happens during sports but also in computer-based tasks and systematically structures respiratory phase around relevant events. However, studies also show that trial-by-trial variations in respiratory phase shape brain activity and the speed or accuracy of individual responses. We show that both phenomena, the alignment of respiration to expected events and the explanatory power of the respiratory phase on behaviour co-exist. In fact, both the average respiratory phase of an individual relative to the experimental trials and trial-to-trial variations in respiratory phase hold significant predictive power on behavioural performance, in particular for reaction times. This co-modulation of respiration and behaviour emerges regardless of whether an individual generally breathes faster or slower and is strongest for the respiratory phase about two seconds prior to participant's responses. The persistence of these effects across 12 datasets with 277 participants performing sensory-cognitive tasks confirm the robustness of these results, and suggest a profound and time-lagged influence of structured respiration on sensory-motor responses.

Chronobiological rhythms control of site- and cell-specific miRNA and mRNA genes and networks across the central nervous system
Biological rhythms control gene expression, but effects on central nervous system (CNS) cells and structures remain undefined. While circadian (24-hour) rhythms are most studied, many genes have periods of greater and less than 24-hours; these fluctuations can be both site- and cell-specific. Identifying patterns of gene rhythmicity across the CNS is necessary for both the study of chronobiology and to make sense of data obtained in the laboratory. We now identify cycling mRNAs, miRNAs, gene networks and novel mRNA-miRNA co-expression pairs in the cortex, hypothalamus, and corpus striatum using high-dimensional datasets. A searchable catalogue (https://www.ghasemloulab.ca/chronoCNS) was created to help refine the analysis of cellular/molecular rhythmicity across the CNS. Immunofluorescence was also used to confirm the rhythmicity of key targets across cells in these structures, with strong cycling signatures in resting oligodendrocytes. Our study sheds light on the contribution of circadian, ultradian, and infradian rhythms and mRNA-miRNA interactions to CNS function.

Probing other's Presence: Probabilistic Inference Across Brain Scales Reveals Enhanced Excitatory Synaptic Efficacy
The presence of conspecifics is a fundamental and arguably invariant prerequisite of social cognition across numerous animal species. While the influence of social presence on behavior has been among the focal points of investigation in social psychology for over a century, its underlying neural mechanisms remain largely unexplored. Here, we attempt to bridge this gap by investigating how the presence of conspecifics changes synaptic efficacy from measurements across spatiotemporal brain scales, and how such changes could lead to modulations of task performance in monkeys and humans. In monkeys performing an association learning task, social presence increased excitatory synaptic efficacy in attention-oriented regions dorsolateral prefrontal cortex and anterior cingulate cortex. In humans performing a visuomotor task, the presence of conspecifics facilitated performance in one of the subject groups, and this facilitation was linked to enhanced excitatory synaptic efficacy within the dorsal and ventral attention networks. We propose that presence-induced improvements in task performance arise from attentional modulation mediated by changes in excitatory synaptic efficacy across three spatiotemporal brain scales, namely, micro-scale (single neurons), meso-scale (cortical columns) and macro-scale (whole-brain). Our findings from Bayesian learning converge to establish a novel, multi-scale framework for understanding the neural underpinnings of social presence effects. This probabilistic framework offers a fresh perspective on social presence research, and lays the groundwork for future investigations into the complex interplay between social presence, neural dynamics, and behavior.

Cognitive-and lifestyle-related microstructural variation in the ageing human hippocampus
Ageing is a biological process associated with the natural degeneration of various regions of the brain. Alteration of neural tissue in the hippocampus with ageing typically results in cognitive decline that may serve as a risk factor for dementia and other neurodegenerative diseases. Modifiable lifestyle factors may help preserve hippocampal neural tissue (microstructure) and slow down neurodegeneration and thus promote healthy cognition in old age. In this study, we sought to identify potential modifiable lifestyle factors that may help preserve microstructure in the hippocampus. We used data from 494 subjects (36-100 years old) without clinical cognitive impairment from the Human Connectome Project-Aging study. We estimated hippocampal microstructure using myelin-sensitive (T1w/T2w ratio), inflammation-sensitive (MD) and fiber-sensitive (FA) MRI markers. Non-negative matrix factorization was used to integrate the signals of these images into a multivariate spatial signature of microstructure covariance across the hippocampus. The associations between hippocampal microstructural patterns and lifestyle factors & cognition were identified using partial least squares analysis. Our results reveal that the preservation of axon density and myelin in regions corresponding to subicular regions and CA1 to CA3 regions of the hippocampi of younger adults is associated with improved performance in executive function tasks, however, this is also associated with a decreased performance in memory tasks. We also show that microstructure is preserved across the hippocampus when there is normal hearing levels, physical fitness and normal insulin levels in younger adults of our study even in the presence of cardiovascular risk factors like high body mass index, blood pressure, triglycerides and blood glucose known to be associated with hippocampal neurodegeneration. This preservation is not observed in older adults when there are no normal levels of insulin, physical fitness and hearing. Taken together, our results suggest that certain lifestyle factors like normal hearing, physical fitness and normal insulin levels may help preserve hippocampal microstructure which may be useful in maintaining optimum performance on executive function tasks and potentially other modes of cognition.

Unsupervised, piecewise linear decoding enables an accurate prediction of muscle activity in a multi-task brain computer interface
Objective. Creating an intracortical brain-computer interface (iBCI) capable of seamless transitions between tasks and contexts would greatly enhance user experience. However, the nonlinearity in neural activity presents challenges to computing a global iBCI decoder. We aimed to develop a method that differs from a globally optimized decoder to address this issue. Approach. We devised an unsupervised approach that relies on the structure of a low-dimensional neural manifold to implement a piecewise linear decoder. We created a distinctive dataset in which monkeys performed a diverse set of tasks, some trained, others innate, while we recorded neural signals from the motor cortex (M1) and electromyographs (EMGs) from upper limb muscles. We used both linear and nonlinear dimensionality reduction techniques to discover neural manifolds and applied unsupervised algorithms to identify clusters within those spaces. Finally, we fit a linear decoder of EMG for each cluster. A specific decoder was activated corresponding to the cluster each new neural data point belonged to. Main results. We found clusters in the neural manifolds corresponding with the different tasks or task sub-phases. The performance of piecewise decoding improved as the number of clusters increased and plateaued gradually. With only two clusters it already outperformed a global linear decoder, and unexpectedly, it outperformed even a global recurrent neural network (RNN) decoder with 10-12 clusters. Significance. This study introduced a computationally lightweight solution for creating iBCI decoders that can function effectively across a broad range of tasks. EMG decoding is particularly challenging, as muscle activity is used, under varying contexts, to control interaction forces and limb stiffness, as well as motion. The results suggest that a piecewise linear decoder can provide a good approximation to the nonlinearity between neural activity and motor outputs, a result of our increased understanding of the structure of neural manifolds in motor cortex.

