Biology subjects

Roy, D.

Publications and source records attributed to Roy, D..

At least 55 records · Page 3Linked to original sources

bioRxiv2023

How repetition hinders priority switching in visual working memory states: An EEG study

Visual Working memory (VWM) is a limited-capacity system where working memory items compete for retrieval. Some items are maintained in the working memory in the "region of direct access," which holds information readily available for processing, while other items are in a passive or activated long-term memory state and require cognitive control. Moreover, their recognition requires moving from the most active template in VWM to another one with the shift of attention. Stimulus properties based on similarity can link items together, which can facilitate their retrieval due to prioritization. To investigate the neural dynamics of differential processing of repeated versus not-repeated items in working memory, we designed a modified Sternberg task for testing recognition in a VWM-based EEG study where human participants respond to a probe for an items presence or absence in the representation of an encoded memory array containing repeated and not repeated items. Significantly slower response times and comparatively poor accuracy for recognising not-repeated items suggest that they are not prioritized. We identified specific differences in spectral perturbations for sensor clusters in the power of different frequency bands as the neural correlate of probe matching for not-repeated vs. repeated conditions, reflecting biased access to VWM items. For not-repeated item probe matching, delay in beta desynchronization suggests poor memory-guided action selection behaviour. An increase in frontal theta and parietal alpha power demonstrated a demand for stronger cognitive control for retrieving items for not-repeated probe matching by shielding them from distracting repeated items. In summary, our study provides crucial empirical evidence of facilitation and prioritization of repeated items over non-repeated items and explains the probable role of different EEG rhythms in facilitated recognition of repeated items over goal-relevant, not-repeated items in VWM.

neuroscience↗

bioRxiv2023

Developmental stability and segregation of Theory of Mind and Pain networks carry distinct temporal signatures during naturalistic viewing

Temporally stable large-scale functional brain connectivity among distributed brain regions is crucial during brain development. Recently, many studies highlighted an association between temporal dynamics during development and their alterations across various time scales. However, systematic characterization of temporal stability patterns of brain networks that represent the bodies and minds of others in children remains unexplored. To address this, we apply an unsupervised approach to reduce high-dimensional dynamic functional connectivity (dFC) features via low-dimensional patterns and characterize temporal stability using quantitative metrics across neurodevelopment. This study characterizes the development of temporal stability of the Theory of Mind (ToM) and Pain networks to address the functional maturation of these networks. The dataset used for this investigation comprised 155 subjects (children (n=122, 3-12 years) and adults (n=33)) watching engaging movie clips while undergoing fMRI data acquisition. The movie clips highlighted cartoon characters and their bodily sensations (often pain) and mental states (beliefs, desires, emotions) of others, activating ToM and Pain network regions of young children. Our findings demonstrate that ToM and pain networks display distinct temporal stability patterns by age 3 years. Finally, the temporal stability and specialization of the two functional networks increase with age and predict ToM behavior.

neuroscience↗

bioRxiv2023

RNA polymerase II pausing is essential during spermatogenesis for appropriate gene expression and completion of meiosis

Male germ cell development requires precise regulation of gene activity in a cell-type and stage-specific manner, with perturbations in gene expression during spermatogenesis associated with infertility. Here, we use steady-state, nascent and single-cell RNA sequencing strategies to comprehensively characterize gene expression across male germ cell populations, to dissect the mechanisms of gene control and provide new insights towards therapy. We discover a requirement for pausing of RNA Polymerase II (Pol II) at the earliest stages of sperm differentiation to establish the landscape of gene activity across development. Accordingly, genetic knockout of the Pol II pause-inducing factor NELF in immature germ cells blocks differentiation to mature spermatids. Further, we uncover unanticipated roles for Pol II pausing in the regulation of meiosis during spermatogenesis, with the presence of paused Pol II associated with double strand break formation by SPO11, and disruption of SPO11 expression in germ cells lacking NELF.

genomics↗

bioRxiv2023

Neuromolecular interactions guiding homeostatic mechanisms underlying healthy ageing: A view from computational microscope

