bioRxiv Subject Collection: Neuroscience's Journal

Glutathione Oxidation in Cerebrospinal Fluid as a Biomarker of Oxidative Stress in Amyotrophic Lateral Sclerosis
Background: Oxidative stress is a key feature of several neurodegenerative diseases, including Amyotrophic Lateral Sclerosis (ALS). Identification of reliable biomarkers of oxidative stress would be beneficial for drug-target engagement studies. Methods: We performed unbiased quantitative mass spectrometry (MS)-based analysis to measure changes in protein abundance and oxidation in cerebrospinal fluid (CSF) from a cohort of ALS patients and healthy controls at two time points (approximately four months apart) to capture disease progression. In addition, we developed a sensitive and targeted quantitative MS method to measure glutathione oxidation state in the same sets of CSF samples. Results: Proteomic analysis of CSF revealed statistically significant changes in the abundance of several proteins, including CHIT1, CHI3L1, CHI3L2 and COL18A1 in ALS patients compared to healthy controls at both time points. Several sites of protein oxidation were significantly altered in ALS compared to healthy controls, and total levels of reversible protein oxidation were elevated in ALS patients. Given that glutathione oxidation could be a useful biomarker of oxidative stress, we also measured glutathione and its oxidation state in CSF in the same cohorts of samples. Total GSH (tGSH), GSSG levels and the GSSG/GSH ratio were significantly higher in the ALS than in the healthy control group for both time points. For the first visit, fold changes of tGSH, GSSG, and GSSG/GSH ratio in ALS compared to HC were 1.33 (p = 0.0215), 1.54 (p = 0.0041) and 1.80 (p = 0.0454), respectively. For the second visit, these values were 1.50 (p = 0.0143), 2.00 (p = 0.0018) and 2.14 (p = 0.0120), respectively. Furthermore, we found positive correlations between disease duration until the first visit and total glutathione (tGSH), GSSG and GSSG/GSH ratio. Finally, there was a strong positive correlation between the total intensity of reversibly oxidised proteins and the ratio of GSSG/GSH in ALS patients at both visits. Conclusion: We propose that measuring levels of glutathione oxidation in CSF could act as a stratification biomarker to select ALS patients for antioxidant therapy and an approach to monitor the treatment response to therapeutic agents targeting oxidative stress.

Activity-dependent lateral inhibition enables ensemble synchronization of odor-activated neurons in the olfactory bulb
Information in the brain is represented by the activity of neuronal ensembles. These ensembles are adaptive and dynamic, formed and truncated based on the animal's experience. One mechanism by which spatially distributed neurons form an ensemble is synchronizing their spiking activity in response to a sensory event. In the olfactory bulb, odor stimulation evokes rhythmic gamma activity in spatially distributed mitral and tufted cells (MTCs). This rhythmic activity is thought to enhance the relay of odor information to the downstream olfactory targets. However, how only the odor-activated MTCs are synchronized to form an ensemble is unknown. Here, we demonstrate that light activating one set of MTCs can gamma-entrain the spiking activity of another set. This lateral synchronization is particularly effective when both MTCs fired at the gamma rhythm, facilitating the synchronization of only the odor-activated MTCs. Furthermore, we show that lateral synchronization does not depend on the distance between the MTCs and is mediated by Granule cells. In contrast, lateral inhibition between MTCs that reduced their firing rates was spatially restricted to adjacent MTCs and was not mediated by Granule cells. Our findings reveal a simple yet robust mechanism by which spatially distributed neurons entrain each other's spiking activity to form an ensemble.

Functional ultrasound neuroimaging reveals mesoscopic organization of saccades in the lateral intraparietal area of posterior parietal cortex
The lateral intraparietal cortex (LIP) located within the posterior parietal cortex (PPC) is an important area for the transformation of spatial information into accurate saccadic eye movements. Despite extensive research, we do not fully understand the functional anatomy of intended movement directions within LIP. This is in part due to technical challenges. Electrophysiology recordings can only record from small regions of the PPC, while fMRI and other whole-brain techniques lack sufficient spatiotemporal resolution. Here, we use functional ultrasound imaging (fUSI), an emerging technique with high sensitivity, large spatial coverage, and good spatial resolution, to determine how movement direction is encoded across PPC. We used fUSI to record local changes in cerebral blood volume in PPC as two monkeys performed memory-guided saccades to targets throughout their visual field. We then analyzed the distribution of preferred directional response fields within each coronal plane of PPC. Many subregions within LIP demonstrated strong directional tuning that was consistent across several months to years. These mesoscopic maps revealed a highly heterogenous organization within LIP with many small patches of neighboring cortex encoding different directions. LIP had a rough topography where anterior LIP represented more contralateral upward movements and posterior LIP represented more contralateral downward movements. These results address two fundamental gaps in our understanding of LIP's functional organization: the neighborhood organization of patches and the broader organization across LIP. These findings were achieved by tracking the same LIP populations across many months to years and developing mesoscopic maps of direction specificity previously unattainable with fMRI or electrophysiology methods.

Ultradian rhythms of CRHPVN neuron activity, behaviour and stress hormone secretion
The stress axis is always active, even in the absence of any threat. This manifests as hourly pulses of corticosteroid stress hormone secretion over the day. Corticotropin-releasing hormone neurons in the paraventricular nucleus of the hypothalamus (CRHPVN) control both the neuroendocrine stress axis as well as stress-associated behaviours. However, it is currently unclear how the resting activity of these neurons is coordinated with both spontaneous behaviour and ultradian pulses of corticosteroid secretion. To investigate this, we performed fiber photometry recordings of CRHPVN neuron activity in Crh-Ires-Cre mice and a newly generated line of Crh-Ires-Cre rats. In both mice and rats, CRHPVN neurons displayed an ultradian rhythm of activity with reoccurring upstates of activity approximately once per hour over the 24-hour day. Upstates in activity were coordinated with increases in animal activity/arousal. Chemogenetic activation of CRHPVN neurons was also sufficient to induce behavioural arousal. In rats, increases in CRH neural activity preceded some pulses of corticosteroid secretion but not others. Thus, while CRHPVN neurons display an ultradian rhythm of activity over the 24-hour day that is coordinated with behavioural arousal, the relationship between CRHPVN activity and pulses of corticosteroid secretion is not one-to-one.

Sensorimotor awareness requires intention: Evidence from minuscule eye movements.
Microsaccades are tiny eye movements that are thought to occur spontaneously and without awareness but can also be intentionally controlled with high precision. We used these tiny visual actions to investigate how intention modulates sensorimotor awareness by directly comparing intended, unintended, and spontaneous microsaccades. In addition, we dissociated the effects of action intention and the actions' visual consequences on awareness. In 80% of all trials, we presented a stimulus at high temporal frequency rendering it invisible during stable fixation. Critically, the stimulus became visible when a microsaccade in the same direction caused it to slow down on the retina (generated microsaccade condition; 40% of trials) or when the microsaccades' visual consequence was replayed (replayed microsaccade condition; 40% of trials). Participants reported whether they perceived the stimulus (visual sensitivity), whether they believed they had made a microsaccade (microsaccade sensitivity), and their level of confidence that their eye movement behavior was linked to their perception (causality assignment). Visual sensitivity was high for both, generated and replayed microsaccades and comparable for intended, unintended, and spontaneous eye movements. Microsaccade sensitivity, however, was low for spontaneous microsaccades, but heightened for both intended and unintended eye movements, showing that the intention to saccade or fixate enhances awareness of otherwise undetected eye movements. Visual consequences failed to aid eye movement awareness, and confidence ratings revealed a poor understanding of a causal relationship between eye movement and sensory consequence. These findings highlight the functional relevance of intention in sensorimotor awareness at the smallest scale of visual actions.

