Unraveling the enigmatic role of the subthalamic nucleus.

Subpopulations of neurons in the subthalamic nucleus have distinct activity patterns that relate to the three hypotheses of the Drift Diffusion Model.

The Transdiagnostic Connectome Project: a richly phenotyped open dataset for advancing the study of brain-behavior relationships in psychiatry.

An important aim in psychiatry is the establishment of valid and reliable associations linking profiles of brain functioning to clinically relevant symptoms and behaviors across patient populations. To advance progress in this area, we introduce an open dataset containing behavioral and neuroimaging data from 241 individuals aged 18 to 70, comprising 148 individuals meeting diagnostic criteria for a broad range of psychiatric illnesses and a healthy comparison group of 93 individuals. These data include high-resolution anatomical scans, multiple resting-state, and task-based functional MRI runs. Additionally, participants completed over 50 psychological and cognitive assessments. Here, we detail available behavioral data as well as raw and processed MRI derivatives. Associations between data processing and quality metrics, such as head motion, are reported. Processed data exhibit classic task activation effects and canonical functional network organization. Overall, we provide a comprehensive and analysis-ready transdiagnostic dataset, which we hope will accelerate the identification of illness-relevant features of brain functioning, enabling future discoveries in basic and clinical neuroscience.

A lever hypothesis for Synaptotagmin-1 action in neurotransmitter release.

Neurotransmitter release is triggered in microseconds by Ca2+-binding to the Synaptotagmin-1 C2 domains and by SNARE complexes that form four-helix bundles between synaptic vesicles and plasma membranes, but the coupling mechanism between Ca2+-sensing and membrane fusion is unknown. Release requires extension of SNARE helices into juxtamembrane linkers that precede transmembrane regions (linker zippering) and binding of the Synaptotagmin-1 C2B domain to SNARE complexes through a 'primary interface' comprising two regions (I and II). The Synaptotagmin-1 Ca2+-binding loops were believed to accelerate membrane fusion by inducing membrane curvature, perturbing lipid bilayers or helping bridge the membranes, but SNARE complex binding orients the Ca2+-binding loops away from the fusion site, hindering these putative activities. Molecular dynamics simulations now suggest that Synaptotagmin-1 C2 domains near the site of fusion hinder SNARE action, providing an explanation for this paradox and arguing against previous models of Sytnaptotagmin-1 action. NMR experiments reveal that binding of C2B domain arginines to SNARE acidic residues at region II remains after disruption of region I. These results and fluorescence resonance energy transfer assays, together with previous data, suggest that Ca2+ causes reorientation of the C2B domain on the membrane and dissociation from the SNAREs at region I but not region II. Based on these results and molecular modeling, we propose that Synaptotagmin-1 acts as a lever that pulls the SNARE complex when Ca2+ causes reorientation of the C2B domain, facilitating linker zippering and fast membrane fusion. This hypothesis is supported by the electrophysiological data described in the accompanying paper.

Protein biomarker signature in patients with spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a slowly progressing disease with limited sensitive biomarkers that support clinical research. We analyzed plasma and serum samples from patients with SBMA and matched healthy controls in multiple cohorts, identifying 40 highly reproducible SBMA-associated proteins out of nearly 3,000 measured. These proteins were robustly enriched in gene sets of skeletal muscle expression and processes related to mitochondria and calcium signaling. Many proteins outperformed currently used clinical laboratory tests (e.g., creatine kinase [CK]) in distinguishing patients from controls and in their correlations with clinical and functional traits in patients. Two of the 40 proteins, Ectodysplasin A2 receptor (EDA2R) and Repulsive guidance molecule A (RGMA), were found to be associated with decreased survival and body weight in a mouse model of SBMA. In summary, we identified what we believe to be a robust and novel set of fluid protein biomarkers in SBMA that are linked with relevant disease features in patients and in a mouse model of disease. Changes in these SBMA-associated proteins could be used as an early predictor of treatment effects in clinical trials.

A high-performance general computer cursor control scheme based on a hybrid BCI combining motor imagery and eye-tracking.

This study introduces a novel virtual cursor control system designed to empower individuals with neuromuscular disabilities in the digital world. By combining eye-tracking with motor imagery (MI) in a hybrid brain-computer interface (BCI), the system enhances cursor control accuracy and simplicity. Real-time classification accuracy reaches 87.92% (peak of 93.33%), with cursor stability in the gazing state at 96.1%. Integrated into common operating systems, it enables tasks like text entry, online chatting, email, web surfing, and picture dragging, with an average text input rate of 53.2 characters per minute (CPM). This technology facilitates fundamental computing tasks for patients, fostering their integration into the online community and paving the way for future developments in BCI systems.