Effort in Oculomotor Control: Role of Instructions and Reward on Spatio-temporal Eye Movement Dynamics
Effort is an important construct in several psychological disciplines, yet there is little consensus on how it manifests in behavior. Here, we focus on effort in terms of performance improvements beyond speed-accuracy tradeoffs and argue that oculomotor kinematics are conducive to a more fine-grained understanding of effortful behavior. Specifically, we investigated the efficiency and persistence of mere task instructions to induce transient effort. In a saccadic selection task, participants were instructed to look at targets as quickly and accurately as possible (standard instructions) or to mobilize all resources and respond even faster and more accurately ('to give 110%', effort instructions). We compared results to standard speeded performance (baseline block) and to a potential upper performance limit linking effort to performance-contingent rewards (reward block). Performance improved beyond speed-accuracy tradeoffs when reward was present. Effort instructions reduced saccade latencies, increased amplitudes and changed the saccade main sequence relationship. Yet, these effects were more strongly pronounced and more persistent over time when effort was additionally rewarded. Altogether, the present findings underscore the possibility to intentionally activate cognitive resources for regulating oculomotor performance. Yet, its effectiveness and maintenance over time are more successful when behavior is rendered purposeful by the presence of reward.

A unified model of hippocampal spatial and object cells involving bidirectionally coupled Lateral and Medial Entorhinal Cortical layers
Popularly referred to as the GPS of the brain, the hippocampus has a variety of neurons that encode spatial properties of the environment. These spatial cells of the hippocampus may be broadly placed under two categories - those that encode spatial locations (e.g., place cells, grid cells, etc.) and those that encode spatial objects (e.g., Object-sensitive cells. Object-trace cells, etc.). Some computational models explain the emergence of specific types of spatial cells, but it is challenging to construct integrative models that can demonstrate the emergence of the complete range of spatial cells, both space and object type. We present a simple, unified computational model that explains the emergence of a wide variety of object- and spatially-sensitive neurons in the hippocampus. The model is essentially a deep neural network that combines visual and path integration information. The visual information is received by a part of the model analogous to the Lateral Entorhinal Cortex (LEC), and path integration information is received by a layer analogous to the Medial Entorhinal Cortex (MEC). LEC and MEC in the model are connected laterally using a Graph Neural Network to arrive at a consistent position estimate. The model is trained to predict the position, orientation, and reward of a simulated agent. The agent explores a box-like environment with colored walls and objects on the floor and is rewarded based on its encounters with objects. The model demonstrates the emergence of the following 7 types of spatial and object cells - place, grid, border, object, object-sensitive, object-vector, and object-trace cells. The model findings compare favorably with a large body of experimental literature on hippocampal spatial cells.

Overcoming the limitations of motion sensor models by considering dendritic computations
The estimation of motion is a fundamental process for any sighted animal. Computational models for motion sensors have a long and successful history but they still suffer from fundamental shortcomings, as they disagree with physiological evidence and each model is dedicated to a specific type of motion, which is controversial from a biological standpoint. In this work we propose a new approach for modeling motion sensors that considers dendritic computations, a key aspect for predicting single-neuron responses that had previously been absent from motion models. We show how, by taking into account the dynamic and input-dependent nature of dendritic nonlinearities, our motion sensor model is able to overcome the fundamental limitations of standard approaches.

The myokine FGF21 associates with enhanced survival in ALS and mitigates stress-induced cytotoxicity
Amyotrophic lateral sclerosis (ALS) is an age-related and fatal neurodegenerative disease characterized by progressive muscle weakness. There is marked heterogeneity in clinical presentation, progression, and pathophysiology with only modest treatments to slow disease progression. Molecular markers that provide insight into this heterogeneity are crucial for clinical management and identification of new therapeutic targets. In a prior muscle miRNA sequencing investigation, we identified altered FGF pathways in ALS muscle, leading us to investigate FGF21. We analyzed human ALS muscle biopsy samples and found a large increase in FGF21 expression with localization to atrophic myofibers and surrounding endomysium. A concomitant increase in FGF21 was detected in ALS spinal cords which correlated with muscle levels. FGF21 was increased in the SOD1G93A mouse beginning in presymptomatic stages. In parallel, there was dysregulation of the co-receptor, {beta}-Klotho. Plasma FGF21 levels were increased and high levels correlated with slower disease progression, prolonged survival, and increased body mass index. In NSC-34 motor neurons and C2C12 muscle cells expressing SOD1G93A or exposed to oxidative stress, ectopic FGF21 mitigated loss of cell viability. In summary, FGF21 is a novel biomarker in ALS that correlates with slower disease progression and exerts trophic effects under conditions of cellular stress.

Dual-format attentional template during preparation in human visual cortex
Goal-directed attention relies on forming internal templates of key information relevant for guiding behavior, particularly when preparing for upcoming sensory inputs. However, evidence on how these attentional templates is represented during preparation remains controversial. Here, we combine functional magnetic resonance imaging (fMRI) with an orientation cueing task to isolate preparatory activity from stimulus-evoked responses. Using multivariate pattern analysis, we found decodable information of the to-be-attended orientation during preparation; yet preparatory activity patterns were different from those evoked when actual orientations were perceived. When perturbing the neural activity by means of a visual impulse ('pinging' technique), the preparatory activity patterns in visual cortex resembled those associated with perceiving these orientations. The observed differential patterns with and without the impulse perturbation suggest a predominantly non-sensory format and a latent, sensory-like format of representation during preparation. Furthermore, the emergence of the sensory-like template coincided with enhanced information connectivity between V1 and frontoparietal areas and was associated with improved behavioral performance. This dual-format mechanism suggests that during preparation the brain encodes more detailed template information beyond its immediate use, potentially providing advantages for adaptive attentional control. Consistent with recent theories of non-veridical, 'good-enough' attentional template for initial guidance, our findings established a neural basis for implementing two representational formats in different functional states during preparation: a predominantly non-sensory format for guidance and a latent sensory-like format for prospective stimulus processing.

Contrasting patterns of specificity and transfer in human odor discrimination learning
Practice enhances olfactory performance. However, laboratory studies to date suggest that olfactory learning is largely restricted to the trained odors, posing a significant challenge for training-based rehabilitation therapies for olfactory loss. In this study, we introduce various types of odors to olfactory discrimination training, conducted unilaterally. We demonstrate contrasting patterns of specificity and transfer of learning, independent of adaptation and task difficulty. Individuals trained with odor mixtures of different ratios show long-term perceptual gains that completely transfer to the untrained nostril and effectively generalize to untrained mixtures dissimilar in structure and odor quality from the trained ones. Conversely, those trained with odor enantiomers show no transfer of learning across nostrils or to unrelated enantiomers, replicating our earlier findings (Feng and Zhou, 2019). Our observations indicate that concentration ratio and chirality represent distinct olfactory attributes. Furthermore, discrimination learning occurs at different stages of olfactory processing, depending on which attribute is task-relevant. These findings open up new avenues to enhance the effectiveness of olfactory training.

Effect of Alcohol and Cocaine Abuse on Neuronal and Non-Neuronal Cell Turnover in the Adult Human Hippocampus
Clinical studies on humans with a history of chronic abuse of alcohol or cocaine show cognitive impairments associated with hippocampal atrophy. Adult hippocampal neurogenesis is a process important for memory formation and has been shown to be impaired by alcohol and cocaine in rodent models. It has thus been suggested that a reduction in adult neurogenesis may contribute to cognitive dysfunctions seen in patients with abuse. In addition, reduced adult neurogenesis has been suggested to play a role in the pathology of addiction vulnerability. We have previously demonstrated persistent adult hippocampal neurogenesis throughout life by measuring 14C concentrations in genomic DNA, incorporated during cell division, in a mixed cohort of subjects. In this study, we use the same strategy to assess the extent of cell turnover of neuronal and nonneuronal cells in the hippocampus of humans with known history of alcohol and cocaine abuse and compare these with healthy controls. We find that there is significant neuronal and nonneuronal turnover in healthy controls, as well as in individuals with long term alcohol use or cocaine use. Using mathematical modelling, we compare the extent of cell turnover of neurons and non-neuronal cells and did not find any significant difference between healthy controls and the two addiction groups. While we cannot exclude scenarios of altered adult neurogenesis over shorter periods of time, our data does not support the theory of low neurogenesis as a mechanism of addiction vulnerability.