The aging musician: Evidence of a downward trend in song tempo as a function of artist age
Correspondences between the timing of motor behaviour and that of musical performance are well-established. Motor behaviour, however, is known to degrade across the adult lifespan due to neurobiological decay. In particular, performance on speed-dependent motor tasks deteriorates, spontaneous motor tempo (SMT) slows, and upper motor rate limit falls. Here, we examine whether this slowdown in motor behaviour impacts tempo of musical performance as a function of age. We analysed 14,556 songs released between 1956 and 2020 by artists with careers spanning at least 20 years. Generalised Additive Mixed Models (GAMMs) and Linear Mixed Models (LMMs) were employed to assess the effects of age, operationalised by subtracting birth year from release year of each track, on musical tempo. Results revealed a slight tempo increase from early adulthood to age 30, followed by a marked, linear slowdown with age across the remainder of the lifespan. From artists' thirties to their eighties, tempo decreased by almost 10 bpm, averaging around 2 bpm per decade. This decrease aligns with the slowing-with-age hypothesis and mirrors rates of decline observed in studies of spontaneous motor tempo (SMT) and gait speed. Our findings highlight a significant gap in understanding of creative performance across the lifespan, particularly the role of age as a mediating factor in musical tempo. Moreover, that a discernible decrease in tempo is apparent even in commercial recordings further emphasises the inescapable connection between dynamics of motor behaviour and timing of musical performance.

Scene context and attention independently facilitate MEG decoding of object category
Many of the objects we encounter in our everyday environments would be hard to recognize without any expectations about these objects. For example, a distant silhouette may be perceived as a car because we expect objects of that size, positioned on a road, to be cars. Accordingly, neuroimaging studies have shown that when objects are poorly visible, expectations derived from scene context facilitate the representations of these objects in visual cortex from around 300 ms after scene onset. The current magnetoencephalography (MEG) decoding study tested whether this facilitation occurs independently of attention and task relevance. Participants viewed degraded objects alone or within their original scene context while they either attended the scenes (attended condition) or the fixation cross (unattended condition), temporally directing attention away from the scenes. Results showed that at 300 ms after stimulus onset, multivariate classifiers trained to distinguish clearly visible animate vs inanimate objects generalized to distinguish degraded objects in scenes better than degraded objects alone, despite the added clutter of the scene background. Attention also modulated object representations at this latency, with better category decoding in the attended than the unattended condition. The modulatory effects of context and attention were independent of each other. Finally, data from the current study and a previous study were combined (N=51) to provide a more detailed temporal characterization of contextual facilitation. These results extend previous work by showing that facilitatory scene-object interactions are independent of the specific task performed on the visual input.

Maternal dietary deficiencies in folic acid and choline change metabolites levels in offspring after ischemic stroke
Ischemic stroke is a debilitating disease, with nutrition being a modifiable risk factor. Changes in levels of metabolites can be used to measure the alterations in the gut, a significant marker for the etiology of diseases. This study utilized untargeted metabolomics to investigate changes in fecal samples of offspring in response to maternal dietary deficiencies and ischemic stroke. Female mice were placed on control (CD), folic acid- (FADD), or choline-deficient (ChDD) diets prior to, during pregnancy, and lactation. Offspring were weaned on to CD and at 2 months of age an ischemic stroke was induced. Fecal samples were collected prior to ischemic stroke, and at 1- and 4-weeks post-stroke for analysis. Sex and maternal dietary differences in metabolites were observed at both the 1- and 4-week post-stroke timepoints. At the 1-week post-stroke, female FADD offspring had more changes in metabolites than males. Comparatively, at the 4-week post-stroke timepoint, female offspring on either FADD or ChDD demonstrated metabolite changes. This study demonstrates a long-lasting impact of maternal dietary deficiencies on central nervous system and gut microbiome function after ischemic stroke.

Neuronal networks quantified as vector fields
Brain function is defined by the interactions between the neurons of the brain. But these neurons exist in tremendous numbers, are continuously active and densely interconnected. Thereby they form one of the most complex dynamical systems known and there is a lack of approaches to characterize the functional properties of such biological neuronal networks. Here we introduce an approach to describe these functional properties by using its constituents, the weights of the synaptic connections and the current activity of its neurons. We show how a high-dimensional vector field, which describes how the activity of each individual neuron is impacted at each instant of time, naturally emerges from these constituents. We show the factors that impact the structural richness of that vector field, including how rapid changes in neuron activity continually reshapes its structure. We argue that this structural richness is the foundation of the functional diversity and thereby the adaptability that characterizes biological behavior.

Neural Stem Cell Relay from B1 to B2 cells in the adult mouse Ventricular-Subventricular Zone
Neurogenesis and gliogenesis continue in the Ventricular-Subventricular Zone (V-SVZ) of the adult rodent brain. B1 cells are astroglial cells derived from radial glia that function as primary progenitor neural stem cells (NSCs)in the V-SVZ. B1 cells, which have a small apical contact with the ventricle, decline in numbers during early postnatal life, yet neurogenesis continues into adulthood. Here we found that a second population of V-SVZ astroglial cells (B2 cells), that do not contact the ventricle, function as NSCs in the adult brain. B2 cell numbers increase postnatally, remain constant in 12-month-old mice and decrease by 18 months. Transcriptomic analysis of ventricular-contacting and non-contacting B cells revealed key molecular differences to distinguish B1 from B2 cells. Transplantation and lineage tracing of B2 cells demonstrate their function as primary progenitors for adult neurogenesis. This study reveals how NSC function is relayed from B1 to B2 progenitors to maintain adult neurogenesis.

The RNA binding ubiquitination ligase MEX3B regulates bFGF-dependent neuronal proliferation.
E3 ubiquitin ligases, integral components of the proteasomal degradation cascade, are critical for regulating the cellular proteome via canonical proteasome-mediated protein degradation; however, the non-canonical functions of these ligases in neuronal development are poorly understood. Our study focuses on a special class of E3 ubiquitin ligases known as RNA Binding Ubiquitin Ligases (RBUL) that harbour RNA-binding domains; allowing them to acquire all the properties of RNA-binding proteins (RBPs) and regulate transcriptional or post-transcriptional changes associated with the control of gene expression in cellular phenotypes. We aim to identify one such RUBL in the context of the highly dynamic yet stringently controlled process of neural proliferation and neural fate determination. MEX3B protein is a member of the MEX3 family and a part of the RBUL class of E3 ligases. It is differentially expressed in Neural Progenitor Cells (NPCs) upon differentiation. Mex3b RNA and protein were found to have temporally opposing expression patterns in presence of basic fibroblast growth factor (bFGF), a key signalling protein involved in neuronal proliferation. MEX3B is required for maintenance of the proliferative state of NPCs, whereas, its knockdown promotes transition from proliferative to differentiation state even in presence of bFGF that restricts differentiation. Furthermore, the knockdown of MEX3B protein results in the appearance of morphological hallmarks associated with early stages of neuronal differentiation including increase in neurite length and complexity. MEX3B interacts with the pro-proliferative transcription activator REST and the long non-coding RNA, HOTAIR. The study suggests the existence of a bFGF-dependent, combinatorial axis involving Mex3b, REST and HOTAIR, for the maintenance of NPC proliferative states. MEX3B, containing RNA binding motifs, is a unique E3 ligase that is necessary for bFGF-dependent proliferation. Mex3b protein invokes its non-canonical function of an RNA binding protein to form a tripartite complex with the transcription activator REST and HOTAIR lncRNA to define the proliferative state of NPCs. The study highlights a unique feature of special E3 ligases in neuronal proliferation during brain development that was previously overlooked.

