Biology subjects

Shine, J.

Publications and source records attributed to Shine, J..

33 records · Page 2Linked to original sources

bioRxiv2023

SIRT6 activation rescues the age-related decline in DNA damage repair in primary human chondrocytes

While advanced age has long been recognized as the greatest risk factor for osteoarthritis (OA), the biological mechanisms behind this connection remain unclear. Previous work has demonstrated that chondrocytes from older cadaveric donors have elevated levels of DNA damage as compared to chondrocytes from younger donors. The purpose of this study was to determine whether a decline in DNA repair efficiency is one explanation for the accumulation of DNA damage with age, and to quantify the improvement in repair with activation of Sirtuin 6 (SIRT6). Using an acute irradiation model to bring the baseline level of all donors to the same starting point, this study demonstrates a decline in repair efficiency during aging when comparing chondrocytes from young ([≤]45 years old), middle-aged (50-65 years old), or older (>70 years old) cadaveric donors with no known history of OA or macroscopic cartilage degradation at isolation. Activation of SIRT6 in middle-aged chondrocytes with MDL-800 (20 M) improved the repair efficiency, while inhibition with EX-527 (10 M) inhibited the rate of repair and the increased the percentage of cells that retained high levels of damage. Treating chondrocytes from older donors with MDL-800 for 48 hours significantly reduced the amount of DNA damage, despite this damage having accumulated over decades. Lastly, chondrocytes isolated from the proximal femurs of mice between 4 months and 22 months of age revealed both an increase in DNA damage with aging, and a decrease in DNA damage following MDL-800 treatment.

cell biology↗

bioRxiv2022

Locus Coeruleus firing patterns selectively modulate brain activity and dynamics

Noradrenaline (NA) release from the brainstem nucleus locus coeruleus (LC) changes activity and connectivity in neuronal networks across the brain, thus modulating multiple behavioural states. NA release is mediated by both tonic and burst-like neuronal LC activity. However, it remains unknown whether the functional changes in downstream projection areas depend on these firing patterns. Using optogenetics, pupillometry, photometry, and functional MRI in mice, we show that tonic and burst LC firing patterns elicit brain responses that are specific to the activation frequency and temporal pattern. Tonic activation of the LC evokes nonlinear responses in prefrontal, limbic, and cerebellar regions, in line with the proposed inverted-U relationship between LC activity and behaviour. We further demonstrate that LC activity enhances network integration and acts as a facilitator of brain state transitions, hence increasing brain flexibility. Together, these findings reveal how the LC-NA system achieves a nuanced regulation of global circuit operations.

neuroscience↗

bioRxiv2022

Macroscale Thalamic Functional Organization Disturbances And Underlying Core Cytoarchitecture In Early-Onset Schizophrenia

Schizophrenia is a polygenetic mental disorder with heterogeneous positive and negative symptom constellations, and is associated with abnormal cortical connectivity. The thalamus has a coordinative role in cortical function and is key to the development of the cerebral cortex. Conversely, altered functional organization of the thalamus might relate to overarching cortical disruptions in schizophrenia, anchored in development. Here, we contrasted resting-state fMRI in 99 antipsychotic-naive first-episode early-onset schizophrenia (EOS) patients and 100 typically developing controls to study whether macroscale thalamic organization is altered in EOS. Employing dimensional reduction techniques on thalamocortical functional connectome, we derived lateral-medial and anterior-posterior thalamic functional axes. We observed increased segregation of macroscale thalamic functional organization in EOS patients, which was related to altered thalamocortical interactions both in unimodal and transmodal networks. Using an ex vivo approximation of core-matrix cell distribution, we found that core cells particularly underlie the macroscale abnormalities in EOS patients. Moreover, the disruptions were associated with schizophrenia-related gene expression maps. Behavioral and disorder decoding analyses indicated that the macroscale hierarchy disturbances might perturb both perceptual and abstract cognitive functions and contribute to negative syndromes in schizophrenia, suggesting a unitary pathophysiological framework of schizophrenia.