Neocortical and hippocampal theta oscillations track audiovisual integration and replay of speech memories
"Are you talkin to me?!" If you ever watched the masterpiece Taxi driver directed by Martin Scorsese, you certainly recall the famous monologue during which Travis Bickle rehearses an imaginary confrontation in front of a mirror. While remembering this scene, you recollect a myriad of speech features across visual and auditory senses with a smooth sensation of unified memory. The aim of this study was to investigate how brain oscillations integrate the fine-grained synchrony between coinciding visual and auditory features when forming multisensory speech memories. We developed a memory task presenting participants with short synchronous or asynchronous movie clips focusing on the face of speakers engaged in real interviews. In the synchronous condition, the natural alignment between visual and auditory onsets was kept intact. In the asynchronous condition, auditory onsets were delayed to present lip movements and speech sounds in antiphase specifically with respect to the theta oscillation synchronising them in the original movie. We recorded magnetoencephalographic (MEG) activity to investigate brain oscillations in response to audiovisual asynchrony in the theta band. Our results first showed that theta oscillations in the neocortex and hippocampus were modulated by the level of synchrony between lip movements and syllables during audiovisual speech perception. Second, the accuracy of subsequent theta oscillation reinstatement during memory recollection was decreased when lip movements and the auditory envelope were encoded in asynchrony during speech perception. We demonstrate that neural theta oscillations in the neocortex and the hippocampus integrated lip movements and syllables during natural speech. We conclude that neural theta oscillations play a pivotal role in both aspects of audiovisual speech memories, i.e., encoding and retrieval.

Focused ultrasound enhanced antibody delivery for the treatment of Parkinson's Disease
Treatment of neurological disorders is partly impeded by the size of large pharmacological agents which are thereby unable to bypass the blood brain barrier. Focused ultrasound in conjunction with systemically administered microbubbles has been shown to safely noninvasively and transiently open the BBB allowing the passage of large biomolecules to the brain parenchyma through the otherwise impermeable barrier. This pilot study assessed the feasibility of FUS mediated delivery of an anti alpha synuclein monoclonal antibody in Parkinsons disease mouse models that exhibit aggregates. Mice underwent FUS on a weekly basis over the course of 2 to 3 weeks followed by a one month survival period. MRI and microscopy were performed to confirm BBB opening with FUS and visualize antibody delivery. Safety was assessed in vivo using passive cavitation detection and immunohistochemistry to evaluate microglial and astrocyte activity ex vivo. It was found that treatment sessions for multiple FUS sessions of targeted antibody delivery was feasible in alpha-synuclein models facilitating immunotherapeutics.

Lower perceived stress enhances neural synchrony in perceptual and attentional cortices during naturalistic processing
Perceived stress is the subjective appraisal of the level of stress experienced by an individual in response to external or internal demands. Recent research on perceived stress has highlighted its role in influencing cognition, leading to a disruption in cognitive processes, such as emotional processing, attention, and perception. However, most neuroimaging studies examining stress have used static stimuli (e.g., still images) that do not encapsulate real-life multimodal processing in the brain. The current research uses data from the Naturalistic Neuroimaging Database (v2.0; Aliko et al., 2020) to examine differences in neural synchrony (as measured by intersubject correlations; ISCs) associated with perceived stress using functional magnetic resonance imaging (fMRI). We evaluated how self-reported perceived stress levels influence neural synchrony patterns in response to different naturalistic stimuli by examining the differences in neural synchrony between individuals with low and high perceived stress levels. We determined that lower perceived stress was observed with greater neural synchrony areas associated with perceptual and attention processing, including the lateral occipital cortex, superior temporal gyrus, superior parietal lobule, orbital frontal cortex, and the occipital pole. These results indicate that high levels of perceived stress heavily alter neural processing of complex audiovisual stimuli. Together, these results provide evidence that perceived stress influences cognitive processing in everyday life.

Retinoic acid-mediated homeostatic plasticity drives cell type-specific CP-AMPAR accumulation in nucleus accumbens core and incubation of cocaine craving
Abstract Incubation of cocaine craving, a translationally relevant model for the persistence of drug craving during abstinence, ultimately depends on strengthening of nucleus accumbens core (NAcc) synapses through synaptic insertion of homomeric GluA1 Ca2+-permeable AMPA receptors (CP-AMPARs). Here we tested the hypothesis that CP-AMPAR upregulation results from a form of homeostatic plasticity, previously characterized in vitro and in other brain regions, that depends on retinoic acid (RA) signaling in dendrites. Under normal conditions, ongoing synaptic transmission maintains intracellular Ca2+ at levels sufficient to suppress RA synthesis. Prolonged blockade of neuronal activity results in disinhibition of RA synthesis, leading to increased GluA1 translation and synaptic insertion of homomeric GluA1 CP-AMPARs. Using slice recordings, we found that increasing RA signaling in NAcc medium spiny neurons (MSN) from drug-naive rats rapidly upregulates CP-AMPARs, and that this pathway is operative only in MSN expressing the D1 dopamine receptor. In MSN recorded from rats that have undergone incubation of craving, this effect of RA is occluded; instead, interruption of RA signaling in the slice normalizes the incubation-associated elevation of synaptic CP-AMPARs. Paralleling this in vitro finding, interruption of RA signaling in the NAcc of 'incubated rats' normalizes the incubation-associated elevation of cue-induced cocaine seeking. These results suggest that RA signaling becomes tonically active in the NAcc during cocaine withdrawal and, by maintaining elevated CP-AMPAR levels, contributes to the incubation of cocaine craving.

Selective expansion of motor cortical projections in the evolution of vocal novelty
Deciphering how cortical architecture evolves to drive behavioral innovations is a long-standing challenge in neuroscience and evolutionary biology. Here, we leverage a striking behavioral novelty in the Alston's singing mouse (Scotinomys teguina), compared to the laboratory mouse (Mus musculus), to quantitatively test models of motor cortical evolution. We used bulk tracing, serial two-photon tomography, and high-throughput DNA sequencing of over 76,000 barcoded neurons to discover a specific and substantial expansion (~200%) of orofacial motor cortical (OMC) projections to the auditory cortical region (AudR) and the midbrain periaqueductal gray (PAG), both implicated in vocal behaviors. Moreover, analysis of individual OMC neurons' projection motifs revealed preferential expansion of exclusive projections to AudR. Our results imply that selective expansion of ancestral motor cortical projections can underlie behavioral divergence over short evolutionary timescales, suggesting potential mechanisms for the evolution of enhanced cortical control over vocalizations, a crucial preadaptation for human language.