Sporadic feeding regulates robust food entrainable circadian clocks in blind cavefish.

The circadian clock represents a key timing system entrained by various periodic signals that ensure synchronization with the environment. Many investigations have pointed to the existence of two distinct circadian oscillators: one regulated by the light-dark cycle and the other set by feeding time. Blind cavefish have evolved under extreme conditions where they completely lack light exposure and experience food deprivation. Here, we have investigated feeding regulated clocks in two cavefish species, the Somalian cavefish Phreatichthys andruzzii and the Mexican cavefish Astyanax mexicanus, in comparison with the surface-dwelling zebrafish Danio rerio. Our results reveal that feeding represents an extremely strong synchronizer for circadian locomotor rhythmicity in subterranean cavefish. Indeed, we showed that consuming just one meal every 4 days is sufficient to entrain circadian rhythmicity in both cavefish species, but not in zebrafish. These profound adaptations to an extreme environment provide insight into the connections between feeding and circadian clocks.

Pleiotropic brain function of whirlin identified by a novel mutation.

Despite some evidence indicating diverse roles of whirlin in neurons, the functional corollary of whirlin gene function and behavior has not been investigated or broadly characterized. A single nucleotide variant was identified from our recessive ENU-mutagenesis screen at a donor-splice site in whirlin, a protein critical for proper sensorineural hearing function. The mutation (head-bob, hb) led to partial intron-retention causing a frameshift and introducing a premature termination codon. Mutant mice had a head-bobbing phenotype and significant hyperactivity across several phenotyping tests. Lack of complementation of head-bob with whirler mutant mice confirmed the head-bob mutation as functionally distinct with compound mutants having a mild-moderate hearing defect. Utilizing transgenics, we demonstrate rescue of the hyperactive phenotype and combined with the expression profiling data conclude whirlin plays an essential role in activity-related behaviors. These results highlight a pleiotropic role of whirlin within the brain and implicate alternative, central mediated pathways in its function.

The virtual multiple sclerosis patient.

Multiple sclerosis (MS) diagnosis typically involves assessing clinical symptoms, MRI findings, and ruling out alternative explanations. While myelin damage broadly affects conduction speeds, traditional tests focus on specific white-matter tracts, which may not reflect overall impairment accurately. In this study, we integrate diffusion tensor immaging (DTI) and magnetoencephalography (MEG) data into individualized virtual brain models to estimate conduction velocities for MS patients and controls. Using Bayesian inference, we demonstrated a causal link between empirical spectral changes and inferred slower conduction velocities in patients. Remarkably, these velocities proved superior predictors of clinical disability compared to structural damage. Our findings underscore a nuanced relationship between conduction delays and large-scale brain dynamics, suggesting that individualized velocity alterations at the whole-brain level contribute causatively to clinical outcomes in MS.

20S proteasome enhancers prevent cytotoxic tubulin polymerization-promoting protein induced α-synuclein aggregation.

Synucleinopathies are a class of neurodegenerative diseases defined by the presence of α-synuclein inclusions. The location and composition of these α-synuclein inclusions directly correlate to the disease pattern. The inclusions in Multiple System Atrophy are located predominantly in oligodendrocytes and are rich in a second protein, p25α. P25α plays a key role in neuronal myelination by oligodendrocytes. In healthy oligodendrocytes, there is little to no α-synuclein present. If aberrant α-synuclein is present, p25α leaves the myelin sheaths and quickly co-aggregates with α-synuclein, resulting in the disruption of the cellular process and ultimately cell death. Herein, we report that p25α is susceptible for 20S proteasome-mediated degradation and that p25α induces α-synuclein aggregation, resulting in proteasome impairment and cell death. In addition, we identified small molecules 20S proteasome enhancers that prevent p25α induced α-synuclein fibrilization, restore proteasome impairment, and enhance cell viability.

Virtual, mixed, and augmented realities: A commentary on their significance in cognitive neuroscience and neuropsychology.