NREM sleep brain networks modulate cognitive recovery from sleep deprivation
Decrease in cognitive performance after sleep deprivation followed by recovery after sleep suggests its key role, and especially non-rapid eye movement (NREM) sleep, in the maintenance of cognition. It remains unknown whether brain network reorganization in NREM sleep stages N2 and N3 can uniquely be mapped onto individual differences in cognitive performance after a recovery nap following sleep deprivation. Using resting state functional magnetic resonance imaging (fMRI), we quantified the integration and segregation of brain networks during NREM sleep stages N2 and N3 while participants took a 1-hour nap following 24-hour sleep deprivation, compared to well-rested wakefulness. Here, we advance a new analytic framework called the hierarchical segregation index (HSI) to quantify network segregation across spatial scales, from whole-brain to the voxel level, by identifying spatio-temporally overlapping large-scale networks and the corresponding voxel-to-region hierarchy. Our results show that network segregation increased in the default mode, dorsal attention and somatomotor networks during NREM sleep compared to wakefulness. Segregation within the visual, limbic, and executive control networks exhibited N2 versus N3 sleep-specific voxel-level patterns. More segregation during N3 was associated with worse recovery of working memory, executive attention, and psychomotor vigilance after the nap. The level of spatial resolution of network segregation varied among brain regions and was associated with the recovery of performance in distinct cognitive tasks. We demonstrated the sensitivity and reliability of voxel-level HSI to provide key insights into within-region variation, suggesting a mechanistic understanding of how NREM sleep replenishes cognition after sleep deprivation.

A high-throughput approach for the efficient prediction of perceived similarity of natural objects
Perceived similarity offers a window into the mental representations underlying our ability to make sense of our visual world, yet, the collection of similarity judgments quickly becomes infeasible for larger datasets, limiting their generality. To address this challenge, here we introduce a computational approach that predicts perceived similarity from neural network activations through a set of 49 interpretable dimensions learned on 1.46 million triplet odd-one-out judgments. The approach allowed us to predict separate, independently-sampled similarity scores with an accuracy of up to 0.898. Combining this approach with human ratings of the same dimensions led only to small improvements, indicating that the neural network captured much of human knowledge in this task. Predicting the similarity of highly homogenous image classes revealed that performance critically depends on the granularity of the training data. Our approach allowed us to improve the brain-behavior correspondence in a large-scale neuroimaging dataset and visualize candidate image features humans use for making similarity judgments, thus highlighting which image parts carry behaviorally-relevant information. Together, our results demonstrate that neural networks can carry information sufficient for capturing broadly-sampled similarity scores, offering a pathway towards the automated collection of human similarity judgments for natural images.

Nucleus accumbens sub-regions experience distinct dopamine release responses following acute and chronic morphine exposure
It is well established that dopamine neurons of the ventral tegmental area (VTA) play a critical role in reward and aversion as well as pathologies including drug dependence and addiction. The distinct effects of acute and chronic opioid exposure have been previously characterized at VTA synapses. Recent work suggests that distinct VTA projections that target the medial and lateral shell of the nucleus accumbens (NAc), may play opposing roles in modulating behavior. It is possible that these two anatomically and functionally distinct pathways also have disparate roles in opioid reward, tolerance, and withdrawal in the brain. In this study we monitored dopamine release in the medial or lateral shell of the NAc of male mice during a week-long morphine treatment paradigm. We measured dopamine release in response to an intravenous morphine injection both acutely and following a week of repeated morphine. We also measured dopamine in response to a naloxone injection both prior to and following repeated morphine treatment. Morphine induced a transient increase in dopamine in the medial NAc shell that was much larger than the slower rise observed in the lateral shell. Surprisingly, chronic morphine treatment induced a sensitization of the medial dopamine response to morphine that opposed a diminished response observed in the saline-treated control group. This study expands on our current understanding of the medial NAc shell as hub of opioid-induced dopamine fluctuation. It also highlights the need for future opioid studies to appreciate the heterogeneity of dopamine neurons.

Frontal-posterior loop integrating captured attention into visual consciousness in the human brain
The emergence of subjective consciousness in the brain remains a profound puzzle, with attention at its core. Despite enduring debates on whether consciousness requires attention, the mechanisms by which attention becomes integrated into consciousness have been insufficiently explored. Here we show it is the bottom-up captured attention rather than top-down supplied attention that contributes to conscious experience, and revealed landmark neural dynamics underlying this process. Combining psychophysics with intracranial electroencephalography (iEEG) data from 21 epilepsy patients, we examined consciousness-related neural activity (visible versus invisible) under conditions of both poor and sufficient integration of attention into consciousness. In scenarios where attention was poorly integrated, we observed sustained and homogeneous neural representations in the posterior brain, despite its functional disconnection from the frontal brain. This observation supports the proposal of a preconscious buffer state situated between unconscious and conscious states. Conversely, in scenarios where attention was sufficiently integrated into consciousness, even before frontal-posterior coupling was established (thus still in a preconscious state), supplied attention primed the entire brain for subsequent attentional integration. This priming involved selecting signals-to-be-perceived by the posterior brain and stabilizing attentional supply by the frontal brain. Subsequently, the functional coupling between the frontal and posterior brain formed a closed loop. Notably, within this loop, what continuously broadcasted were coarse-grained binary signals of consciousness emergence, opposing views attributing consciousness to the global broadcasting of fine-grained contents. These findings show what and how attention gets integrated into visual consciousness, and the resulting outcomes call for a significant revision of current theories of consciousness. In response, we propose an attentional integration model of consciousness (AIM) aimed at reconciling the sharp discrepancies in this field.

Layer-specific reorganization of mnemonic representations in primate retrosplenial cortex during learning
Rapid learning of associations between co-occurring stimuli is essential for episodic memory formation. The retrosplenial cortex (RSC) is strongly interconnected with the hippocampus, and in rodents, the RSC has been shown to support spatial navigation and fear conditioning. Although lesion and neuroimaging studies in humans and macaques have further implicated the RSC in episodic memory, it is unclear how memory representations form and evolve in the RSC. Here we show that representations of memorized contexts in primate RSC form within minutes. These initial representations reorganize as the memory matures, with a shift in the weight of neuronal contributions from superficial to deep RSC layers across an hour and increased local connectivity between deep layer neurons. Because RSC superficial and deep layers represent input and output layers respectively, it suggests that hippocampal inputs provide context information to superficial layers during early learning, and this context information consolidates in deep RSC layers.

Modular organization of synapses within a neuromere for distinct axial locomotion in Drosophila larvae
The ability to generate diverse patterns of behavior is advantageous for animal survival. However, it is still unclear how interneurons in a single nervous system are organized to exhibit distinct motions by coordinating the same set of motor neurons. In this study, we analyze the populational dynamics of synaptic activity when fly larvae exhibit two distinct fictive locomotion, forward and backward waves. Based on neurotransmitter phenotypes, the hemi-neuromere is demarcated into ten domains. Calcium imaging analysis shows that one pair of the domains exhibits a consistent recruitment order in synaptic activity in forward and backward waves, while most other domains show the opposite orders in the distinct fictive locomotion. Connectomics-based mapping indicates that these two domains contain pre- and post-synaptic terminals of interneurons involved in motor control. These results suggest that the identified domains serve as a convergence region of forward and backward crawling programs.

