bioRxiv Subject Collection: Neuroscience's Journal
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Thursday, April 11th, 2024
| Time |
Event |
| 12:16a |
Conditioned medium from painful schwannomatosis tumors increases pain behaviors in mice.
The majority of schwannomatosis (SWN) patients experience debilitating pain. Yet, it is not known why only some schwannomas cause pain or whether mutations in SWN-related genes, (SMARCB1 or LZTR1) differentially influence pain signaling pathways. Here, we established cell lines from SWN tumors resected from patients with varying degrees of pain and bearing mutations in different SWN-related mutations. Compared with conditioned medium (CM) collected from nonpainful SWN tumors, CM from painful SWN tumors contained elevated levels of specific inflammatory cytokines (IL-6, IL-8, VEGF), and was able to enhance sensory neuron responsiveness to noxious TRPV1 and TRPA1 agonists in vitro. In in vivo studies, injection of CM from painful SWN into the hind paws of healthy mice evoked both more acute pain behavior and greater enhancement of mechanical stimulus-evoked behavioral responses than did CM from nonpainful SWN. Furthermore, the behavioral effects of painful CM differed as a function of the SWN-related gene mutations identified in the tumors of origin. Painful SMARCB1 mutant CM, for example, sensitized mice to mechanical stimulation at low forces, compared to non-painful tumor CM and control media, but this effect waned over time. In contrast, CM from a painful tumor with no detectable mutation in either SMARCB1 or LZTR1 caused the greatest increase in responsiveness to low mechanical forces and this effect lasted for 2 days post-injection. These experiments establish a paradigm for examining the mechanisms by which painful SWN tumors bearing different mutations produce their sensory effects and will thus facilitate better understanding and, potentially, treatment of the pain endured by SWN patients. | | 12:16a |
PIEZO1 and PIEZO2 Blade domains are differentially required for channel localization and function.
PIEZO1 and PIEZO2 are critical force-gated ion channels, detecting and transducing mechanical forces into ionic currents in many eukaryotic cell types, serving essential physiological roles. CryoEM and structure-function studies have revealed that three PIEZO monomers assemble as a 3-blade propeller, highlighting essential structural aspects for channel function. One of the most prominent features in PIEZO architecture is the Blade, a large membrane embedded domain that comprises 36 transmembrane fragments organized in 9 THU (Transmembrane Helix Units). Despite its suggested role in force transduction, the contribution of the Blade domain in channel physiology remains unclear. By systematically generating different truncated versions of PIEZO1 and PIEZO2, lacking parts of the Blade, we show the intact PIEZO1 Blade is essential for proper localization and function. Conversely, our results indicate the PIEZO2 Distal Blade segments (THU1-3) are dispensable for normal mechanical sensitivity. However, it plays a central role in channel stability and localization, containing a region that mediates the intracellular retention of a chimeric membrane protein. Our study indicates that, in addition to their biophysical properties, PIEZO1 and PIEZO2 also differ in the regulation of their localization, adding a new layer of control on PIEZO2 activity. | | 1:31a |
Predictive posture stabilization before contact with moving objects: equivalence of smooth pursuit tracking and peripheral vision
Postural stabilization is essential to effectively interact with our environment. Humans preemptively adjust their posture to counteract impending disturbances, such as those encountered during interactions with moving objects, a phenomenon known as anticipatory postural adjustments (APAs). APAs are thought to be influenced by predictive models that incorporate object motion via retinal motion and extra-retinal signals. Building on our previous work that examined APAs in relation to the perceived momentum of moving objects, here we explored the impact of object motion within different visual field sectors on the human capacity to anticipate motion and prepare APAs for contact between virtual moving objects and the limb. Participants interacted with objects moving towards them under different gaze conditions. In one condition, participants fixated on either a central point (central fixation) or left-right of the moving object (peripheral fixation), while in another, they followed the moving object with smooth pursuit eye movements (SPEM). We found that APAs had the smallest magnitude in the central fixation condition and that no notable differences in APAs were apparent between the SPEM and peripheral fixation conditions. This suggests that the visual system can accurately perceive motion of objects in peripheral vision for posture stabilization. Using Bayesian Model Averaging, we also evaluated the contribution of different gaze variables, such as eye velocity and gain (ratio of eye and object velocity) and showed that both eye velocity and gain signals were significant predictors of APAs. Taken together, our study underscores the roles of oculomotor signals in modulation of APAs.