Ageing brain is associated with a slow drift in structural network properties over the lifespan accompanied by reorganization in neuromolecular interactions giving rise to changes in global functional markers. What are the guiding principles of the homeostatic mechanisms that maintain the desired performance of functional neural circuits and preserve brain health during healthy ageing? We hypothesize that an ageing brain alters two primary neurotransmitters, glutamate and{gamma} -aminobutyric acid (GABA), responsible for excitation-inhibition regulation, concomitant with anatomical demyelination to preserve critical neural dynamics that are necessary to uphold optimal network performance. Thus, often observed re-organized functional connectivity with age by several investigations is a byproduct of this adaptive process. We demonstrate that the adaptive mechanism is driven by the tuning of glutamate and GABA concentration over a very slow time scale (lifespan) that can be estimated by tracking criticality from co-ordinated neural dynamics at a resting state via a biophysically driven computational framework, introduced as a computational microscope. We validate several empirical observations and model predictions across three independent aging cohorts using this computational microscope. One of the key mechanisms we discover is the reduction in local glutamate levels employed by brain regions to maintain a homeostatic balance with aging. This is further supported by the invariance of measures of global functional integration during the healthy ageing process.

neuroscience↗

bioRxiv2023

Effective networks mediate right hemispheric dominance of human 40 Hz auditory steady-state response

Auditory steady-state responses (ASSR) are induced from the brainstem to the neocortex when humans hear periodic amplitude-modulated tonal signals. ASSRs have been argued to be a key marker of auditory temporal processing and pathological reorganization of ASSR - a biomarker of neurodegenerative disorders. However, most of the earlier studies reporting the neural basis of ASSRs were focused on looking at individual brain regions. Here, we seek to characterize the large-scale directed information flow among cortical sources of ASSR entrained by 40 Hz external signals. Entrained brain rhythms with power peaking at 40 Hz were generated using both monaural and binaural tonal stimulation. First, we confirm the presence of ASSRs and their well-known right hemispheric dominance during binaural and both monaural conditions. Thereafter, reconstruction of source activity employing individual anatomy of the participant and subsequent network analysis revealed that while the sources are common among different stimulation conditions, differential levels of source activation and differential patterns of directed information flow using Granger causality among sources underlie processing of binaurally and monaurally presented tones. Particularly, we show bidirectional interactions involving the right superior temporal gyrus and inferior frontal gyrus underlie right hemispheric dominance of 40 Hz ASSR during both monaural and binaural conditions. On the other hand, for monaural conditions, the strength of inter-hemispheric flow from left primary auditory areas to right superior temporal areas followed a pattern that comply with the generally observed contralateral dominance of sensory signal processing.

neuroscience↗

bioRxiv2023

End-to-End Explainable AI: Derived Theory-of-Mind Fingerprints to Distinguish Between Autistic and Typically developing and Social Symptom Severity

Theory-of-Mind (ToM) is an evolving ability that significantly impacts human learning and cognition. Early development of ToM ability allow one to comprehend other peoples aims and ambitions, as well as thinking that differs from ones own. Autism Spectrum Disorder (ASD) is the prevalent pervasive neurodevelopmental disorder in which participants brains appeared to be marked by diffuse variations throughout large-scale brain systems made up of functionally connected but physically separated brain areas that got abnormalities in willed action, self-monitoring and monitoring the intents of others, often known as ToM. Although functional neuroimaging techniques have been widely used to establish the neural correlates implicated in ToM, the specific mechanisms still need to be clarified. The availability of current Big data and Artificial Intelligence (AI) frameworks paves the way for systematically identifying Autistics from typically developing by identifying neural correlates and connectome-based features to generate accurate classifications and predictions of socio-cognitive impairment. In this work, we develop an Ex-AI model that quantifies the common sources of variability in ToM brain regions between typically developing and ASD individuals. Our results identify a feature set on which the classification model can be trained to learn characteristics differences and classify ASD and TD ToM development more distinctly. This approach can also estimate heterogeneity within ASD ToM subtypes and their association with the symptom severity scores based on socio-cognitive impairments. Based on our proposed framework, we obtain an average accuracy of more than 90 % using Explainable ML (Ex-Ml) models and an average of 96 % classification accuracy using Explainable Deep Neural Network (Ex-DNN) models. Our findings identify three important sub-groups within ASD samples based on the key differences and heterogeneity in resting state ToM regions functional connectivity patterns and predictive of mild to severe atypical social cognition and communication deficits through early developmental stages.