neuroscience↗

bioRxiv2022

Dynamic regulation of neural variability during working memory reflects dopamine, functional integration, and decision-making

The regulation of moment-to-moment neural variability may permit effective responses to changing cognitive demands. However, the mechanisms that support variability regulation are unknown. In the context of working memory, we leverage the largest available PET and fMRI dataset to jointly consider three lenses through which neural variability regulation could be understood: dopamine capacity, network-level functional integration, and flexible decision processes. We show that with greater working memory load, upregulation of variability was associated with elevated dopamine capacity and heightened functional integration, effects dominantly expressed in the striato-thalamic system rather than cortex. Strikingly, behavioral modeling revealed that working memory load evoked substantial decision biases during evidence accumulation, and those who jointly expressed a more optimal decision bias and higher dopamine capacity were most likely to upregulate striato-thalamic variability under load. We argue that the ability to align striato-thalamic variability to level of demand may be a hallmark of a well-functioning brain.

neuroscience↗

bioRxiv2021

Mapping neurotransmitter systems to the structural and functional organization of the human neocortex

Neurotransmitter receptors support the propagation of signals in the human brain. How receptor systems are situated within macroscale neuroanatomy and how they shape emergent function remains poorly understood, and there exists no comprehensive atlas of receptors. Here we collate positron emission tomography data from >1 200 healthy individuals to construct a whole-brain 3-D normative atlas of 19 receptors and transporters across 9 different neurotransmitter systems. We find that receptor profiles align with structural connectivity and mediate function, including neurophysiological oscillatory dynamics and resting state hemodynamic functional connectivity. Using the Neurosynth cognitive atlas, we uncover a topographic gradient of overlapping receptor distributions that separates extrinsic and intrinsic psychological processes. Finally, we find both expected and novel associations between receptor distributions and cortical thinning patterns across 13 disorders. We replicate all findings in an independently collected autoradiography dataset. This work demonstrates how chemoarchitecture shapes brain structure and function, providing a new direction for studying multi-scale brain organization.

neuroscience↗

bioRxiv2021

Global and Local Head Direction Coding in the Human Brain

Orientation-specific head direction (HD) cells increase their firing rate to indicate ones facing direction in the environment. Rodent studies suggest HD cells in distinct areas of thalamus and retrosplenial cortex (RSC) code either for global (relative to the wider environment) or local (e.g., room-specific) reference frames. To investigate whether similar neuroanatomical dissociations exist in humans, we reanalysed functional magnetic resonance imaging data in which participants learned the orientation of unique images in separate local environments relative to distinct global landmarks (Shine, Valdes-Herrera, Hegarty, & Wolbers, 2016). The environment layout meant that we could establish two separate multivariate analysis models in which the HD on individual trials was coded relative either to global (North, South, East, West) or local (Front, Back, Right, Left) reference frames. Examining the data first in key regions of interest (ROI) for HD coding, we replicated our previous results and found that global HD was decodable in the thalamus and precuneus; the RSC, however, was sensitive only to local HD. Extending recent findings in both humans and rodents, V1 was sensitive to both HD reference frames. Additional small volume-corrected searchlight analyses supported the ROI results and indicated that the anatomical locus of the thalamic global HD coding was located in the medial thalamus, bordering the anterior thalamus, a region critical for global HD coding in rodents. Our findings elucidate further the putative neural basis of HD coding in humans, and suggest that distinct brain regions code for different frames of reference in HD. Significance statementHead direction (HD) cells provide a neural signal as to ones orientation in the environment. HD can be coded relative to global or local (e.g., room-specific) reference frames, with studies suggesting that distinct areas of thalamus and retrosplenial cortex (RSC) code for this information. We reanalysed fMRI data where human participants associated images with global HDs before undergoing scanning. The design enabled us to examine both global and local HD coding. Supporting previous findings, global HD was decodable in thalamus, however the RSC coded only for local HD. We found evidence also for both reference frames in V1. These findings elucidate the putative neural basis of HD coding in humans, with distinct brain regions coding for different HD reference frames.