The Surgical Method of Craniectomy Differentially Affects Acute Seizures, Brain Deformation and Behavior in a TBI Animal Model
Traumatic brain injury (TBI) is the leading cause of morbidity and mortality worldwide. Multiple injury models have been developed to study this neurological disorder. One such model is the lateral fluid-percussion injury (LFPI) rodent model. The LFPI model can be generated with different surgical procedures that could affect the injury and be reflected in neurobehavioral dysfunction and acute EEG changes. A craniectomy was performed either with a trephine hand drill or with a trephine electric drill that was centered over the left hemisphere of adult, male Sprague Dawley rats. Sham craniectomy groups were assessed by hand-drilled (ShamHMRI) and electric-drilled (ShamEMRI) to evaluate by MRI. Then, TBI was induced in separate groups (TBIH) and (TBIE) using a fluid-percussion device. Sham-injured rats (ShamH/ShamE) underwent the same surgical procedures as the TBI rats. During the same surgery session, rats were implanted with screw and microwire electrodes positioned in the neocortex and hippocampus and the EEG activity was recorded 24 hours for the first 7 days after TBI for assessing the acute EEG seizure and Gamma Event Coupling (GEC). The electric drilling craniectomy induced greater tissue damage and sensorimotor deficits compared to the hand drill. Analysis of the EEG revealed acute seizures in at least one animal from each group after the procedure. Both TBI and Sham rats from the electric drill groups had a significant greater total number of seizures than the animals that were craniectomized manually (p<0.05). Similarly, EEG functional connectivity was lower in ShamE compared to ShamH rats. These results suggest that electrical versus hand drilling craniectomies produce cortical injury in addition to the LFPI which increases the likelihood for acute post-traumatic seizures. Differences in the surgical approach could be one reason for the variability in the injury that makes it difficult to replicate results between preclinical TBI studies.

Assessing data quality on fetal brain MRI reconstruction: a multi-site and multi-rater study
Quality assessment (QA) has long been considered essential to guarantee the reliability of neuroimaging studies. It is particularly important for fetal brain MRI, where unpredictable fetal motion can lead to substantial artifacts in the acquired images. Multiple images are then combined into a single volume through super-resolution reconstruction (SRR) pipelines, a step that can also introduce additional artifacts. While multiple studies designed automated quality control pipelines, no work evaluated the reproducibility of the manual quality ratings used to train these pipelines. In this work, our objective is twofold. First, we assess the inter- and intra-rater variability of the quality scoring performed by three experts on over 100 SRR images reconstructed using three different SRR pipelines. The raters were asked to assess the quality of images following 8 specific criteria like blurring or tissue contrast, providing a multi-dimensional view on image quality. We show that, using a protocol and training sessions, artifacts like bias field and blur level still have a low agreement (ICC below 0.5), while global quality scores show very high agreement (ICC = 0.9) across raters. We also observe that the SRR methods are influenced differently by factors like gestational age, input data quality and number of stacks used by reconstruction. Finally, our quality scores allow us to unveil systematic weaknesses of the different pipelines, indicating how further development could lead to more robust, well rounded SRR methods.

Mixed recurrent connectivity architecture in primate prefrontal cortex
The functional properties of a network depend on its connectivity, which includes the strength of its inputs and the strength of the connections between its units, or recurrent connectivity. Because we lack a detailed description of the recurrent connectivity in the lateral prefrontal cortex of primates, we developed an indirect method to estimate it. This method leverages the elevated noise correlation of mutually-connected units. To estimate the connectivity of prefrontal regions, we trained recurrent neural network models with varying percentages of bump attractor architecture and noise levels to match the noise correlation properties observed in two specific prefrontal regions: the dorsolateral prefrontal cortex and the frontal eye field. We found that models initialized with approximately 20% and 7.5% bump attractor architecture closely matched the noise correlation properties of the frontal eye field and dorsolateral prefrontal cortex, respectively. These findings suggest that the different percentages of bump attractor architecture may reflect distinct functional roles of these brain regions. Specifically, lower percentages of bump attractor units, associated with higher-dimensional representations, likely support more abstract neural representations in more anterior regions.

Rod-shaped microglia interact with neuronal dendrites to regulate cortical excitability in TDP-43 related neurodegeneration
Motor cortical hyperexcitability is well-documented in the presymptomatic stage of amyotrophic lateral sclerosis (ALS). However, the mechanisms underlying this early dysregulation are not fully understood. Microglia, as the principal immune cells of the central nervous system, have emerged as important players in sensing and regulating neuronal activity. Here we investigated the role of microglia in the motor cortical circuits in a mouse model of TDP-43 neurodegeneration (rNLS8). Utilizing multichannel probe recording and longitudinal in vivo calcium imaging in awake mice, we observed neuronal hyperactivity at the initial stage of disease progression. Spatial and single-cell RNA sequencing revealed that microglia are the primary responders to motor cortical hyperactivity. We further identified a unique subpopulation of microglia, rod-shaped microglia, which are characterized by a distinct morphology and transcriptional profile. Notably, rod-shaped microglia predominantly interact with neuronal dendrites and excitatory synaptic inputs to attenuate motor cortical hyperactivity. The elimination of rod-shaped microglia through TREM2 deficiency increased neuronal hyperactivity, exacerbated motor deficits, and further decreased survival rates of rNLS8 mice. Together, our results suggest that rod-shaped microglia play a neuroprotective role by attenuating cortical hyperexcitability in the mouse model of TDP-43 related neurodegeneration.

Cerebral Microvascular Density, Permeability of the Blood-Brain Barrier, and Neuroinflammatory Responses Indicate Early Aging Characteristics in a Marfan Syndrome Mouse Model
Marfan Syndrome (MFS) is a connective tissue disorder due to mutations in fibrillin-1 (Fbn1), where a Fbn1 missense mutation (Fbn1C1039G/+) can result in systemic increases in the bioavailability and signaling of transforming growth factor-{beta} (TGF-{beta}). In a well-established mouse model of MFS (Fbn1C1041G/+), pre-mature aging of the aortic wall and the progression of aortic root aneurysm are observed by 6-months-of-age. TGF-{beta} signaling has been implicated in cerebrovascular dysfunction, loss of blood-brain barrier (BBB) integrity, and age-related neuroinflammation. We have reported that pre-mature vascular aging in MFS mice could extend to cerebrovasculature, where peak blood flow velocity in the posterior cerebral artery (PCA) of 6-month-old (6M) MFS mice was reduced, similarly to 12-month-old (12M) control mice. Case studies of MFS patients have documented neurovascular manifestations, including intracranial aneurysms, stroke, arterial tortuosity, as well as headaches and migraines, with reported incidence of pain and chronic fatigue. Despite these significant clinical observations, investigation into cerebrovascular dysfunction and neuropathology in MFS remains limited. Using 6M-control (C57BL/6) and 6M-MFS (Fbn1C1041G/+) and healthy 12M-control male and female mice, we test the hypothesis that abnormal Fbn1 protein expression is associated with altered cerebral microvascular density, BBB permeability, and neuroinflammation in the PCA-perfused hippocampus, all indicative of a pre-mature aging brain phenotype.