neuroscience↗

bioRxiv2022

Altered global modular organization of intrinsic functional connectivity in autism arises from atypical node-level processing

Autistic spectrum disorder (ASD) is a neurodevelopmental condition characterized by restricted interests and repetitive behaviors as well as social-communication deficits. These traits are associated with atypicality of functional brain networks. Modular organization in the brain plays a crucial role in network stability and adaptability for neurodevelopment. Previous neuroimaging research demonstrates discrepancies in studies of functional brain modular organization in ASD. These discrepancies result from the examination of mixed age groups. Furthermore, recent findings suggest while much attention has been given to deriving atlases and measuring the connections between nodes, the within nodes information may be crucial in determining altered modular organization in ASD compared with TD. However, altered modular organization originating from systematic nodal changes are yet to be explored in younger children with ASD. Here, we used graph-theoretical measures to fill this knowledge gap. To this end, we utilized multicenter resting-state BOLD fMRI data collected from 5-10-year-old children - 34 ASD and 40 typically developing obtained from the Autism Brain Image Data Exchange (ABIDE) I and II. We demonstrated alterations in the topological roles and modular cohesiveness are the two key properties of the brain regions anchored in default mode, sensorimotor, and salience networks primarily relates to social and sensory deficits in ASD children. These results demonstrate atypical global network organization in ASD children arise from nodal role changes and contribute to the growing body of literature suggesting that there is interesting information within nodes providing critical marker of functional brain networks in Autistic children.

neuroscience↗

bioRxiv2022

Apolipoprotein E4 has extensive conformational heterogeneity in lipid free and bound forms

The {varepsilon}4-allele variant of Apolipoprotein E (ApoE4) is the strongest genetic risk factor for Alzheimers disease, though it only differs from its neutral counterpart ApoE3 by a single amino acid substitution. While ApoE4 influences the formation of plaques and neurofibrillary tangles, the structural determinants of pathogenicity remain undetermined due to limited structural information. We apply a combination of single-molecule spectroscopy and molecular dynamics simulations to construct an atomically-detailed model of monomeric ApoE4 and probe the effect of lipid association. Our data reveal that ApoE4 is far more disordered than previously thought and retains significant conformational heterogeneity after binding lipids. In particular, the behavior of the hinge region and C-terminal domain of ApoE4 differs substantially from that proposed in previous models and provides a crucial foundation for understanding how ApoE4 differs from non-pathogenic and protective variants of the protein.

biophysics↗

bioRxiv2022

Characterizing Variability of Audiovisual Speech Perception Based on Periodic and Aperiodic Features of Prestimulus Brain Activity

Studies have reported that prestimulus brain oscillations guide perceptual experiences during AV speech perception. However, what features of these prestimulus activity drives perception remains unknown. In this electroencephalography (EEG) study, we investigated the relationship between prestimulus periodic oscillations and aperiodic components with subsequent perception of the McGurk illusion at single-trial levels. Using logistic mixed-effect models, we determined which spectral features from different sensor regions predicted response to the illusory perception. We found that lower alpha (8-12 Hz) and beta (15-30 Hz) band oscillations over parieto-occipital sensors predicted illusion perception. We also found lower aperiodic offset values over parieto-temporal sensors, and lower global effect of exponent over the scalp, that predicted the response to McGurk illusion. We conclude that the predominant source of the prestimulus oscillatory state is aperiodic background activity, and that variations in these arrhythmic components account for inter-trial and inter-individual variability in perception of the McGurk illusion.