neuroscience↗

bioRxiv2021

The ascending arousal system shapes low-dimensional brain dynamics to mediate awareness of changes in intrinsic cognitive states

Models of cognitive function typically focus on the cerebral cortex and hence overlook functional links to subcortical structures. This view neglects the highly-conserved ascending arousal systems role and the computational capacities it provides the brain. In this study, we test the hypothesis that the ascending arousal system modulates cortical neural gain to alter the low-dimensional energy landscape of cortical dynamics. Our analyses of spontaneous functional magnetic resonance imaging data and phasic bursts in both locus coeruleus and basal forebrain demonstrate precise time-locked relationships between brainstem activity, low-dimensional energy landscapes, network topology, and spatiotemporal travelling waves. We extend our analysis to a cohort of experienced meditators and demonstrate locus coeruleus-mediated network dynamics were associated with internal shifts in conscious awareness. Together, these results present a novel view of brain organization that highlights the ascending arousal systems role in shaping both the dynamics of the cerebral cortex and conscious awareness.

neuroscience↗

bioRxiv2020

The ascending arousal system promotes optimal performance through meso-scale network integration in a visuospatial attentional task

Previous research has shown that the autonomic nervous system provides essential constraints over ongoing cognitive function. However, there is currently a relative lack of direct empirical evidence for how this interaction manifests in the brain at the macro-scale level. Here, we examine the role of ascending arousal and attentional load on large-scale network dynamics by combining pupillometry, functional MRI and graph theoretical analysis to analyze data from a visual motion-tracking task with a parametric load manipulation. We found that attentional load effects were observable in measures of pupil diameter and in a set of brain regions that parametrically modulated their BOLD activity and meso-scale network-level integration. In addition, the regional patterns of network reconfiguration were correlated with the spatial distribution of the 2a adrenergic receptor. Our results further solidify the relationship between ascending noradrenergic activity, large-scale network integration, and cognitive task performance. Author SummaryIn our daily lives, it is usual to encounter highly demanding cognitive tasks. They have been traditionally regarded as challenges that are solved mainly through cerebral activity, specifically via information-processing steps carried by neurons in the cerebral cortex. Activity in cortical networks thus constitutes a key factor for improving our understanding cognitive processes. However, recent evidence has shown that evolutionary older players in the central nervous system, such as brainstems ascending modulatory systems, might play an equally important role in diverse cognitive mechanisms. Our article examines the role of the ascending arousal system on large-scale network dynamics by combining pupillometry, functional MRI and graph theoretical analysis.

neuroscience↗

bioRxiv2020

Diffuse neural coupling mediates complex network dynamics through the formation of quasi-critical brain states

The biological mechanisms that allow the brain to balance flexibility and integration remain poorly understood. A potential solution to this mystery may lie in a unique aspect of neurobiology, which is that numerous brain systems contain diffuse synaptic connectivity. In this manuscript, we demonstrate that increasing diffuse cortical coupling within a validated biophysical corticothalamic model traverses the system through a quasi-critical regime in which spatial heterogeneities in input noise support transient critical dynamics in distributed sub-regions. We then demonstrate that the presence of quasi-critical states coincides with known signatures of complex, adaptive brain network dynamics. Finally, we demonstrate the presence of similar dynamic signatures in empirical whole brain human neuroimaging data. Together, our results establish that modulating the balance between local and diffuse synaptic coupling in a thalamocortical model subtends the emergence of quasi-critical brain states that act to flexibly transition the brain between unique modes of information processing.

neuroscience↗

bioRxiv2020

Core and Matrix Thalamic Sub-Populations Relate to Spatio-Temporal Cortical Connectivity Gradients