New and NoteworthySpatial vision decreases as a function of retinal eccentricity of the target location, yet the capacity to distinguish motion and visual processing speed either remains stable or, surprisingly, improves in the peripheral vision. Here, we show that the human visuomotor system can detect motion in the peripheral vision and make anticipatory adjustments to posture before making contact with moving objects, just as effectively as when the eye movement system tracks those objects through smooth pursuit eye movements (SPEM). These findings pave the way for further research into how changes in spatial vision, eye movements, and motion perception due to aging could affect the control of limb movements and postural stability during motion-mediated interactions with objects. | | 1:31a |
Neurological Research in 47 Asian Countries
Neurology research in the Asian region has seen significant growth and development over the past decade, yet comprehensive analyses of its progress remain scarce. This study aims to address this gap by providing a detailed examination of neurology research in 47 Asian countries from 2013 to 2022. Data was extracted from the Scopus database, encompassing scholarly output, citations, and citation impact metrics. Findings reveal a total of 128,306 research documents published with 1,725,678 total citations, demonstrating a commendable level of research activity. However, disparities exist among countries, with China, Japan, and Australia emerging as leading contributors in terms of both quantity and citation impact. Despite this, a substantial number of countries and universities have published fewer than 100 papers, indicating room for improvement and the need for targeted capacity-building efforts. | | 1:31a |
Assessing Cognitive Functions Remotely Using a Music-Game-Like Program
There is a growing need to develop ways of assessing cognitive functions remotely and providing interventions using a web-based approach. The Ipsilon Test is a music-based cognitive assessment and training tablet application. On each trial, it presents simplified musical notation with colours, spatial cues, and gestural references so that users can translate spatial information into motor actions by tapping on the screen. In this study, we examined the correlation between the performance of a group of healthy older adults on the Ipsilon test and standard measures of cognitive function--a total of 30 participants aged 58 and over were recruited for the study. Before and after one week of training using the web-based program Ipsilon, all participants completed an online version of the Montreal Cognitive Assessment (MoCA) and the visual Stroop task. Of the participants recruited, 22 participants completed the Ipsilon training and cognitive testing. In our sample, performance on the Ipsilon test was generally high, with all participants scoring above the chance level. Importantly, we found a correlation between Ipsilon test performance and pre-Ipsilon MoCA scores. In addition, participants who scored higher on the Ipsilon test also showed improvement in the visual Stroop task after Ipsilon training, particularly in the ability to inhibit irrelevant information. These results suggest the Ipsilon test is a practical web-based cognitive assessment and training tool. Future research will explore its relationship with other cognitive tests and its diagnostic power for differentiating individuals with normal cognition from those with cognitive disorders. | | 1:31a |
In humans, insulo-striate structural connectivity is largely biased toward either striosome-like or matrix-like striatal compartments
The insula is an integral component of sensory, motor, limbic, and executive functions, and insular dysfunction is associated with numerous human neuropsychiatric disorders. Insular afferents project widely, but insulo-striate projections are especially numerous. The targets of these insulo-striate projections are organized into tissue compartments, the striosome and matrix. These striatal compartments have distinct embryologic origins, afferent and efferent connectivity, dopamine pharmacology, and susceptibility to injury. Striosome and matrix appear to occupy separate sets of cortico-striato-thalamo-cortical loops, so a bias in insulo-striate projections towards one compartment may also embed an insular subregion in distinct regulatory and functional networks. Compartment-specific mapping of insulo-striate structural connectivity is sparse; the insular subregions are largely unmapped for compartment-specific projections.