neuroscience↗

bioRxiv2021

Emotion Dynamics as Hierarchical Bayesian Inference in Time

What fundamental property of our environment would be most valuable and optimal in characterizing the emotional dynamics we experience in our daily life? Empirical work has shown that an accurate estimation of uncertainty is necessary for our optimal perception, learning, and decision-making. However, the role of this uncertainty in governing our affective dynamics remains unexplored. Using Bayesian encoding, decoding and computational modelling, we show that emotional experiences naturally arise due to ongoing uncertainty estimations in a hierarchical neural architecture. This hierarchical organization involves a number of prefrontal sub-regions, with the lateral orbitofrontal cortex having the highest representational complexity of uncertainty. Crucially, this representational complexity, was sensitive to temporal fluctuations in uncertainty and was predictive of participants predisposition to anxiety. Furthermore, the temporal dynamics of uncertainty revealed a distinct functional double dissociation within the OFC. Specifically, the medial OFC showed higher connectivity with the DMN, while the lateral OFC with that of the FPN in response to the evolving affect. Finally, we uncovered a temporally predictive code updating individuals beliefs swiftly in the face of fluctuating uncertainty in the lateral OFC. A biologically relevant and computationally crucial parameter in theories of brain function, we extend uncertainty to be a defining component of complex emotions.

neuroscience↗

bioRxiv2021

How synchrony and metastable network dynamics are affected in fast and slow timescales with aging: Implication for Cognition

Both healthy and pathological aging exhibits gradual deterioration of structure but in-terestingly in healthy aging adults often maintains a high level of cognitive performance in a variety of cognitively demanding task till late age. What are the relevant network measures that could possibly track these dynamic changes which may be critically relevant for maintenance of cognitive functions through lifespan and how does these measures affected by the specific alterations in underlying anatomical connectivity till day remains an open question. In this work, we propose that whole-brain computational models are required to test the hypothesis that aging affects the brain network dynamics through two highly relevant network measures synchrony and metastability. Since aging entails complex processes involving multiple timescales we test the additional hypothesis that whether these two network measures remain invariant or exhibit different behavior in the fast and slow timescales respectively. The altered global synchrony and metastability with aging can be related to shifts in the dynamic working point of the system based on biophysical parameters e.g., time delay, and inter-areal coupling constrained by the underlying structural connectivity matrix.Using diffusion tensor imaging (DTI) data, we estimate structural connectivity (SC) of individual group of participants and obtain network level synchrony, metastability indexing network dynamics from resting state functional MRI data for both young and elderly participants in the age range of 18-89 years. Subsequently, we simulate a whole-brain Kuramoto model of coupled oscillators with appropriate conduction delay and interareal coupling strength to test the hypothesis of shifting of dynamic working point with age-associated alteration in network dynamics in both neural and ultraslow BOLD signal time scales. Specifically, we investigate the age-associated difference in metastable brain dynamics across large-scale neurocognitive brain networks e.g., salience network (SN), default mode network (DMN), and central executive network (CEN) to test spatio-temporal changes in default to executive coupling hypothesis with age. Interestingly, we find that the metastability of the SN increases substantially with age, whereas the metastability of the CEN and DMN networks do not substantially vary with age suggesting a clear role of conduction delay and global coupling in mediating altered dynamics in these networks. Moreover, our finding suggests that the metastability changes from slow to fast timescales confirming previous findings that variability of brain signals relates differently in slower and faster time scales with aging. However, synchrony remains invariant network measure across timescales and agnostic to the filtering of fast signals. Finally, we demonstrate both numerically and analytically longrange anatomical connections as oppose to shot-range or mid-range connection alterations is responsible for the overall neural difference in large-scale brain network dynamics captured by the network measure metastability. In summary, we propose a theoretical framework providing a systematic account of tracking age-associated variability and synchrony at multiple time scales across lifespan which may pave the way for developing dynamical theories of cognitive aging.

neuroscience↗

bioRxiv2021

Preservation of neural synchrony at peak alpha frequency via global synaptic scaling compensates for white matter structural decline over adult lifespan

We propose that preservation of functional integration, estimated from measures of neural synchrony, is a key neurocompensatory mechanism associated with healthy human ageing. To support this proposal, we demonstrate how phase-locking at peak alpha frequency from Magnetoencephalography (MEG) data is invariant over lifespan in a large cohort of human participants, aged 18-88 years. Using empirically derived connection topologies from diffusion tensor imaging (DTI) data, we create an in-silico model of whole-brain alpha dynamics. We show that enhancing inter-areal coupling can cancel the effect of increased axonal transmission delay associated with age-related degeneration of white matter tracts and thus, preserve neural synchrony. Together with analytical solutions for non-biological all-to-all connection scenarios, our model establishes the theoretical principles by which frequency slowing with age, frequently observed in the alpha band in diverse populations, can be viewed as an epiphenomenon of the underlying neurocompensatory mechanisms.

neuroscience↗

bioRxiv2021

Hippocampus maintains a flexible and coherent map under reward flavor-landmark cue conflict.