Using Glut1 staining, 6M-MFS mice and 12M-CTRL similarly present decreased microvascular density in the dentate gyrus (DG), cornu ammonis 1 (CA1), and cornu ammonis 3 (CA3) regions of the hippocampus. 6M-MFS mice exhibit increased BBB permeability in the DG, CA1, and CA3 as evident by Immunoglobulin G (IgG) staining, which was more comparable to 12M-CTRL mice. 6M-MFS mice show a higher number of microglia in the hippocampus compared to age-matched control mice, a pattern resembling that of 12M-CTRL mice.

This study represents the first known investigation into neuropathology in a mouse model of MFS and indicates that the pathophysiology underlying MFS leads to a systemic pre-mature aging phenotype. This study is crucial for identifying and understanding MFS-associated neurovascular and neurological abnormalities, underscoring the need for research aimed at improving the quality of life and managing pre-mature aging symptoms in MFS and related connective tissue disorders.

Axonal Tau sorting depends on the PRR2 domain and 0N4R-specific interactions hint at distinct roles of Tau isoforms in synaptic plasticity
Tau pathology is a major hallmark of Alzheimers disease (AD) and related diseases, called tauopathies. While Tau is normally enriched in axons, somatodendritic missorting of the microtubule-associated protein is a key event in early disease development. Tau missorting promotes synaptic loss and neuronal dysfunction but the mechanisms underlying both normal axonal sorting and pathological missorting remain unclear. Interestingly, the disease-associated Tau brain isoforms show different axodendritic distribution, but the distinct role of these isoforms in health and disease largely unknown. Here, we aimed to identify domains or motifs of Tau and cellular binding partners that are required for efficient axonal Tau sorting, and we studied the differences of the isoform-specific Tau interactome. By using human MAPT-KO induced pluripotent stem cell (iPSC)-derived glutamatergic neurons, we analyzed the sorting behavior of more than 20 truncated or phosphorylation-mutant Tau constructs, and we used TurboID-based proximity labelling and proteomics to identify sorting- and isoform-specific Tau interactors. We found that efficient axonal Tau sorting was independent of the N-terminal tail, the C-terminal repeat domains, and the general microtubule affinity of Tau. In contrast, the presence of the proline-rich region 2 (PRR2) was necessary for successful sorting. Our interactome data revealed peroxisomal accumulation of the Tau N-terminal half, while axonal Tau interacted with the PP2A activator HSP110. When we compared the interactome of 0N3R- and 0N4R-Tau, we observed specific interactions of 0N4R-Tau with regulators of presynaptic exocytosis and postsynaptic plasticity, which are partially associated with AD pathogenesis, such as members of the CDC42 pathway and the RAB11 proteins, while 0N3R-Tau bound to MAP4 and other cytoskeletal elements. In sum, our study postulates that axonal Tau sorting relies on the PRR2 domain but not on microtubule affinity, and unravels a potential isoform-specific role in synaptic function and AD-related dysfunction.

Towards a simplified model of primary visual cortex
Artificial neural networks (ANNs) have been shown to predict neural responses in primary visual cortex (V1) better than classical models. However, this performance comes at the expense of simplicity because the ANN models typically have many hidden layers with many feature maps in each layer. Here we show that ANN models of V1 can be substantially simplified while retaining high predictive power. To demonstrate this, we first recorded a new dataset of over 29,000 neurons responding to up to 65,000 natural image presentations in mouse V1. We found that ANN models required only two convolutional layers for good performance, with a relatively small first layer. We further found that we could make the second layer small without loss of performance, by fitting a separate "minimodel" to each neuron. Similar simplifications applied for models of monkey V1 neurons. We show that these relatively simple models can nonetheless be useful for tasks such as object and visual texture recognition and we use the models to gain insight into how texture invariance arises in biological neurons.

Anatomical and functional analysis of the corticospinal tract in an FRDA mouse model
Friedreich's ataxia (FRDA) is one of the most common hereditary ataxias. It is caused by a GAA repeat in the first intron of the FXN gene, which encodes an essential mitochondrial protein. Patients suffer from progressive motor dysfunction due to the degeneration of mechanoreceptive and proprioceptive neurons in dorsal root ganglia (DRG) and cerebellar dentate nucleus neurons, especially at early disease stages. Postmortem analyses of FRDA patients also indicate pathological changes in motor cortex including in the projection neurons that give rise to the cortical spinal tract (CST). Yet, it remains poorly understood how early in the disease cortical spinal neurons (CSNs) show these alterations, or whether CSN/CST pathology resembles the abnormalities observed in other tissues affected by FXN loss. To address these questions, we examined CSN driven motor behaviors and pathology in the YG8JR FRDA mouse model. We find that FRDA mice show impaired motor skills, exhibit significant reductions in CSN functional output, and, among other pathological changes, show abnormal mitochondrial distributions in CSN neurons and CST axonal tracts. Moreover, some of these alterations were observed as early as two months of age, suggesting that CSN/CST pathology may be an earlier event in FRDA disease than previously appreciated. These studies warrant a detailed mechanistic understanding of how FXN loss impacts CSN health and functionality.

Critical roles of ERK and Akt signaling in metabolically dependent memory formation in Drosophila larvae.
In the fruit fly Drosophila, memory formation is intricately linked to metabolic state. Our previous findings showed that the preferential support of memory under increased energy levels is mediated by the insulin receptor in the mushroom body (MB), a key memory center in the insect brain. This study analyzed the role of the insulin receptors downstream pathways, Ras-Raf-MEK-ERK and PI3K/Akt, in metabolically dependent memory formation. We evaluated their impact on memory processes by employing RNA interference-mediated downregulation of key components, extracellular signal-regulated kinase (ERK) and protein kinase B (Akt), in the MB of Drosophila larvae. To enhance energy levels, larvae were fed sugar for 60 minutes prior to aversive olfactory conditioning. Our findings revealed that genetically downregulating ERK and Akt in the MB significantly impaired metabolically dependent memory formation, without affecting naive sensory perception or olfactory learning. Immunohistochemical analysis confirmed the presence of active forms of ERK and Akt in the MB, underscoring their roles in modulating memory processes under elevated energy levels. The pivotal roles of these kinases suggest a broader implication of insulin signaling in memory formation under different metabolic conditions, and illuminate the connections between metabolic regulation and memory dynamics in the MB.

Responses to visual motion of neurons in the extrastriate visual cortex of macaque monkeys with experimental amblyopia
Amblyopia is a developmental disorder that results from abnormal visual experience in early life. Amblyopia typically reduces visual performance in one eye. We studied the representation of visual motion information in area MT and nearby extrastriate visual areas in two monkeys made amblyopic by creating an artificial strabismus in early life, and in a single age-matched control monkey. Tested monocularly, cortical responses to moving dot patterns, gratings, and plaids were qualitatively normal in awake, fixating amblyopic monkeys, with primarily subtle differences between the eyes. However, the number of binocularly driven neurons was substantially lower than normal; of the neurons driven predominantly by one eye, the great majority responded only to stimuli presented to the fellow eye. The small population driven by the amblyopic eye showed reduced coherence sensitivity and a preference for faster speeds in much the same way as behavioral deficits. We conclude that, while we do find important differences between neurons driven by the two eyes, amblyopia does not lead to a large scale reorganization of visual receptive fields in the dorsal stream when tested through the amblyopic eye, but rather creates a substantial shift in eye preference toward the fellow eye.