Operant alcohol self-administration targets GluA2-containing AMPAR expression and synaptic activity in the nucleus accumbens in a manner that drives the reinforcing properties of the drug
Rationale: The positive reinforcing effects of alcohol (ethanol) drive its repetitive use and contribute to alcohol use disorder (AUD). Ethanol alters the expression of glutamate AMPA receptor (AMPAR) subunits in reward-related brain regions, but the extent to which this molecular effect regulates ethanol reinforcement is unclear. Objective: This study investigates whether ethanol self-administration changes AMPAR subunit expression and synaptic activity in the nucleus accumbens core (AcbC) to regulate ethanol reinforcement in male C57BL/6J mice. Results: Sucrose-sweetened ethanol self-administration (0.81 g/kg/day) increased AMPAR GluA2 protein expression in the AcbC, without effect on GluA1, compared to sucrose-only controls. Infusion of myristoylated Pep2m in the AcbC, which blocks GluA2 binding to N-ethylmaleimide-sensitive fusion protein (NSF) and reduces GluA2-containing AMPAR activity, reduced ethanol-reinforced responding without affecting sucrose-only self-administration or motor activity. Antagonizing GluA2-lacking AMPARs, through AcbC infusion of NASPM, had no effect on ethanol self-administration. AcbC neurons receiving projections from the basolateral amygdala (BLA) showed increased sEPSC frequency and GluA2-like decay kinetics in ethanol self-administering mice as compared to sucrose. Optogenetic activation of these neurons revealed an ethanol-enhanced AMPA/NMDA ratio and reduced paired-pulse ratio, indicating elevated AMPAR activity and glutamate release specifically at AcbC terminals of BLA projecting neurons. Conclusions: Ethanol use upregulates GluA2 protein expression in the AcbC and AMPAR synaptic activity in AcbC neurons receiving BLA projections. GluA2-containing AMPAR activity in the AcbC regulates the positive reinforcing effects of ethanol through an NSF-dependent mechanism. This highlights a potential target for therapeutic interventions in AUD.

A modulator of cognitive function: Cerebellum modifies human cortical network dynamics via integration
The cerebellum, with distinctive architecture and extensive cortical connections, has long been associated with motor control; however, evidence suggests its role extends beyond motor functions, playing a crucial role in cognitive processes. Despite these insights, how cerebellar computations modulate cortical networks remains elusive. Here, we evaluate dynamic network reconfigurations in the cerebral cortex connectivity following noninvasive inhibitory repetitive transcranial magnetic stimulation (rTMS) targeting the right cerebellum. Using dynamic community detection, we uncover the dynamic network properties by which cerebellar stimulation spreads through the cortex, inspecting the evolution of modular network structures prior to and after cerebellar stimulation. Our results indicate that: (1) flexibility, or the likelihood of network nodes to change module allegiances, increases post stimulation; (2) dynamic patterns in which module allegiances emerge and evolve are individualistic and do not follow a single functional prototype; and (3) cerebellar nodes play the role of integrators for distinct network modules. These results suggest that the cerebellum plays a pivotal role in modulating distributed cortical activity, seamlessly integrating and segregating information beyond motor control. This integrative capacity may underlie the cerebellum's contributions to high-level cognitive functions and, more broadly, to the foundation of human intelligence. Keywords: Brain network dynamics, Cerebellum, rTMS, flexibility

Distinct basal ganglia decision dynamics under conflict and uncertainty
The basal ganglia (BG) play a key role in decision-making, preventing impulsive actions in some contexts while facilitating fast adaptations in others. The specific contributions of different BG structures to this nuanced behavior remain unclear, particularly under varying situations of noisy and conflicting information that necessitate ongoing adjustments in the balance between speed and accuracy. Theoretical accounts suggest that dynamic regulation of the amount of evidence required to commit to a decision (a dynamic decision boundary) may be necessary to meet these competing demands. Through the application of novel computational modeling tools in tandem with direct neural recordings from human BG areas, we find that neural dynamics in the theta band manifest as variations in a collapsing decision boundary as a function of conflict and uncertainty. We collected intracranial recordings from patients diagnosed with either Parkinson's disease (n=14) or dystonia (n=3) in the subthalamic nucleus (STN), globus pallidus internus (GPi), and externus (GPe) during their performance of a novel perceptual discrimination task in which we independently manipulated uncertainty and conflict. To formally characterize whether these task and neural components influenced decision dynamics, we leveraged modified diffusion decision models (DDMs). Behavioral choices and response time distributions were best characterized by a modified DDM in which the decision boundary collapsed over time, but where the onset and shape of this collapse varied with conflict. Moreover, theta dynamics in BG structures predicted the onset and shape of this collapse but differentially across task conditions. In STN, theta activity was related to a prolonged decision boundary (indexed by slower collapse and therefore more deliberate choices) during high-conflict situations. Conversely, rapid declines in GPe theta during low conflict conditions were related to rapidly collapsing boundaries and expedited choices, with additional complementary decision bound adjustments during high uncertainty situations. Finally, GPi theta effects were uniform across conditions, with increases in theta prolonging the collapse of decision bounds. Together, these findings provide a nuanced understanding of how our brain thwarts impulsive actions while nonetheless enabling behavioral adaptation amidst noisy and conflicting information.

Neuro-musculoskeletal modeling reveals muscle-level neural dynamics of adaptive learning in sensorimotor cortex
The neural activity of the brain is intimately coupled to the dynamics of the body. Yet how our hierarchical sensorimotor system dynamically orchestrates the generation of movement while adapting to incoming sensory information remains unclear. In mice, the extent of encoding from posture to muscle-level features across the motor (M1) and primary sensory forelimb (S1) cortex and how these are shaped during learning are unknown. To address this, we built a large-scale model that captures hypothesized neural computations and use this to control a novel 50-muscle model of the adult forelimb amenable to studying motor control and learning in a physics simulation environment. We show that we can imitate 3D limb kinematics collected during a joystick task by solving inverse kinematics and deriving a sensorimotor control model that drives the same actions. Using the internal computations from our model, we find that populations of layer 2/3 M1 and S1 neurons encode high-level position, and lower-level muscle space and proprioceptive dynamics. During adaptive learning, these functionally distinct neurons map onto specific computational motifs. Strikingly, S1 neurons more prominently encode sensorimotor prediction errors, and M1 and S1 support optimal state estimation. Moreover, we find that neural latent dynamics differentially change in S1 vs. M1 during this within-session learning. Together, our results provide a new model of how neural dynamics in cortex enables adaptive learning.

Savings in visuomotor learning is associated with connectivity changes within a cerebello-thalamo-cortical network encoding movement errors
Savings refers to faster relearning upon re-exposure to a previously experienced movement perturbation. One theory suggests that the brain recognizes past errors and is therefore more able to learn from them. If true, there should be a modification of the neural response to errors during re-exposure to a perturbation. To test this idea, we imaged the brains of participants who underwent two sessions (1 day apart) of adaptation to a visuomotor perturbation and investigated brain responses to movement errors. The magnitude of movement error was entered into different types of GLMs to study error-related activation and co-activation (or functional connectivity). We identified a cerebello-thalamo-cortical network involved in the processing of movement errors during adaptation. We found that connectivity between regions of this network (i.e., between the cerebellum and the thalamus, and between the primary somatosensory cortex and the anterior cingulate cortex) became stronger during re-adaptation. Importantly, participants with the largest increases in connectivity strength were those who demonstrated the largest amounts of savings. These results establish a relationship between the ability of the brain to represent errors and the phenomenon of savings.