Recent neuroimaging experiments have defined low-dimensional gradients of functional connectivity in the cerebral cortex that subserve a spectrum of capacities that span from sensation to cognition. Despite well-known anatomical connections to the cortex, the subcortical areas that support cortical functional organization have been relatively overlooked. One such structure is the thalamus, which maintains extensive anatomical and functional connections with the cerebral cortex across the cortical mantle. The thalamus has a heterogeneous cytoarchitecture, with at least two distinct cell classes that send differential projections to the cortex: granular-projecting Core cells and supragranular-projecting Matrix cells. Here we use high-resolution 7T resting-state fMRI data and the relative amount of two calcium-binding proteins, parvalbumin and calbindin, to infer the relative distribution of these two cell-types (Core and Matrix, respectively) in the thalamus. First, we demonstrate that thalamocortical connectivity recapitulates large-scale, low-dimensional connectivity gradients within the cerebral cortex. Next, we show that diffusely-projecting Matrix regions preferentially correlate with cortical regions with longer intrinsic fMRI timescales. We then show that the Core-Matrix architecture of the thalamus is important for understanding network topology in a manner that supports dynamic integration of signals distributed across the brain. Finally, we replicate our main results in a distinct 3T resting-state fMRI dataset. Linking molecular and functional neuroimaging data, our findings highlight the importance of the thalamic organization for understanding low-dimensional gradients of cortical connectivity.

neuroscience↗

bioRxiv2018

Evidence for allocentric boundary and goal direction information in the human entorhinal cortex and subiculum

In rodents, cells in the medial entorhinal cortex (EC) and subiculum code for the allocentric direction to environment boundaries, which is an important prerequisite for accurate positional coding. Although in humans boundary-related signals have been reported, there is no evidence that they contain allocentric direction information. Furthermore, it has not been possible to separate boundary versus goal direction signals in the EC/subiculum. To address these important questions, participants learned a virtual environment containing four unique boundaries, after which they underwent fMRI scanning where they made judgments about the allocentric direction of a cue object. Using multivariate decoding, we found information regarding allocentric boundary direction in posterior EC and subiculum, whereas in anterior EC and subiculum we could decode allocentric goal direction. These data provide the first evidence of allocentric boundary coding in humans, and are consistent with recent conceptualisations of a division of labour within the EC.

neuroscience↗

bioRxiv2017

Hippocampal atrophy and intrinsic brain network alterations relate to impaired capacity for mind wandering in neurodegeneration

Mind wandering represents the human capacity for internally focussed thought, and relies upon the brains default network and its interactions with attentional networks. Studies have characterised mind wandering in healthy people, yet there is limited understanding of how this capacity is affected in clinical populations. This study used a validated thought-sampling task to probe mind wandering capacity in two neurodegenerative disorders: behavioural variant frontotemporal dementia (bvFTD; n=35) and Alzheimers disease (AD; n=24), compared to older controls (n=37). These patient groups were selected due to canonical structural and functional changes across sites of the default and frontoparietal networks, and well-defined impairments in cognitive processes that support mind wandering. Relative to controls, bvFTD patients displayed significantly reduced mind wandering capacity, offset by a significant increase in stimulus-bound thought. In contrast, AD patients demonstrated comparable levels of mind wandering to controls, in the context of a relatively subtle shift towards stimulus-/task-related forms of thought. In the patient groups, mind wandering was associated with grey matter integrity in the hippocampus/parahippocampus, striatum, insula and orbitofrontal cortex. Resting state functional connectivity revealed associations between mind wandering capacity and connectivity within and between regions of the frontoparietal and default networks, with distinct patterns evident in patients vs. controls. These findings support a relationship between altered mind wandering capacity in neurodegenerative disorders, and structural and functional integrity of the default and frontoparietal networks. This study highlights a dimension of cognitive dysfunction not well documented in neurodegenerative disorders, and validates current models of mind wandering in a clinical population.\n\nSignificance statementHumans spend much of their waking life engaged in mind wandering. Underlying brain systems supporting this complex ability have been established in healthy individuals, yet it remains unclear how mind wandering is altered in neuropsychiatric populations. We reveal changes in the thought profiles elicited during periods of low cognitive demand in dementia, resulting in reduced mind wandering and an increased propensity towards stimulus-bound thought. These altered thought profiles were associated with structural and functional brain changes in the hippocampus, default and frontoparietal networks; key regions implicated in internal mentation in healthy individuals. Our findings provide a unique clinical validation of current theoretical models of mind wandering, and reveal a dimension of cognitive dysfunction that has received scant attention in dementia.