Myelin-informed forward models for M/EEG source reconstruction
Magnetoencephalography (MEG) and Electroencephalography (EEG) provide direct electrophysiological measures at an excellent temporal resolution, but the spatial resolution of source-reconstructed current activity is limited to several millimetres. Here we show, using simulations of MEG signals and Bayesian model comparison, that non-invasive myelin estimates from high-resolution quantitative magnetic resonance imaging (MRI) can enhance MEG/EEG source reconstruction. Our approach assumes that MEG/EEG signals primarily arise from the synchronised activity of pyramidal cells, and since most of the myelin in the cortical sheet originates from these cells, myelin density can predict the strength of cortical sources measured by MEG/EEG. Leveraging recent advances in quantitative MRI, we exploit this structure-function relationship and scale the leadfields of the forward model according to the local myelin density estimates from in vivo quantitative MRI to inform MEG/EEG source reconstruction. Using Bayesian model comparison and dipole localisation errors (DLEs), we demonstrate that adapting local forward fields to reflect increased local myelination at the site of a simulated source explains the simulated data better than models without such leadfield scaling. Our model comparison framework proves sensitive to myelin changes in simulations with exact coregistration and moderate-to-high sensor-level signal-to-noise ratios ([≥]10 dB) for the multiple sparse priors (MSP) and empirical Bayesian beamformer (EBB) approaches. Furthermore, we sought to infer the microstructure giving rise to specific functional activation patterns by comparing the myelin-informed model which was used to generate the activation with a set of test forward models incorporating different myelination patterns. We found that the direction of myelin changes, however not their magnitude, can be inferred by Bayesian model comparison. Finally, we apply myelin-informed forward models to MEG data from a visuo-motor experiment. We demonstrate improved source reconstruction accuracy using myelin estimates from a quantitative longitudinal relaxation (R1) map and discuss the limitations of our approach.

Self-organizing recruitment of compensatory areas maximizes residual motor performance post-stroke
Whereas the orderly recruitment of compensatory motor cortical areas after stroke depends on the size of the motor cortex lesion affecting arm and hand movements, the mechanisms underlying this reorganization are unknown. Here, we hypothesized that the recruitment of compensatory areas results from the motor system's goal to optimize performance given the anatomical constraints before and after the lesion. This optimization is achieved through two complementary plastic processes: a homeostatic regulation process, which maximizes information transfer in sensory-motor networks, and a reinforcement learning process, which minimizes movement error and effort. To test this hypothesis, we developed a neuro-musculoskeletal model that controls a 7-muscle planar arm via a cortical network that includes a primary motor cortex and a premotor cortex that directly project to spinal motor neurons, and a contra-lesional primary motor cortex that projects to spinal motor neurons via the reticular formation. Synapses in the cortical areas are updated via reinforcement learning and the activity of spinal motor neurons is adjusted through homeostatic regulation. The model replicated neural, muscular, and behavioral outcomes in both non-lesioned and lesioned brains. With increasing lesion sizes, the model demonstrated systematic recruitment of the remaining primary motor cortex, premotor cortex, and contra-lesional cortex. The premotor cortex acted as a reserve area for fine motor control recovery, while the contra-lesional cortex helped avoid paralysis at the cost of poor joint control. Plasticity in spinal motor neurons enabled force generation after large cortical lesions despite weak corticospinal inputs. Compensatory activity in the premotor and contra-lesional motor cortex was more prominent in the early recovery period, gradually decreasing as the network minimized effort. Thus, the orderly recruitment of compensatory areas following strokes of varying sizes results from biologically plausible local plastic processes that maximize performance, whether the brain is intact or lesioned.

Transdiagnostic Neurobiology of Social Cognition and Individual Variability as Measured by Fractional Amplitude of Low-Frequency Fluctuation in Schizophrenia and Autism Spectrum Disorders
Fractional amplitude of low-frequency fluctuation (fALFF) is a validated measure of resting-state spontaneous brain activity. Previous fALFF findings in autism and schizophrenia spectrum disorders (ASDs and SSDs) have been highly heterogeneous. We aimed to use fALFF in a large sample of typically developing control (TDC), ASD and SSD participants to explore group differences and relationships with inter-individual variability of fALFF maps and social cognition. fALFF from 495 participants (185 TDC, 68 ASD, and 242 SSD) was computed using functional magnetic resonance imaging as signal power within two frequency bands (i.e., slow-4 and slow-5), normalized by the power in the remaining frequency spectrum. Permutation analysis of linear models was employed to investigate the relationship of fALFF with diagnostic groups, higher-level social cognition, and lower-level social cognition. For each participant, the average distance of fALFF map to all others was defined as a variability score, with higher scores indicating less typical maps. Lower fALFF in the visual and higher fALFF in the frontal regions were found in both SSD and ASD participants compared with TDCs. Limited differences were observed between ASD and SSD participants in the cuneus regions only. Associations between slow-4 fALFF and higher-level social cognitive scores across the whole sample were observed in the lateral occipitotemporal and temporoparietal junction. Individual variability within the ASD and SSD groups was also significantly higher compared with TDC. Similar patterns of fALFF and individual variability in ASD and SSD suggest some common neurobiological deficits across these related heterogeneous conditions.

A 3.5-minute-long reading-based fMRI localizer for the language network
The field of human cognitive neuroscience is increasingly acknowledging inter-individual differences in the precise locations of functional areas and the corresponding need for individual-level analyses in fMRI studies. One approach to identifying functional areas and networks within individual brains is based on robust and extensively validated 'localizer' paradigms--contrasts of conditions that aim to isolate some mental process of interest. Here, we present a new version of a localizer for the fronto-temporal language-selective network. This localizer is similar to a commonly-used localizer based on the reading of sentences and nonword sequences (Fedorenko et al., 2010) but uses speeded presentation (200ms per word/nonword). Based on a direct comparison between the standard version (450ms per word/nonword) and the speeded versions of the language localizer in 24 participants, we show that a single run of the speeded localizer (3.5 min) is highly effective at identifying the language-selective areas: indeed, it is more effective than the standard localizer given that it leads to an increased response to the critical (sentence) condition and a decreased response to the control (nonwords) condition. This localizer may therefore become the version of choice for identifying the language network in neurotypical adults or special populations (as long as they are proficient readers), especially when time is of essence.

Enhanced purinergic signaling in the paraventricular hypothalamus induces hyperphagic obesity and insulin resistance
Body energy homeostasis is tightly regulated by hypothalamic neural circuits. However, their remodeling upon metabolic stress remains incompletely characterized, translating to unprecedented challenges to develop safe medications against the surge of metabolic diseases. Oxytocin (OXT) neurons in the paraventricular nucleus of the hypothalamus (PVH) are one of the key appetite-suppressing effectors within the melanocortin system. In this work, we report that metabolic stress in mice evokes spatiotemporally selective ATP release (Inflares) from PVH astrocytes, accompanied with the expression of hematopoietic lineage-specific ADP/ATP receptor P2Y12 on OXT (PVHOXT) neurons. Importantly, "ectopic" emergence of P2Y12 on OXT neurons of patients with diabetes mellitus suggests an evolutionary conserved purinergic response to metabolic stress. Strikingly, increased purinergic signaling leads to impaired responsiveness of PVHOXT neurons accompanied with hyperphagic obesity and insulin resistance in mice. Moreover, nasal administration of clinically approved doses of P2Y12 inhibitors counteracts diet-induced obesity and insulin resistance in mice and spontaneous weight gain in monkeys, paving the way for their application in patients with metabolic disorders.