In 100 healthy adults, we utilized probabilistic diffusion tractography to map and quantify structural connectivity between 19 structurally-defined insular subregions and each striatal compartment. Insulo-striate streamlines that reached striosome-like and matrix-like voxels were concentrated in distinct insular zones (striosome: rostro- and caudoventral; matrix: caudodorsal) and followed different paths to reach the striatum. Though tractography was generated independently in each hemisphere, the spatial distribution and relative bias of striosome-like and matrix-like streamlines were highly similar in the left and right insula. 16 insular subregions were significantly biased towards one compartment: seven toward striosome-like voxels and nine toward matrix-like voxels. Striosome-favoring bundles had significantly higher streamline density, especially from rostroventral insular subregions. The biases in insulo-striate structural connectivity we identified mirrored the compartment-specific biases identified in prior studies that utilized injected tract tracers, cytoarchitecture, or functional MRI. Segregating insulo-striate structural connectivity through either striosome or matrix may be an anatomic substrate for functional specialization among the insular subregions. | | 1:31a |
Analysis of Longitudinal Change Patterns in Developing Brain Using Functional and Structural Magnetic Resonance Imaging via Multimodal Fusion
Functional and structural magnetic resonance imaging (fMRI and sMRI) are complementary approaches that can be used to study longitudinal brain changes in adolescents. Each individual modality offers distinct insights into the brain. Each individual modality may overlook crucial aspects of brain analysis. By combining them, we can uncover hidden brain connections and gain a more comprehensive understanding. In previous work, we identified multivariate patterns of change in whole-brain function during adolescence. In this work, we focus on linking functional change patterns (FCPs) to brain structure. We introduce two approaches and applied them to data from the Adolescent Brain and Cognitive Development (ABCD) dataset. First, we evaluate voxelwise sMRI-FCP coupling to identify structural patterns linked to our previously identified FCPs. Our approach revealed multiple interesting patterns in functional network connectivity (FNC) and gray matter volume (GMV) data that were linked to subject level variation. FCP components 2 and 4 exhibit extensive associations between their loadings and voxel-wise GMV data. Secondly, we leveraged a symmetric multimodal fusion technique called multiset canonical correlation analysis (mCCA) + joint independent component analysis (jICA). Using this approach, we identify structured FCPs such as one showing increased connectivity between visual and sensorimotor domains and decreased connectivity between sensorimotor and cognitive control domains, linked to structural change patterns (SCPs) including alterations in the bilateral sensorimotor cortex. Interestingly, females exhibit stronger coupling between brain functional and structural changes than males, highlighting sex-related differences. The combined results from both asymmetric and symmetric multimodal fusion methods underscore the intricate sex-specific nuances in neural dynamics. By utilizing two complementary multimodal approaches, our study enhances our understanding of the dynamic nature of brain connectivity and structure during the adolescent period, shedding light on the nuanced processes underlying adolescent brain development. | | 1:31a |
Forebrain neuronal SMC3 regulates body weight and metabolic health partially through regulation of hypothalamic Melanocortin 4 receptor
SMC3 is a major component of the cohesin complex that regulates higher-order chromatin organization and gene expression. Mutations in SMC3 gene are found in patients with Cornelia de Lange syndrome (CdLs). This syndrome is characterized by intellectual disabilities, behavioral patterns as self-injury, as well as metabolic dysregulation. Nonetheless, little is known about the role of neuronal SMC3 in gene expression and physiology in adulthood. This study determined the role of SMC3 in adulthood brain, by knocking out Smc3 specifically in adulthood forebrain excitatory neurons. Excitatory conditional neuron-specific SMC3 knockout (cKO) mice displayed a very strong metabolic phenotype in both male and female mice, including a robust overweight phenotype, loss of muscle mass, increased food consumption, lower respiratory exchange ratio, lower energy expenditure and hormonal changes. The hypothalamus displayed dysregulated neuronal morphology and associated transcriptional abnormalities in RNA-seq analysis across various cellular pathways, including decrease of Melanocortin 4 receptor (Mc4r) expression level, a pivotal regulator of appetite and metabolism. Correspondingly, ChIP-seq analysis revealed genome-wide alterations in the binding dynamics of SMC3 of the cKO animals, including Mc4r associated regions. Notably, a significant correlation emerged between multiple sites exhibiting a marked decrease in binding and downregulated genes. The administration of Setmelanotide, an MC4r agonist, to cKO group resulted in a notable reduction in both weight and food consumption in these mice. Therefore, we have identified specific and reversable metabolic parameters that are regulated by neuronal Smc3 in adulthood. | | 4:45a |
Loss of precise auditory sampling as a sign of value-driven visual attentional capture