The CHCHD2-CHCHD10 protein complex is modulated by mitochondrial dysfunction and alters lipid homeostasis in the mouse brain.
The highly conserved CHCHD2 and CHCHD10 are small mitochondrial proteins residing in the intermembrane space. Recently, mutations in the CHCHD2 and CHCHD10 genes have been linked to severe disorders, including Parkinson s disease and amyotrophic lateral sclerosis. In cultured cells, a small fraction of CHCHD2 and CHCHD10 oligomerize to form a high molecular weight complex of unknown function. Here, we generated a whole-body Chchd2 knockout mouse to investigate the in vivo role of CHCHD2 and its protein complex. We show that CHCHD2 is crucial for sustaining full motor capacity, normal striatal dopamine levels, and lipid homeostasis in the brain of adult male mice. We also demonstrate that in mouse tissues, CHCHD2 and CHCHD10 exist exclusively as a high molecular weight complex, whose levels are finely tuned under physiological conditions. In response to mitochondrial dysfunction, the abundance and size of the CHCHD2-CHCHD10 complex increases, a mechanism conserved across different tissues. Although the loss of CHCHD2 does not abolish CHCHD10 oligomerization, it enhances cell vulnerability to mitochondrial stress, suggesting that CHCHD2 is protective against mitochondrial damage. Our findings uncover the role of CHCHD2 in preserving tissue homeostasis and provide important insights into the involvement of the CHCHD2-CHCHD10 complex in human diseases.

Behavioral Evidence for Two Modes of Attention
Attention modulates sensory gain to select and optimize the processing of behaviorally relevant events. It has been hypothesized that attention can operate in either a rhythmic or continuous mode, depending on the nature of sensory stimulation. Despite this conceptual framework, direct behavioral evidence has been scarce. Our study explores when attention operates in a rhythmic mode through a series of nine interrelated behavioral experiments with varying stream lengths, stimulus types, attended features, and tasks. The rhythmic mode optimally operates at approximately 1.5 Hz and is prevalent in perceptual tasks involving long (> 7 s) auditory streams. Our results are supported by a model of coupled oscillators, illustrating that variations in the system's noise level can induce shifts between continuous and rhythmic modes. Finally, the rhythmic mode is absent in syllable categorization tasks. Overall, this study provides empirical evidence for two modes of attention and defines their conditions of operation.

Bimodal dendritic processing in basket cells drives distinct memory-related oscillations
Hippocampal oscillations span from slow to high-frequency bands that are linked to different memory stages and behavioral states. We show that fast spiking basket cells (FSBCs) with bimodal nonlinear dendritic trees modulate these oscillations. Supralinear FSBC dendritic activation enhances high-frequency oscillations, while sublinear activation increases slow oscillatory power, adjusting the Excitation/Inhibition balance in the network. This underscores a new link between FSBCs nonlinear dendritic integration and memory-related oscillations.

Task-relevant representational formats in multi-layered memory traces
During encoding, stimuli are embedded into memory traces that allow for their later retrieval. This process is selective, however, because not every aspect of our experiences can be remembered. In addition, post-encoding stages including consolidation are widely assumed to induce transformation processes of the memory trace. It is unclear, however, how selective the memory trace is, whether irrelevant information is completely removed during encoding and/or consolidation, and how this affects retrieval of either general (gist-like) or specific (perceptual) information. Here we show that memory traces consist of multi-layered representational spaces whose formats are flexibly strengthened or weakened during encoding and consolidation depending on task instructions, distinctly shaping their affordances for general or specific retrieval. In a series of behavioral experiments, participants first compared pairs of natural images on either two conceptual or two perceptual dimensions, leading them to incorporate the images into representational spaces defined by Euclidean distances. We found that distances in task-relevant but not irrelevant spaces affected memory strengths. Conceptual encoding benefitted general without impairing specific retrieval, suggesting that perceptual information remained in the memory trace even if it was task-irrelevant. By contrast, targeted memory reactivation (TMR) of conceptual encoding improved memory strength but deteriorated perceptual discrimination during retrieval, indicating that it weakened the accessibility of perceptual formats. Our results demonstrate the flexibility of representational formats that are incorporated into memory traces, and more generally show how the organization of information in representational spaces shapes human behavior.

Ethograms reveal a fear conditioned visual cue to organize diverse behaviors in rats
Recognizing and responding to threat cues is essential to survival. In rats, freezing is the most common behavior measured. Previously we demonstrated a threat cue can organize diverse behaviors (Chu et al., 2024). However, the experimental design of Chu et al. (2024) was complex and the findings descriptive. Here, we gave female and male Long Evans rats simple paired or unpaired presentations of a light and foot shock (8 total) in a conditioned suppression setting, using a range of shock intensities (0.15, 0.25, 0.35 or 0.5 mA). We found that conditioned suppression was only observed at higher foot shock intensities (0.35 mA and 0.5 mA). We constructed comprehensive, temporal ethograms by scoring 22,272 frames of behavior for 12 mutually exclusive behavior categories in 200 ms intervals around cue presentation. A 0.5 mA and 0.35 mA shock-paired visual cue suppressed reward seeking, rearing and scaling, as well as light-directed rearing and light-directed scaling. The shock-paired visual paired cue further elicited locomotion and freezing. Linear discriminant analyses showed that ethogram data could accurately classify rats into paired and unpaired groups. Considering the complete ethogram data produced superior classification than considering subsets of behaviors. The results demonstrate diverse threat-elicited behaviors - in a simple Pavlovian fear conditioning design - containing sufficient information to distinguish the fear learning status of individual rats.

A double hit affecting the IKZF1-IKZF2 tandem in immune cells of schizophrenic patients regulate specific symptoms
Schizophrenia is a complex multifactorial disorder and increasing evidence suggests the involvement of immune dysregulations in its pathogenesis. We observed that IKZF1 and IKZF2, classic immune-related transcription factors (TFs), were both downregulated in patients peripheral blood mononuclear cells (PBMCs) but not in their brain. We generated a new mutant mouse model with a reduction in Ikzf1 and Ikzf2 to study the impact of those changes. Such mice developed deficits in the three dimensions (positive-negative-cognitive) of schizophrenic-like phenotypes associated with alterations in structural synaptic plasticity. We then studied the secretomes of cultured PBMCs obtained from human patients and identified potentially secreted molecules, which depended on IKZF1 and IKZF2 levels, and that in turn have an impact on neural synchrony, structural synaptic plasticity and schizophrenic-like symptoms in in vivo and in vitro models. Our results point out that IKZF1-IKZF2-dependent immune signals negatively impact on essential neural circuits involved in schizophrenia.