The integration of virtual, mixed, and augmented reality technologies in cognitive neuroscience and neuropsychology represents a transformative frontier. In this Commentary, we conducted a meta-analysis of studies that explored the impact of Virtual Reality (VR), Mixed Reality (MR), and Augmented Reality (AR) on cognitive neuroscience and neuropsychology. Our review highlights the versatile applications of VR, ranging from spatial cognition assessments to rehabilitation for Traumatic Brain Injury. We found that MR and AR offer innovative avenues for cognitive training, particularly in memory-related disorders. The applications extend to addressing social cognition disorders and serving as therapeutic interventions for mental health issues. Collaborative efforts between neuroscientists and technology developers are crucial, with reinforcement learning and neuroimaging studies enhancing the potential for improved outcomes. Ethical considerations, including informed consent, privacy, and accessibility, demand careful attention. Our review identified common aspects of the meta-analysis, including the potential of VR technologies in cognitive neuroscience and neuropsychology, the use of MR and AR in memory research, and the role of VR in neurorehabilitation and therapy.

Sex-specific resilience of neocortex to food restriction.

Mammals have evolved sex-specific adaptations to reduce energy usage in times of food scarcity. These adaptations are well described for peripheral tissue, though much less is known about how the energy-expensive brain adapts to food restriction, and how such adaptations differ across the sexes. Here, we examined how food restriction impacts energy usage and function in the primary visual cortex (V1) of adult male and female mice. Molecular analysis and RNA sequencing in V1 revealed that in males, but not in females, food restriction significantly modulated canonical, energy-regulating pathways, including pathways associated waith AMP-activated protein kinase, peroxisome proliferator-activated receptor alpha, mammalian target of rapamycin, and oxidative phosphorylation. Moreover, we found that in contrast to males, food restriction in females did not significantly affect V1 ATP usage or visual coding precision (assessed by orientation selectivity). Decreased serum leptin is known to be necessary for triggering energy-saving changes in V1 during food restriction. Consistent with this, we found significantly decreased serum leptin in food-restricted males but no significant change in food-restricted females. Collectively, our findings demonstrate that cortical function and energy usage in female mice are more resilient to food restriction than in males. The neocortex, therefore, contributes to sex-specific, energy-saving adaptations in response to food restriction.

EEG-fMRI in awake rat and whole-brain simulations show decreased brain responsiveness to sensory stimulations during absence seizures.

In patients suffering absence epilepsy, recurring seizures can significantly decrease their quality of life and lead to yet untreatable comorbidities. Absence seizures are characterized by spike-and-wave discharges on the electroencephalogram associated with a transient alteration of consciousness. However, it is still unknown how the brain responds to external stimuli during and outside of seizures. This study aimed to investigate responsiveness to visual and somatosensory stimulation in Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well-established rat model for absence epilepsy. Animals were imaged under non-curarized awake state using a quiet, zero echo time, functional magnetic resonance imaging (fMRI) sequence. Sensory stimulations were applied during interictal and ictal periods. Whole-brain hemodynamic responses were compared between these two states. Additionally, a mean-field simulation model was used to explain the changes of neural responsiveness to visual stimulation between states. During a seizure, whole-brain responses to both sensory stimulations were suppressed and spatially hindered. In the cortex, hemodynamic responses were negatively polarized during seizures, despite the application of a stimulus. The mean-field simulation revealed restricted propagation of activity due to stimulation and agreed well with fMRI findings. Results suggest that sensory processing is hindered or even suppressed by the occurrence of an absence seizure, potentially contributing to decreased responsiveness during this absence epileptic process.

Ventral zona incerta parvalbumin neurons modulate sensory-induced and stress-induced self-grooming via input-dependent mechanisms in mice.

Self-grooming is an innate stereotyped behavior influenced by sense and emotion. It is considered an important characteristic in various disease models. However, the neural circuit mechanism underlying sensory-induced and emotion-driven self-grooming remains unclear. We found that the ventral zona incerta (Ziv) was activated during spontaneous self-grooming (SG), corn oil-induced sensory self-grooming (OG), and tail suspension-induced stress self-grooming (TG). Optogenetic excitation of Ziv parvalbumin (PV) neurons increased the duration of SG. Conversely, optogenetic inhibition of ZivPV neurons significantly reduced self-grooming in all three models. Furthermore, glutamatergic inputs from the primary sensory cortex activated the Ziv and contributed to OG. Activation of GABAergic inputs from the central amygdala to the Ziv increased SG, OG, and TG, potentially through local negative regulation of the Ziv. These findings suggest that the Ziv may play a crucial role in processing sensory and emotional information related to self-grooming, making it a potential target for regulating stereotyped behavior.