Animals predominantly use salient visual cues (landmarks) for efficient navigation over other sensory modalities. When the relative position of the visual cues is altered, the hippocampal population exhibits heterogeneous responses and constructs context-specific spatial maps. Another critical factor that can strongly modulate spatial representation is the presence of reward. Reward features can drive behavior and are known to bias spatial attention. However, it is unclear whether reward flavors are used for spatial reference in the presence of distal cues and how the hippocampus population dynamics changes when the association between reward flavors and distal cues is altered. We investigated these questions by recording place cells from the CA1 while the rats ran in an environment with the conflicting association between reward flavors and distal cues. We report that the hippocampal place cells coherently and dynamically bind to reward flavors or distal cues across sessions, but not simultaneously suggesting the use of a single spatial map. We found that place cells maintained their spatial offset in the cue conflict conditions, thus showing a robust spatial coupling featuring an attractor-like property in the CA1. When the textures were added on the track, the coherency of the CA1 is degraded, as the hippocampus showed a heterogeneous response and weak spatial coupling of co-recorded cells suggesting a break away from the attractor network. These results indicate that reward flavors alone may be used for spatial reference but may not cause sufficient input difference to create context-specific spatial maps in the CA1.

neuroscience↗

bioRxiv2021

Super-resolution imaging of highly curved membrane structures in giant vesicles encapsulating molecular condensates

Molecular crowding is an inherent feature of the cell interior. Synthetic cells as provided by giant unilamellar vesicles (GUVs) encapsulating macromolecules (polyethylene-glycol and dextran) represent an excellent mimetic system to study membrane transformations associated with molecular crowding and protein condensation. Similarly to cells, such GUVs loaded with macromolecules exhibit highly curved structures such as internal nanotubes. In addition, upon liquid-liquid phase separation as inside living cells, the membrane of GUVs encapsulating an aqueous two-phase system deforms to form apparent kinks at the contact line of the interface between the two aqueous phases. These structures, nanotubes and kinks, have dimensions below optical resolution and if resolved, can provide information about material properties such as membrane spontaneous curvature and intrinsic contact angle describing the wettability contrast of the encapsulated phases to the membrane. Previous experimental studies were based on conventional optical microscopy which cannot resolve these membrane and wetting properties. Here, we studied these structures with super-resolution microscopy, namely stimulated emission depletion (STED) microscopy, together with microfluidic manipulation. We demonstrate the cylindrical nature of the nanotubes with unprecedented detail based on the superior resolution of STED and automated data analysis. The spontaneous curvature deduced from the nanotube diameters is in excellent agreement with theoretical predictions. Furthermore, we were able to resolve the membrane "kink" structure as a smoothly curved membrane demonstrating the existence of the intrinsic contact angle. We find very good agreement between the directly measured values and the theoretically predicted ones based on the apparent contact angles on the micrometer scale. During different stages of cellular events, biomembranes undergo a variety of shape transformations such as the formation of buds and nanotubes regulated by membrane necks. We demonstrate that these highly curved membrane structures are amenable to STED imaging and show that such studies provide important insights in the membrane properties and interactions underlying cellular activities.

biophysics↗

bioRxiv2021

Unsupervised characterization of dynamic functional connectivity reveals age-associated differences in temporal stability and connectivity states during rest and task