Sex-specific loss of mitochondrial membrane integrity and mass in the auditory brainstem of a mouse model of Fragile X syndrome
Sound sensitivity is one of the most common sensory complaints for people with autism spectrum disorders (ASDs). How and why sounds are perceived as overwhelming by affected people is unknown. To process sound information properly, the brain requires high activity and fast processing, as seen in areas like the medial nucleus of the trapezoid body (MNTB) of the auditory brainstem. Recent work has shown dysfunction in mitochondria, which are the primary source of energy in cells, in a genetic model of ASD, Fragile X syndrome (FXS). Whether mitochondrial functions are also altered in sound-processing neurons, has not been characterized yet. To address this question, we imaged the MNTB in a mouse model of FXS. We stained MNTB brain slices from wild-type and FXS mice with two mitochondrial markers, TOMM20 and PMPCB, located on the Outer Mitochondrial Membrane and in the matrix, respectively. These markers allow exploration of mitochondrial subcompartments. Our integrated imaging pipeline reveals significant sex-specific differences in the degree of mitochondrial length in FXS. Significant differences are also observable in the overall number of mitochondria in male FXS mice, however, colocalization analyses between TOMM20 and PMPCB reveal that the integrity of these compartments is most disrupted in female FXS mice. We highlight a quantitative fluorescence microscopy pipeline to monitor mitochondrial functions in the MNTB from control or FXS mice and provide four complementary readouts. Our approach paves the way to understanding how cellular mechanisms important to sound encoding are altered in ASDs.

1.94 Angstrom structure of synthetic alpha-synuclein fibrils seeding MSA neuropathology
Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease of unknown etiology, typically affecting individuals aged 50-60 and leading to patient death within a decade. Characterized by the presence of oligodendroglial intracellular aggregates (GCIs) primarily composed of fibrillar alpha-synuclein (aSyn), formation of MSA neuropathology presents similarities to prion propagation. While previous investigations have scrutinized fibrils extracted from MSA brains11, their 'protein-only' replication was questioned and their capacity to induce GCIs in animal models was not explored. Conversely, the synthetic fibril strain 1B assembled from recombinant human aSyn self-replicates autonomously in vitro and induces GCIs in mice, suggesting relevance to MSA. Here we report the high-resolution structural analysis of the 1B fibrils revealing similarities with human brain extracted MSA aSyn filaments, particularly the lack of a specific Thioflavin T (ThT) binding pocket. In addition, 1B causes sustained intracerebral GCI spread over the years, prompt lethality in transgenic mice, and transmission of inclusion pathology to wild-type animals after crude brain homogenate inoculation. This points to an underlying prion-like seeding process which we demonstrate in situ using correlative light-electron microscopy. Our findings underscore structural features of aSyn fibrils pivotal for MSA pathogenesis and provide insights for therapeutic development.

Unsilenced inhibitory cortical ensemble gates remote memory retrieval
Acquired information can be consolidated to remote memory for storage but persists in a dormant state until its retrieval. However, it remains unknown how dormant memory is reactivated. Using a combination of simultaneous two-photon calcium imaging and holographic optogenetics in the anterior cingulate cortex (ACC) in vivo, we discover a subset of GABAergic neurons that are specifically associated with dormant memory retrieval. These interneurons display persistent activity and inter-neuronal synchronization at the remote memory stage. In the absence of natural contextual cues, directly activating these interneurons reliably recalls cortical ensembles relevant to remote memory retrieval with context specificity. Conversely, targeted volumetric inactivation of these neurons suppresses context-induced memory retrieval. Our results reveal an unexpected role of unsilenced inhibitory cortical ensembles in causally gating the retrievability of dormant remote memory.

Orthogonalization of spontaneous and stimulus-driven activity by hierarchical neocortical areal network in primates
Understanding how biological neural networks perform reliable information processing in the presence of intensive spontaneous activity (1-3) is an essential question in biological computation. Stimulus-evoked and spontaneous activities show orthogonal (dissimilar) patterns in the primary visual cortex (V1) of mice (4-6), which is likely to be beneficial for separating sensory signals from internally generated noise (5, 7-12); however, those in V1 of carnivores and primates show highly similar patterns (3, 13-17). Consequently, the mechanism of segregation of stimulus information and internally generated noise in carnivores and primates remain unclear. To address this question, we used primate-optimized functional imaging (18) to precisely compare spontaneous and stimulus-evoked activities in multiple areas of the marmoset visual cortical pathway (19). In marmoset V1, but not in mouse V1, spontaneous and stimulus-evoked activity shared similar activity patterns, suggesting a function of spontaneous activity specific to mammals with functional columns. However, in the higher-order visual areas of marmosets, spontaneous and stimulus-evoked activities exhibited dissimilar patterns. Analysis of neural activity geometry further revealed progressive orthogonalization of the two types of activities along the cortical hierarchy in marmosets, which reached a level comparable to that of mouse V1. Thus, orthogonalization of spontaneous and stimulus-evoked activity is a general principle of cortical computation, which, in primates, is implemented by the hierarchical areal network.

A novel behavioral paradigm using mice to study predictive postural control
Postural control circuitry performs the essential function of maintaining balance and body position in response to perturbations that are either self-generated (e.g. reaching to pick up an object) or externally delivered (e.g. being pushed by another person). Human studies have shown that anticipation of predictable postural disturbances can modulate such responses. This indicates that postural control could involve higher-level neural structures associated with predictive functions, rather than being purely reactive. However, the underlying neural circuitry remains largely unknown. To enable studies of predictive postural control circuits, we developed a novel task for mice. In this task, modeled after human studies, a dynamic platform generated reproducible translational perturbations. While mice stood bipedally atop a perch to receive water rewards, they experienced backward translations that were either unpredictable or preceded by an auditory cue. To validate the task, we investigated the effect of the auditory cue on postural responses to perturbations across multiple days in three mice. These preliminary results serve to validate a new postural control model, opening the door to the types of neural recordings and circuit manipulations that are currently possible only in mice.

Startling acoustic stimuli hasten choice reaching tasks by strengthening, but not changing the timing of, express visuomotor responses
Responding to an external stimulus takes ~200 ms, but this can be shortened to as little as ~120 ms with the additional presentation of a startling acoustic stimulus. This StartReact phenomenon is hypothesized to arise from the involuntary release of a fully prepared movement. However, a startling acoustic stimulus also expedites rapid mid-flight, reactive adjustments to unpredictably displaced targets which could not have been prepared in advance. We surmise that for such rapid visuomotor transformations, intersensory facilitation may occur between auditory signals arising from the startling acoustic stimulus and visual signals relayed along a fast subcortical network. To explore this, we examined the StartReact phenomenon in a task that produces express visuomotor responses, which are brief bursts of muscle activity that arise from a fast tectoreticulospinal network. We measured express visuomotor responses on upper limb muscles in humans as they reached either toward or away from a stimulus in blocks of trials where movements could either be fully prepared or not, occasionally pairing stimulus presentation with a startling acoustic stimulus. The startling acoustic stimulus reliably produced larger but fixed-latency express visuomotor responses in a target-selective manner. Consistent with the StartReact phenomenon, it shortened reaction times, which were as fast for prepared and unprepared movements. Our results confirm that the StartReact phenomenon can be elicited for reactive movements without any motor preparation, consistent with intersensory facilitation. We propose the reticular formation to be the likely node for intersensory convergence during the most rapid transformations of vision into targeted reaching actions.