Human microRNA-153-3p targets specific neuronal genes and is associated with the risk of Alzheimer's disease.
Alzheimers disease (AD) is a progressive degenerative disease characterized by a significant loss of neurons and synapses in cognitive brain regions and is the leading cause of dementia worldwide. AD pathology comprises extracellular amyloid plaques and intracellular neurofibrillary tangles. However, the triggers of this pathology are still poorly understood. Repressor element 1-silencing transcription/neuron-restrictive silencer factor (REST/NRSF), a transcription repressor of neuronal genes, is dysregulated during AD pathogenesis. How REST is dysregulated is still poorly understood, especially at the post-transcriptional level. MicroRNAs (miRNAs), a group of short non-coding RNAs, typically regulate protein expression by interacting with target mRNA transcript 3-untranslated region (UTR) and play essential roles in AD pathogenesis. Herein, we demonstrate that miR-153-3p reduces REST 3-UTR activities, mRNA, and protein levels in human cell lines, along with downregulating amyloid {beta} precursor protein (APP) and -synuclein (SNCA). We determine by mutational analyses that miR-153-3p interacts with specific targets via the seed sequence present within the respective mRNA 3-UTR. We show that miR-153-3p treatment alters the expression of these specific proteins in human neuronally differentiated cells and human induced pluripotent stem cells and that miR-153-3p is itself dysregulated in AD. We further find that single nucleotide polymorphisms (SNPs) within 5kb of the MIR153-1 and MIR153-2 genes are associated with AD-related endophenotypes. Elevation of miR-153-3p is associated with reduced AD probability, while elevated REST may associate with a greater AD probability. Our work suggests that a supplement of miR-153-3p would reduce levels of toxic protein aggregates by reducing APP, SNCA, and REST expression, all pointing towards a therapeutic and biomarker potential of miR-153-3p in AD and related dementias.

Sex-dependent effects of a high-fat diet on the hypothalamic response in mouse
Sex differences in rodent models of diet-induced obesity are still poorly documented, particularly regarding how central mechanisms vary between sexes in response to an obesogenic diet. Here, we wanted to determine whether obesity phenotype and hypothalamic response differed between male and female C57Bl/6J mice when exposed to a high-fat diet (HFD). Mice were exposed either a free 60% HFD or standard diet first for both a long- (14 weeks) and shorter-periods of time (3, 7, 14 and 28 days). Analysis of the expression profile of key neuronal, glial and inflammatory hypothalamic markers was performed using RT-qPCR. In addition, astrocytic and microglial morphology was examined in the arcuate nucleus. Monitoring of body weight and composition revealed that body weight and fat mass gain appeared earlier and was more pronounced in male mice. After 14 weeks of HFD exposure, normalized increase of body weight reached similar levels between male and female mice. Overall, both sexes under HFD displayed a decrease of orexigenic neuropeptides expression and an increase in POMC gene expression was observed only in female mice. In addition, changes in the expression of hypothalamic inflammatory markers were relatively modest. We also reported that the glial cell markers expression and morphology were affected by HFD in a sex- and time dependent manner, suggesting a more pronounced glial cell activation in female mice. Taken together, these data show that male and female mice responded differently to HFD exposure, both on short- and long-term and suggest that a strong inflammatory hypothalamic profile is not systematically present in DIO models. Nevertheless, in addition to these present data, the underlying mechanisms should be deciphered in further investigations.

Wakefulness induced by TAAR1 partial agonism is mediated through dopaminergic neurotransmission
Trace amine-associated receptor 1 (TAAR1) is a negative regulator of dopamine (DA) release. The partial TAAR1 agonist RO5263397 promotes wakefulness and suppresses NREM and REM sleep in rodents and non-human primates. We tested the hypothesis that the TAAR1-mediated effects on sleep/wake were due, in part, to DA release. Male C57BL6/J mice (n=8) were intraper-itoneally administered the D1R antagonist SCH23390, the D2R antagonist eticlopride, a combi-nation of D1R+D2R antagonists or saline at ZT5.5, followed 30 min later by RO5263397 or vehi-cle per os. EEG, EMG, subcutaneous temperature, and activity were recorded across the 8 treat-ments and sleep architecture was analyzed for 6 hours post-dosing. As described previously, RO5263397 increased wakefulness and delayed NREM and REM sleep onset. D1, D2, and D1+D2 pretreatment reduced RO5263397-induced wakefulness for 1-2 hours after dosing but only the D1 antagonist significantly reduced the TAAR1-mediated increase in NREM latency. Neither the D1 nor the D2 antagonist affected TAAR1-mediated suppression of REM sleep. These results suggest that, whereas TAAR1 effects on wakefulness are mediated in part through the D2R, D1R activation plays a role in reversing the TAAR1-mediated increase in NREM sleep latency. By contrast, TAAR1-mediated suppression of REM sleep appears not to involve D1R or D2R mechanisms.

Ultrastructural analysis of the brain endothelium by electron tomography
Transmission electron microscopy (TEM) is a powerful imaging technique, yielding ultrastructural investigation of organic and non-organic samples. Despite its ability to reach nanoscale resolutions, conventional TEM presents a major disadvantage by only acquiring two-dimensional snapshots, thus hindering our volumetric understanding of samples. Electron tomography (ET) overcomes this limitation by offering detailed views of a thin specimen in 3 dimensions (3D). This technique is widely used in biology and has expanded our understanding of mitochondrial structure or synaptic organization. Proper brain functioning is highly reliable on a constant nutritional support through its microvasculature lined by endothelial cells. These unique cells form a selective and protective barrier, known as the blood-brain barrier (BBB), which limits the entrance of blood-borne molecules into the brain. In pathological conditions, the BBB is disrupted, resulting in neuronal damage. Understanding the fine changes underlying BBB disruption requires advanced imaging tools such as ET, to detect the finest changes in endothelial ultrastructure. This manuscript briefly explains how TEM and ET function, and then provides a detailed, didactic method for sample preparation, tomogram generation and 3D segmentation of brain endothelial cells using ET.

Modulation of cortico-muscular coupling associated with split-belt locomotor adaptation
Humans can adjust their walking patterns according to the demands of their internal and external environments, referred to as locomotor adaptation. Although significant functional coupling (i.e. cortico-muscular coherence [CMC]) has been shown between cortical and lower-limb muscle activity during steady-state walking, little is known about CMC in locomotor adaptation. Therefore, we investigated the adaptation-dependent modulation of the CMC between the sensorimotor region and the tibialis anterior muscle using a split-belt locomotor adaptation paradigm that can impose an asymmetric perturbation. We hypothesized that the CMC would temporarily decrease after exposure to the asymmetric perturbation and removal of the perturbation because of a mismatch between the predicted and actual sensory feedback. We also hypothesized that the CMC would increase as adaptation and de-adaptation to perturbation progressed because the motor system could become able to predict sensory feedback. Our findings revealed that the CMC temporarily decreased after exposure to and removal of the perturbation. Moreover, the CMC increased with adaptation and de-adaptation to perturbation. Although these results depend on the leg, frequency bands, and gait phases, they partially support our hypothesis. These findings suggest that flexible updating of cortico-muscular coupling in the motor system is a key mechanism underlying locomotor adaptation in humans. The results from our study on healthy young individuals contribute to the understanding of neuromuscular control of gait and provide valuable insight for optimising gait rehabilitation.