Mapping the fly nerve cord.

The first neuronal wiring diagram of an insect nerve cord, which includes biological information on cell type and organisation, enables further investigation into premotor circuit function.

Selective recruitment of the cerebellum evidenced by task-dependent gating of inputs.

Functional magnetic resonance imaging (fMRI) studies have documented cerebellar activity across a wide array of tasks. However, the functional contribution of the cerebellum within these task domains remains unclear because cerebellar activity is often studied in isolation. This is problematic, as cerebellar fMRI activity may simply reflect the transmission of neocortical activity through fixed connections. Here, we present a new approach that addresses this problem. Rather than focus on task-dependent activity changes in the cerebellum alone, we ask if neocortical inputs to the cerebellum are gated in a task-dependent manner. We hypothesize that input is upregulated when the cerebellum functionally contributes to a task. We first validated this approach using a finger movement task, where the integrity of the cerebellum has been shown to be essential for the coordination of rapid alternating movements but not for force generation. While both neocortical and cerebellar activity increased with increasing speed and force, the speed-related changes in the cerebellum were larger than predicted by an optimized cortico-cerebellar connectivity model. We then applied the same approach in a cognitive domain, assessing how the cerebellum supports working memory. Enhanced gating was associated with the encoding of items in working memory, but not with the manipulation or retrieval of the items. Focusing on task-dependent gating of neocortical inputs to the cerebellum offers a promising approach for using fMRI to understand the specific contributions of the cerebellum to cognitive function.

Childhood obesity's impact on cognition and brain connectivity worsens with low family income.

Childhood obesity and its adverse health consequences have risen worldwide, with low socioeconomic status increasing the risk in high-income countries like the US. Understanding the interplay between childhood obesity, cognition, socioeconomic factors, and the brain is crucial for prevention and treatment. Using data from the ABCD study, we investigated how body mass index (BMI) relates to brain structural and functional connectivity metrics. Obese/overweight children (n = 2,356) were more likely to live in poverty and exhibited lower cognitive performance compared to normal weight children (n = 4,754). Higher BMI was associated with multiple brain measures that were strongest for lower longitudinal diffusivity in corpus callosum, increased activity in cerebellum, insula, and somatomotor cortex, and decreased functional connectivity in multimodal brain areas, with effects more pronounced among children from low-income families. Notably, nearly 80% of the association of low income and 70% of the association of impaired cognition on BMI were mediated by higher brain activity in somatomotor areas. Increased resting activity in somatomotor areas and decreased structural and functional connectivity likely contribute to the higher risk of overweight/obesity among children from low-income families. Supporting low-income families and implementing educational interventions to improve cognition may promote healthy brain function and reduce the risk of obesity.

De novo monoallelic Reelin missense variants act in a dominant-negative manner causing neuronal migration disorders.

Reelin (RELN) is a secreted glycoprotein essential for cerebral cortex development. In humans, recessive RELN variants cause cortical and cerebellar malformations, while heterozygous variants were associated to epilepsy, autism and mild cortical abnormalities. However, their functional effects remain unknown. We identified inherited and de novo RELN missense variants in heterozygous patients with neuronal migration disorders (NMDs) as diverse as pachygyria and polymicrogyria. We investigated in culture and in the developing mouse cerebral cortex how different variants impacted RELN function. Polymicrogyria-associated variants behaved as gain-of-function showing an enhanced ability to induce neuronal aggregation, while those linked to pachygyria as loss-of-function leading to defective neuronal aggregation/migration. The pachygyria-associated de novo heterozygous RELN variants acted as dominant-negative by preventing wild-type RELN secretion in culture, animal models and patients, thereby causing dominant NMDs. We demonstrated how mutant RELN proteins in vitro and in vivo predict cortical malformation phenotypes, providing valuable insights into the pathogenesis of such disorders.

Protocol for rearing and using mosquitoes for flight path tracking and behavioral characterization in wind tunnel bioassays.

Mosquito behavioral assays are an important component in vector research and control tool development. Here, we present a protocol for rearing Anopheles mosquitoes, performing host-seeking behavioral bioassays, and collecting 3D flight tracks in a large wind tunnel. We describe steps for setting up host-seeking landing assays, both as a non-choice and as a dual-choice assay, and analyzing flight tracks. This protocol can be applied in the research of several behavioral traits, including nectar seeking, resting, mating, and oviposition behavior. For complete details on the use and execution of this protocol, please refer to Carnaghi et al.1.