By linking with rewards, sensory signals gain salience and the ability to influence selective attention even when they have become irrelevant. The dynamics of reward-driven distraction in the brain remains unclear, particularly at the time of shaping multisensory associations. It is unknown whether reward-driven distraction by visual signals interferes with the robust ability of the brain to phase-lock to auditory modulations. In a dynamic audiovisual (AV) coherence task, we investigated how visual reward associations affect performance and modulate auditory encoding precision. Participants were presented with dual visual object streams flickering at different rates, accompanied by an amplitude-modulated sound matching one of the flicker periods, for subjects to identify the matching visual object. At the periphery, an irrelevant color feature flickers in sync with the target and may capture observers attention, due to a prior color-reward association training regime. Electroencephalography (EEG) recordings assessed participants sensitivity to the audiovisual task. The findings indicate that target discrimination was impoverished in the presence of colors that had previously been associated with reward. The phase locking of auditory responses also decreased, evidencing an attentional shift away from auditory modulation representations. Moreover, down-modulations of auditory phase locking predicted the effect size of participants reward-driven distraction. These findings highlight how value-driven attentional capture fundamentally alters multimodal processing in the temporal domain. They suggest that less precise neural representations of unisensory streams not connected to reward-associated cues undermine the processing of temporal coherence relationships between multisensory streams. Momentary inter-modal competition, induced by reward-driven distraction, appears consistent with the systematic exploit of gaps in active attentional sampling strategies that unfold over time. | | 10:52a |
Hierarchical Target Learning in the Mammalian Neocortex: A Pyramidal Neuron Perspective
1The mammalian neocortex possesses the remarkable ability to translate complex sensory inputs into abstract representations through the coordinated activity of large neuronal ensembles across the sensory hierarchy. While cortical hierarchies are anatomically well described, how learning is or-chestrated across the spatial scales ranging from large neuronal networks to pyramidal neurons and their individual synapses is unknown. Here we address this gap from the ground up by modeling the membrane potential and calcium dynamics of individual pyramidal neuron synapses while working upward toward network learning. Starting at the lowest level, we adopt a calcium-dependent synaptic plasticity rule consistent with a wide range of molecular and electrophysiological findings and implement this rule in a synaptic model. We then embed our synaptic model into a pyramidal cell model with apical and dendritic compartments, and integrate various experimental observations such as bursts, calcium plateaus, and somato-apical coupling. We validate the predictions of our neuron model through direct in vitro electrophysiology experiments on layer 5 (L5) pyramidal neurons from the mouse prefrontal cortex and demonstrate that inputs arriving at apical dendrites guide plasticity at basal synapses. Finally, we investigate the algorithmic principles of hierarchical credit assignment in the mammalian neocortex by embedding our pyramidal neuron model in various biologically-plausible deep learning architectures that have been proposed to explain learning in cortex. We find that our model seamlessly aligns with target learning architectures, where top-down feedback arriving at the apical dendrite modifies pyramidal neuron activities to align with desired higher-level neural activity. Importantly, supported by our biological data, this cortical target learning cannot be easily cast into the backpropagation algorithm. By providing a cross-scale framework for cortical hierarchical learning, our work reveals a potential discrepancy between learning in biological neural networks and conventional deep learning. | | 10:52a |
Spatiotemporal cerebral blood flow dynamics underlies emergence of the limbic-sensorimotor-association cortical gradient in human infancy
Infant cerebral blood flow (CBF) delivers nutrients and oxygen to fulfill brain energy consumption requirements for the fastest period of postnatal brain development across lifespan. However, organizing principle of whole-brain CBF dynamics during infancy remains obscure. Leveraging a unique cohort of 100+ infants with high-resolution arterial spin labeled MRI, we found the emergence of the cortical hierarchy revealed by highest-resolution infant CBF maps available to date. Infant CBF across cortical regions increased in a biphasic pattern with initial rapid and sequentially slower rate, with break-point ages increasing along the limbic-sensorimotor-association cortical gradient. Increases in CBF in sensorimotor cortices were associated with enhanced language and motor skills, and frontoparietal association cortices for cognitive skills. The study discovered emergence of the hierarchical limbic-sensorimotor-association cortical gradient in infancy, and offers standardized reference of infant brain CBF and insight into the physiological basis of cortical specialization and real-world infant developmental functioning. | | 10:52a |
Reward Circuit Local Field Potential Modulations Precede Risk Taking
Risk taking behavior is a symptom of multiple neuropsychiatric disorders and often lacks effective treatments. Reward circuitry regions including the amygdala, orbitofrontal cortex, insula, and anterior cingulate have been implicated in risk-taking by neuroimaging studies. Electrophysiological activity associated with risk taking in these regions is not well understood in humans. Further characterizing the neural signalling that underlies risk-taking may provide therapeutic insight into disorders associated with risk-taking.
Eleven patients with pharmacoresistant epilepsy who underwent stereotactic electroencephalography with electrodes in the amygdala, orbitofrontal cortex, insula, and/or anterior cingulate participated. Patients participated in a gambling task where they wagered on a visible playing card being higher than a hidden card, betting $5 or $20 on this outcome, while local field potentials were recorded from implanted electrodes. We used cluster-based permutation testing to identify reward prediction error signals by comparing oscillatory power following unexpected and expected rewards. We also used cluster-based permutation testing to compare power preceding high and low bets in high-risk (<50% chance of winning) trials and two-way ANOVA with bet and risk level to identify signals associated with risky, risk averse, and optimized decisions. We used linear mixed effects models to evaluate the relationship between reward prediction error and risky decision signals across trials, and a linear regression model for associations between risky decision signal power and Barratt Impulsiveness Scale scores for each patient.