A Statistically-Robust Model Of The Axomyelin Unit Under Normal Physiologic Conditions With Application To Disease States
Despite tremendous progress in characterizing the myriad cellular structures in the nervous system, a full appreciation of the interdependent and intricate interactions between these structures is as yet unfulfilled. Indeed, few more so than the interaction between the myelin internode and its ensheathed axon. More than a half-century after the ultrastructural characterization of this axomyelin unit, we lack a reliable understanding of the physiological properties, the significance and consequence of pathobiological processes, and the means to gauge success or failure of interventions designed to mitigate disease. Herein, we highlight shortcomings in the most common statistical procedures used to characterize the axomyelin unit, with particular emphasis on the underlying principles of simple linear regression. These shortcomings lead to insensitive detection and/or ambiguous interpretation of normal physiology, disease mechanisms and remedial methodologies. To address these problems, we syndicate insights from early seminal myelin studies and use a statistical model of the axomyelin unit that is established in the accompanying article. Herein, we develop and demonstrate a statistically-robust analysis pipeline with which to examine and interpret axomyelin physiology and pathobiology in two disease states, experimental autoimmune encephalomyelitis and the rumpshaker mouse model of leukodystrophy. On a cautionary note, our pipeline is a relatively simple and streamlined approach that is not necessarily a panacea for all g ratio analyses. Rather, it approximates a minimum effort needed to elucidate departures from normal physiology and to determine if more comprehensive studies may lead to deeper insights.

Stab Wound Injury Elicits Transit Amplifying Progenitor-like Phenotype in Parenchymal Astrocytes
Astrocytes exhibit dual roles in central nervous system (CNS) recovery, offering both beneficial and detrimental effects. Following CNS injury, a subset of astrocytes undergoes proliferation, de-differentiation, and acquires self-renewal and neurosphere-forming capabilities in vitro. This subset of astrocytes represents a promising target for initiating brain repair processes and holds potential for neural recovery. However, studying these rare plastic astrocytes is challenging due to the absence of distinct markers. In our study, we characterized these astrocytic subpopulations using comparative single-cell transcriptome analysis. By leveraging the regenerative properties observed in radial glia of zebrafish, we identified and characterized injury-induced plastic astrocytes in mice. These injury-induced astrocytic subpopulations were predominantly proliferative and demonstrated the capacity for self-renewal and neurosphere formation, ultimately differentiating exclusively into astrocytes. Integration with scRNAseq data of the subependymal zone (SEZ) allowed us to trace the origins of these injury-induced plastic astrocytic subpopulations to parenchymal astrocytes. Our analysis revealed that a subset of these injury-induced astrocytes shares transcriptional similarities with endogenous transient amplifying progenitors (TAPs) within the SEZ, rather than with neural stem cells (NSCs). Notably, these injury-induced TAP-like cells exhibit distinct differentiation trajectories, favoring gliogenic over neurogenic differentiation. In summary, our study identifies a rare subset of injury-induced, proliferative plastic astrocytes with neurosphere-forming capacities. These cells originate from reactive astrocytes and resemble TAPs in their transcriptional profile. This study enhances our understanding of astrocyte plasticity post-injury.

Revealing the neural representations underlying other-race face perception
The other-race effect, a disadvantage at recognizing faces of other races than one's own, has received considerable attention, especially regarding its wide scope and underlying mechanisms. Here, we aim to elucidate its neural and representational basis by relating behavioral performance in East Asian and White individuals to neural decoding and image reconstruction relying on electroencephalography data. Our investigation uncovers a reliable neural counterpart of the other-race effect (i.e., a decoding disadvantage for other-race faces) along with its extended dynamics and prominence across individuals. Further, it retrieves, via neural-based image reconstruction, visual representations underlying other-race face perception and their intrinsic biases. Notably, our data-driven approach reveals that other-race faces are perceived not just as more typical but, also, as younger and more expressive. These findings, pointing to multiple visual biases surrounding the other-race effect, speak to the complexity of its neural mechanisms and its social implications.

A brain-body feedback loop driving HPA-axis dysfunction in breast cancer
Breast cancer patients often exhibit disrupted circadian rhythms in circulating glucocorticoids (GCs), such as cortisol. This disruption correlates with reduced quality of life and higher cancer mortality. The exact cause of this phenomenon; whether due to treatments, stress, age, co-morbidities, lifestyle factors, or the cancer itself remains unclear. Here, we demonstrate that primary breast cancer alone blunts host GC rhythms by disinhibiting neurons in the hypothalamus, and that circadian phase-specific neuromodulation of these neurons can attenuate tumor growth by enhancing anti-tumor immunity. We find that mice with mammary tumors exhibit blunted GC rhythms before tumors are palpable, alongside increased activity in paraventricular hypothalamic neurons expressing corticotropin-releasing hormone (i.e., PVNCRH neurons). Tumor-bearing mice have fewer inhibitory synapses contacting PVNCRH neurons and reduced miniature inhibitory post-synaptic current (mIPSC) frequency, leading to net excitation. Tumor-bearing mice experience impaired negative feedback on GC production, but adrenal and pituitary gland functions are largely unaffected, indicating that alterations in PVNCRH neuronal activity are likely a primary cause of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in breast cancer. Using chemogenetics (hM3Dq) to stimulate PVNCRH neurons at different circadian phases, we show that stimulation just before the light-to-dark transition restores normal GC rhythms and reduces tumor progression. These mice have significantly more effector T cells (CD8+) within the tumor than non-stimulated controls, and the anti-tumor effect of PVNCRH neuronal stimulation is absent in mice lacking CD8+ T cells. Our findings demonstrate that breast cancer distally regulates neurons in the hypothalamus that control output of the HPA axis and provide evidence that therapeutic targeting of these neurons could mitigate tumor progression.

TAAR2-9 Knockout Mice Exhibit Reduced Wakefulness and Disrupted REM Sleep
Trace amine-associated receptor 1 (TAAR1) has gained attention for its roles in modulating neural systems, sleep/wake control, and as a therapeutic target for neuropsychiatric disorders. Although TAARs 2-9 were initially identified as non-canonical olfactory receptors, recent studies have identified extra-nasal receptor distribution of multiple TAARs. To evaluate whether TAARs 2-9 have a role in arousal state regulation, we investigated sleep/wake control in male TAAR2-9 knockout (KO) mice. After determination of baseline sleep/wake patterns, the homeostatic response to sleep deprivation and response to TAAR1 agonists were compared between KO and C57BL/6J mice. Although the EEG of TAAR2-9 KO mice had lower power in the delta and theta bands and higher power in the gamma range, sleep/wake states were readily identified. KO mice had more NREM sleep during the dark phase and more REM sleep during the light phase. Sleep/wake was fragmented in KO mice with shorter Wake and REM bouts during the dark phase and more REM bouts during the light phase. KO mice exhibited more REM sleep during a sleep latency test but the homeostatic response to sleep loss did not differ between the strains. A high dose of the TAAR1 agonist RO5256390 increased Wake and reduced NREM sleep in KO mice whereas RO5256390 and the partial TAAR1 agonist RO5263397 suppressed REM sleep. The number of tyrosine hydroxylase-immunoreactive neurons in the ventral tegmental area was significantly elevated in KO mice. These dopaminergic and sleep/wake alterations in TAAR2-9 KO mice highlight the need for further elucidation of the functions of TAAR2-9.