The Neurolipid Atlas: a lipidomics resource for neurodegenerative diseases uncovers cholesterol as a regulator of astrocyte reactivity impaired by ApoE4
Lipid changes in the brain have been implicated in many neurodegenerative diseases including Alzheimer's Disease (AD), Parkinson's disease and Amyotrophic Lateral Sclerosis. To facilitate comparative lipidomic research across brain-diseases we established a data commons named the Neurolipid Atlas, that we have pre-populated with novel human, mouse and isogenic induced pluripotent stem cell (iPSC)-derived lipidomics data for different brain diseases. We show that iPSC-derived neurons, microglia and astrocytes display distinct lipid profiles that recapitulate in vivo lipotypes. Leveraging multiple datasets, we show that the AD risk gene ApoE4 drives cholesterol ester (CE) accumulation in human astrocytes recapitulating CE accumulation measured in the human AD brain. Multi-omic interrogation of iPSC-derived astrocytes revealed that cholesterol plays a major role in astrocyte interferon-dependent pathways such as the immunoproteasome and major histocompatibility complex (MHC) class I presentation. We show that through enhanced cholesterol esterification ApoE4 suppresses immune activation of astrocytes. Our novel data commons, available at neurolipidatlas.com, provides a user-friendly tool and knowledge base for a better understanding of lipid dyshomeostasis in neurodegenerative diseases.

Cognitive neuropsychological and neuroanatomic predictors of naturalistic action performance in left hemisphere stroke: a retrospective analysis
Individuals who have experienced a left hemisphere cerebrovascular accident (LCVA) have been shown to make errors in naturalistic action tasks designed to assess the ability to perform everyday activities such as preparing a cup of coffee. Naturalistic action errors in this population are often attributed to limb apraxia, a common deficit in the representation and performance of object-related actions. However, naturalistic action impairments are also observed in right hemisphere stroke and traumatic brain injury, populations infrequently associated with apraxia, and errors across all these populations are influenced by overall severity. Based on these and other data, an alternative (though not mutually exclusive) account is that naturalistic action errors in LCVA are also a consequence of deficits in general attentional resource availability or allocation. In this study, we conducted a retrospective analysis of data from a large group of 51 individuals with LCVA who had completed a test of naturalistic action, along with a battery of tests assessing praxis, attention allocation and control, reasoning, and language abilities to determine which of these capacities contribute uniquely to naturalistic action impairments. Using a regularized regression method, we found that naturalistic action impairments are predicted by both praxis deficits (hand posture sequencing and gesture recognition), as well as attention allocation and control deficits (orienting and dividing attention), along with language comprehension ability and age. Using support vector regression-lesion symptom mapping (SVR-LSM), we also demonstrated that naturalistic action impairments are associated with lesions to posterior middle temporal gyrus and anterior inferior parietal lobule regions known to be implicated in praxis; as well the middle frontal gyrus that has been implicated in both praxis and attention allocation and control. Taken together, these findings support the hypothesis that naturalistic action impairments in LCVA are a consequence of apraxia as well as deficits in attention allocation and control.

Neural correlates of nightmares revisited: findings from large-scale fMRI cohorts
Study Objectives: Nightmares are linked to daytime distress and psychiatric and neurological disorders. However, knowledge about the brain regions involved in nightmare production is sparse. This study aimed to examine the relationship between nightmare frequency and the functional connectivity of the amygdala with the prefrontal cortex, which is central to emotional regulation. Additionally, the study sought to replicate previous findings on the neural correlates of nightmares using two large cohorts. Methods: 464 participants underwent functional and structural MRI recordings and answered questions assessing nightmare and dream recall frequency. A general linear model assessed the voxelwise correlation between the amygdala-prefrontal cortex connectivity with nightmare frequency. Additionally, regional homogeneity (ReHo) maps were calculated, high and low nightmare frequency and the entire nightmare frequency spectrum contrasts were determined while controlling for age, sex, and dream recall frequency. Results: The study did not find a significant correlation between nightmare frequency and amygdala-prefrontal cortex connectivity. Previous ReHo findings of group differences between high and low nightmare frequency could not be replicated. However, parametric analysis revealed an association between nightmare frequency and ReHo differences in the cerebellum. Conclusions: This failure to confirm hypothesized and previously reported results, especially with a larger sample size, suggests a need to reevaluate the existing knowledge of the neural correlates of nightmares and consider individual differences such as personality, trauma history, and cognitive processes. Overall, our findings highlight the complexities of interpreting neuroimaging data in sleep research.

Preparatory attentional templates in prefrontal and sensory cortex encode target-associated information
Visual search relies on the ability to use information about the target in working memory to guide attention and make target-match decisions. This memory representation is referred to as the "attentional" or "target" template and is typically thought to contain veridical target information. However, more recent studies have shown that in complex visual environments, target-associated information is often used to guide attention (Battistoni et al., 2017; de Lange et al., 2018; Peelen et al., 2024; Vo et al., 2019; Yu et al., 2023). This is particularly true when the target is difficult to discriminate (Zhou & Geng, 2024). Here, we use fMRI and multivariate pattern analysis, to test if attentional guidance by target-associated information is explicitly represented in the preparatory period before search begins, either in conjunction with the target or even in place of it. Participants were first trained on four face-scene category pairings. After learning, they engaged in a cued visual search task that began with a face cue, followed by a delay, and then a search display with two lateralized faces, each superimposed on a scene image. The target face appeared on its previously associated scene on 75% of "scene-valid" trials. Our results show that in the cue period, face information was decoded in the fusiform face area (FFA), superior parietal lobule (SPL), and dorsolateral prefrontal cortex (dLPFC). However, during the delay period, face information was no longer decoded from FFA; instead, scene information was now decoded in the parahippocampal place area (PPA) and inferior frontal junction (IFJ). These findings demonstrate the dynamic nature of template information during visual search and suggest that target-associated information can be used as a guiding template, even replacing actual target information in the active attentional template.

Single-cell transcriptomic changes in oligodendrocytes and precursors derived from Parkinson's disease patient-iPSCs with LRRK2-G2019S mutation
Despite extensive research, the contribution of the LRRK2 p.G2019S mutation to Parkinson's disease (PD) remains unclear. Recent findings indicate oligodendrocytes (ODCs) and their progenitors are vulnerable in PD pathogenesis. Notably, oligodendrocyte precursor cells (OPCs) exhibit high endogenous expression of LRRK2. We induced PD patient-iPSCs with the LRRK2 p.G2019S mutation into oligodendroglial lineages and performed single-cell RNA sequencing. Cell type composition analysis revealed an increase in OPCs, proliferating OPCs and ciliated ependymal cells in LRRK2 lines, all of which are characterized by LRRK2 expression. Differential expression analysis revealed transcriptomic changes in several pathways, including down-regulation of genes related to myelin assembly in ODCs, semaphorin-plexin pathway in OPCs, and cilium movement in proliferating OPCs. Cell-cell communication analysis identified significant alterations in several signaling pathways including a deactivation of PSAP signaling and an activation of MIF signaling in LRRK2 lines. Additionally, we observed an overall increase in SEMA6 signaling communication in LRRK2 cell lines; however, OPCs derived from these LRRK2 lines specifically lost SEMA6 signaling due to a down-regulation of SEMA6A and PLXNA2. Pseudotemporal trajectory analysis revealed that SHH had significantly altered expression along the pseudotime, accompanied by higher expression levels in LRRK2 lines. These findings highlight the need for a deep exploration of the complex interactions among semaphorin-plexin, sonic hedgehog and cilium pathways in PD. We envision that our work will serve as a valuable resource for uncovering potential targets in PD.