Reward prediction error signals were identified in the amygdala (p=0.0066), anterior cingulate (p=0.0092), and orbitofrontal cortex (p=6.0E-4, p=4.0E-4). Risky decisions were predicted by increased oscillatory power in high-gamma frequency range during card presentation in the orbitofrontal cortex (p=0.0022), and by increased power following bet cue presentation across the theta-to-beta range in the orbitofrontal cortex (p=0.0022), high-gamma in the anterior cingulate (p=0.0004), and high-gamma in the insula (p=0.0014). Risk averse decisions were predicted by decreased orbitofrontal cortex gamma power (p=2.0E-4). Optimized decisions that maximized earnings were preceded by decreases within the theta to beta range in orbitofrontal cortex (p=2.0E-4), broad frequencies in amygdala (p=2.0E-4), and theta to low-gamma in insula (p=4.0E-4). Insula risky decision power was associated with orbitofrontal cortex high-gamma reward prediction error signal (p=0.0048) and with patient impulsivity (p=0.00478).
Our findings identify and help characterize reward circuitry activity predictive of risk-taking in humans. These findings may serve as potential biomarkers to inform the development of novel treatment strategies such as closed loop neuromodulation for disorders of risk taking. | | 11:18a |
A human-specific enhancer fine-tunes radial glia potency and corticogenesis
Humans evolved an extraordinarily expanded and complex cerebral cortex, associated with developmental and gene regulatory modifications. Human accelerated regions (HARs) are highly conserved genomic sequences with human-specific nucleotide substitutions. Although there are thousands of annotated HARs, their functional contribution to human-specific cortical development is largely unknown. HARE5 is a HAR transcriptional enhancer of the WNT signaling receptor Frizzled8 (FZD8) active during brain development. Here, using genome-edited mouse and primate models, we demonstrate that human (Hs) HARE5 fine-tunes cortical development and connectivity by controlling the proliferative and neurogenic capacity of neural progenitor cells (NPCs). Hs-HARE5 knock-in mice have significantly enlarged neocortices containing more neurons. By measuring neural dynamics in vivo we show these anatomical features correlate with increased functional independence between cortical regions. To understand the underlying developmental mechanisms, we assess progenitor fate using live imaging, lineage analysis, and single-cell RNA sequencing. This reveals Hs-HARE5 modifies radial glial progenitor behavior, with increased self-renewal at early developmental stages followed by expanded neurogenic potential. We use genome-edited human and chimpanzee (Pt) NPCs and cortical organoids to assess the relative enhancer activity and function of Hs-HARE5 and Pt-HARE5. Using these orthogonal strategies we show four human-specific variants in HARE5 drive increased enhancer activity which promotes progenitor proliferation. These findings illustrate how small changes in regulatory DNA can directly impact critical signaling pathways and brain development. Our study uncovers new functions for HARs as key regulatory elements crucial for the expansion and complexity of the human cerebral cortex. | | 11:18a |
Rapid visual form-based processing of (some) grammatical features in parallel reading: An EEG study in English
Theories of language processing - and typical experimental methodologies - emphasize word-by-word processing of sentences. This paradigm is good for approximating speech or careful text reading, but arguably, not for the common, cursory glances used while reading short sentences (e.g., cellphone notifications, social media posts). How much grammatical information can be gleaned from a single glance? In an electroencephalography (EEG) study, brain responses to grammatical (the dogs chase a ball) stimuli diverged from scrambled counterparts (a dogs chase ball the) [~]300ms post-sentence onset, and from non-lexical consonant strings (thj rjxb zkhtb w lhct) [~]220ms post-sentence onset. This demonstrates early recognition and cursory analysis of linguistic stimuli. However, EEG responses do not diverge between grammatical sentences and their counterparts with ungrammatical agreement (the dogs chases a ball). Additionally, the surprisal of individual words affects the EEG signal at non-uniform time points, from 250ms-600ms. We propose that, in cursory reading in a single glance, readers extract some sentence-level information, such as basic syntactic structure, then fill in some lexical details in a top-down fashion afterwards. This cursory syntactic analysis, however, is not detailed enough to support detection of formal syntactic agreement errors. We suggest this may be due to either the minimal visual salience of agreement morphology in English (-s), or a strategic ignoring of semantically-inert syntactic features for the sake of extracting a semantic gist. |
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