Parechovirus-3 infection disrupts immunometabolism and leads to glutamate excitotoxicity in neural organoids
Parechovirus ahumpari 3 (HPeV-3), is among the main agents causing severe neonatal neurological infections such as encephalitis and meningitis. However, the underlying molecular mechanisms and changes to the host cellular landscape leading to neurological disease has been understudied. Through quantitative proteomic analysis of HPeV-3 infected neural organoids, we identified unique metabolic changes following HPeV-3 infection that indicate immunometabolic dysregulation. Protein and pathway analyses showed significant alterations in neurotransmission and potentially, neuronal excitotoxicity. Elevated levels of extracellular glutamate, lactate dehydrogenase (LDH), and neurofilament light (NfL) confirmed glutamate excitotoxicity to be a key mechanism contributing to neuronal toxicity in HPeV-3 infection and can lead to apoptosis induced by caspase signaling. These insights are pivotal in delineating the metabolic landscape following severe HPeV-3 CNS infection and may identify potential host targets for therapeutic interventions.

The cardiac, respiratory and gastric rhythms independently modulate corticospinal excitability
Interoception refers to the sensing of the internal state of the body and encompasses various bodily axes. Yet many interoceptive signals display unique qualities. The heart, lungs, and stomach each have their distinct frequencies, afferent pathways, and respective functions. At the same time each of these organs has been demonstrated to interact with neural activity and behaviour. To what extent then should different organs be treated as separate modalities in interoception? We here aim to answer this question by assessing in human participants whether the phase of these visceral rhythms is coupled to the corticospinal excitability of the motor system, and whether this coupling happens in an organ-specific or organ-general manner. We combined continuous physiological recordings with single pulse Transcranial Magnetic Stimulation (TMS) to probe phase-amplitude coupling between the phase of the cardiac, respiratory, and gastric rhythm and the amplitude of Motor Evoked Potentials (MEP). All three visceral rhythms contributed to MEP amplitude with similar effect sizes at the group level. However, we found no relation between coupling strengths with corticospinal excitability between the three organs. Thus, participants displaying high coupling with one organ did not necessarily display high coupling to the other organs, suggestive of unique interoceptive profiles. There was also no link between self-reported awareness of the organ and the actual coupling, suggesting these are distinct dimensions of interoception. Together these results show that each coupling is mediated by at least partially independent mechanisms.

Reduction of RAD23A extends lifespan and mitigates pathology in TDP-43 mice
Protein misfolding and aggregation are cardinal features of neurodegenerative disease (NDD) and they contribute to pathophysiology by both loss-of-function (LOF) and gain-of-function (GOF) mechanisms. This is well exemplified by TDP-43 which aggregates and mislocalizes in several NDDs. The depletion of nuclear TDP-43 leads to reduction in its normal function in RNA metabolism and the cytoplasmic accumulation of TDP-43 leads to aberrant protein homeostasis. A modifier screen found that loss of rad23 suppressed TDP-43 pathology in invertebrate and tissue culture models. Here we show in a mouse model of TDP-43 pathology that genetic or antisense oligonucleotide (ASO)-mediated reduction in rad23a confers benefits on survival and behavior, histological hallmarks of disease and reduction of mislocalized and aggregated TDP-43. This results in improved function of the ubiquitin-proteasome system (UPS) and correction of transcriptomic alterations evoked by pathologic TDP-43. RAD23A-dependent remodeling of the insoluble proteome appears to be a key event driving pathology in this model. As TDP-43 pathology is prevalent in both familial and sporadic NDD, targeting RAD23A may have therapeutic potential.

Quantitative cytoarchitectural phenotyping of deparaffinized human brain tissues
Advanced 3D imaging techniques and image segmentation and classification methods can profoundly transform biomedical research by offering deep insights into the cytoarchitecture of the human brain in relation to pathological conditions. Here, we propose a comprehensive pipeline for performing 3D imaging and automated quantitative cellular phenotyping on Formalin-Fixed Paraffin-Embedded (FFPE) human brain specimens, a valuable yet underutilized resource. We exploited the versatility of our method by applying it to different human specimens from both adult and pediatric, normal and abnormal brain regions. Quantitative data on neuronal volume, ellipticity, local density, and spatial clustering level were obtained from a machine learning-based analysis of the 3D cytoarchitectural organization of cells identified by different molecular markers in two subjects with malformations of cortical development (MCD). This approach will grant access to a wide range of physiological and pathological paraffin-embedded clinical specimens, allowing for volumetric imaging and quantitative analysis of human brain samples at cellular resolution. Possible genotype-phenotype correlations can be unveiled, providing new insights into the pathogenesis of various brain diseases and enlarging treatment opportunities.

Cholinergic feedback for context-specific modulation of sensory representations
The brain's ability to prioritize behaviorally relevant sensory information is crucial for adaptive behavior, yet the underlying mechanisms remain unclear. Here, we investigated the role of basal forebrain cholinergic neurons in modulating olfactory bulb (OB) circuits in mice. Calcium imaging of cholinergic feedback axons in OB revealed that their activity is strongly 15 correlated with orofacial movements, with little responses to passively experienced odor stimuli. However, when mice engaged in an odor discrimination task, OB cholinergic axons rapidly shifted their response patterns from movement-correlated activity to odor-aligned responses. Notably, these odor responses during olfactory task engagement were absent in cholinergic axons projecting to the dorsal cortex. The level of odor responses correlated with task 20 performance. Inactivation of OB-projecting cholinergic neurons during task engagement impaired performance and reduced odor responses in OB granule cells. Thus, the cholinergic system dynamically modulates sensory processing in a modality-specific and context-dependent manner, providing a mechanism for a flexible and adaptive sensory prioritization.

In the brain of the beholder: bi-stable motion reveals mesoscopic-scale feedback modulation in V1
Understanding the neural processes underlying conscious perception remains a central goal in neuroscience. Visual illusions, whether static or dynamic, provide an effective ecological paradigm for studying conscious perception, as they induce subjective experiences from constant visual inputs. While previous neuroimaging studies have dissociated perceptual interpretation of visual motion from sensory input within the motion-sensitive area (hMT+) in humans, less is known about the role of V1 and its relationship to hMT+ during a bistable perception. To address this, we conducted a layer-fMRI study at 7 T with human participants exposed to a bistable motion quartet stimulus. Despite a constant sensory input, the bistable motion quartet elicits switching horizontal and vertical apparent motion percepts likely due to lateral and feedback connections across low and high-level brain regions (feedback processing). As control, we used an unambiguous version of the motion quartet, hereafter referred to as physical motion stimulus, where horizontal and vertical motion is physically presented as visual stimulus in an alternated fashion (feedforward processing). With the advantage of a sub-millimeter resolution gained at ultra-high field (7 Tesla), we aimed to unveil the differential laminar modulation of V1 (low visual area) and hMT+ (high-visual area) during the physical and bistable condition. Our results indicate that: 1) hMT+ functional activity correlates with conscious perception during both physical and ambiguous stimuli with similar strength. There is no evidence of differential laminar profiles in hMT+ between the two experimental conditions. 2) Between inducer squares, V1 shows a significantly reduced functional response to the ambiguous stimulus compared to the physical stimulus, as it primarily reflects feedback signals with diminished feedforward input. Distinct V1 laminar profiles differentiate the two experimental conditions. 3) The temporal dynamics of V1 and hMT+ become more similar during the ambiguous condition. 4) V1 exhibits reduced specificity to horizontal and vertical motion perception during the ambiguous condition at the retinotopic locations corresponding to the perceived motion. Our findings demonstrate that during the ambiguous condition, there is a stronger temporal coupling between hMT+ and V1 due to feedback signals from hMT+ to V1. Such feedback to V1 might be contributing to the stabilization of the vivid perception of directed motion at the face of constant ambiguous stimulation.