Understanding brain functions as an outcome of underlying neuro-cognitive network mechanisms in rest and task requires accurate spatiotemporal characterization of the relevant functional brain networks. Recent endeavours of the Neuroimaging community to develop the notion of dynamic functional connectivity is a step in this direction. A key goal is to detect what are the important events in time that delimits how one functional brain network defined by known patterns of correlated brain activity transitions into a "new" network. Such characterization can also lead to more accurate conceptual realization of brain states, thereby, defined in terms of time-resolved correlations. Nonetheless, identifying the canonical temporal window over which dynamic functional connectivity is operational is currently based on an ad-hoc selection of sliding windows that can certainly lead to spurious results. Here, we introduce a data-driven unsupervised approach to characterize the high dimensional dynamic functional connectivity into dynamics of lower dimensional patterns. The whole-brain dynamic functional connectivity states bearing functional significance for task or rest can be explored through the temporal correlations, both short and long range. The present study investigates the stability of such short- and long-range temporal correlations to explore the dynamic network mechanisms across resting state, movie viewing and sensorimotor action tasks requiring varied degrees of attention. As an outcome of applying our methods to the fMRI data of a healthy ageing cohort we could quantify whole-brain temporal dynamics which indicates naturalistic movie watching task is closer to resting state than the sensorimotor task. Our analysis also revealed an overall trend of highest short range temporal network stability in the sensorimotor task, followed by naturalistic movie watching task and resting state that remains similar in both young and old adults. However, the stability of neurocognitive networks in the resting state in young adults is higher than their older counterparts. Thus, healthy ageing related differences in quantification of network stability along task and rest provides a blueprint of how our approach can be used for cohort studies of mental health and neurological disorders.

neuroscience↗

bioRxiv2021

Expression of extracellular Hsp90 is a molecular signature of T cell activation, providing a means to image and target T Cell activation in autoimmune disease

Heat shock protein 90 (Hsp90) maintains cellular proteostasis during stress and has been under investigation as a therapeutic target in cancer for over two decades. We and others have identified an extracellularly expressed form of Hsp90, eHsp90, that previously appeared to be restricted to rapidly proliferating cells exhibiting a metastatic phenotype. Here, we used HS-131, a fluor-tethered eHsp90 inhibitor, to quantify the effect of T cell activation on the expression of eHsp90 in human and mouse T cells. In cell based assays, stimulation of human T cells induced a 20-fold increase in eHsp90 expression at the plasma membrane, suggesting trafficking of eHsp90 is acutely regulated by TCR and inflammatory mediated signaling. Following injection of HS-131 in mouse models of human rheumatoid arthritis and inflammatory bowel disease, we detected localization of the probe at sites of active disease, consistent with immune cell invasion. Moreover, despite rapid hepatobiliary clearance, HS-131 demonstrated efficacy in delaying the onset and progression of disease in the arthritis model. Our results suggest eHsp90 expression at the plasma membrane of T cells is a molecular marker of autoimmune induced activation and potentially a therapeutic target for chronic diseases such as rheumatoid arthritis and inflammatory bowel disease. PerspectiveT cells mediate many maladaptive disease pathologies such as autoimmune disorders. Many immunosuppressants in clinical use act by preventing the activation of T cells. However, this approach can lead to increased rates of opportunistic infection and malignancy. Here, we show for the first time that eHsp90 is upregulated during T cell activation in response to exogenous ligands. Therefore, pharmacological inhibition of eHsp90 may provide a means to target only activated T cells for immunosuppression. Selective targeting of only activated T cells could be efficacious against autoimmune disease without increasing the incidence of undesirable outcomes. Additionally, the presence of eHsp90 on the surface of activated T cells could be diagnostically useful to track the status and progression of autoimmune disease in patients.

pharmacology and toxicology↗

bioRxiv2021

Cingulate-motor circuits update rule representations for sequential choice decisions

Anterior cingulate cortex mediates the flexible updating of an animals choice responses upon rule changes in the environment. However, how anterior cingulate cortex entrains motor cortex to reorganize rule representations and generate required motor outputs remains unclear. Here, we demonstrate that chemogenetic silencing of the projection terminals of cingulate cortical neurons in secondary motor cortex disrupted sequential choice performance in trials immediately following rule switches, suggesting that these inputs are necessary to update rule representations for choice decisions stored in the motor cortex. Indeed, the silencing of cingulate cortex decreased rule selectivity of secondary motor cortical neurons. Furthermore, optogenetic silencing of cingulate cortical neurons that was temporally targeted to error trials immediately after rule switches exacerbated errors in following trials. These results suggest that cingulate cortex monitors behavioral errors and update rule representations in motor cortex, revealing a critical role for cingulate-motor circuits in adaptive choice behaviors.

neuroscience↗