neuroscience↗

bioRxiv2017

Catecholaminergic Manipulation Alters Dynamic Network Topology Across Behavioral States

The human brain is able to flexibly adapt its information processing capacity to meet a variety of cognitive challenges. Recent evidence suggests that this flexibility is reflected in the dynamic reorganization of the functional connectome. The ascending catecholaminergic arousal systems of the brain are a plausible candidate mechanism for driving alterations in network architecture, enabling efficient deployment of cognitive resources when the environment demands them. We tested this hypothesis by analyzing both task-free and task-based fMRI data following the administration of atomoxetine, a noradrenaline reuptake inhibitor, compared to placebo, in two separate human fMRI studies. Our results demonstrate that the manipulation of central catecholamine levels leads to a reorganization of the functional connectome in a manner that is sensitive to ongoing cognitive demands.

neuroscience↗

bioRxiv2017

Accumulation of sensory evidence is impaired in Parkinson’s disease with visual hallucinations

Models of hallucinations across disorders emphasise an imbalance between sensory input and top-down influences over perception. However, the psychological and mechanistic correlates of this imbalance remain underspecified. Visual hallucinations in Parkinsons disease (PD) are associated with impairments in lower level visual processes and attention, accompanied by over activity and connectivity in higher-order association brain networks. PD therefore provides an attractive framework to explore the relative contributions of bottom-up versus top-down disturbances in hallucinations. Here, we characterised sensory processing in PD patients with and without visual hallucinations, and in healthy controls, by fitting a hierarchical drift diffusion model (hDDM) to an attentional task. The hDDM uses Bayesian estimates to decompose reaction time and response output into parameters reflecting drift rates of evidence accumulation, decision thresholds and non-decision time. We observed slower drift rates in PD patients with hallucinations, which were insensitive to changes in task demand. In contrast, wider decision boundaries and shorter non-decision times relative to controls were found in PD regardless of hallucinator status. Inefficient and less flexible sensory evidence accumulation emerge as unique features of PD hallucinators. We integrate these results with current models of hallucinations, suggesting that slow and inefficient sensory input in PD is less informative, and may therefore be down-weighted leading to an over reliance on top-down influences. Our findings provide a novel computational framework to better specify the impairments in dynamic sensory processing that are a risk factor for visual hallucinations.

neuroscience↗

bioRxiv2017

The GridCAT: A toolbox for automated analysis of human grid cell codes in fMRI

Human fMRI studies examining the putative firing of grid cells (i.e., the grid code) suggest that this cellular mechanism supports not only spatial navigation, but also more abstract cognitive processes. This research area, however, remains relatively unexplored, perhaps us to the complexities of data analysis. To overcome this, we have developed the Matlab-based Grid Code Analysis Toolbox (GridCAT), providing a graphical user interface, and open-source code, for the analysis of fMRI data. The GridCAT performs all analyses, from estimation and fitting of the grid code in the general linear model, to the generation of grid code metrics and plots. Moreover, it is flexible in allowing the specification of bespoke analysis pipelines; example data are provided to demonstrate the GridCATs main functionality. We believe the GridCAT is essential to opening this research area to the imaging community, and helping to elucidate the role of human grid codes in higher-order cognitive processes.\n\nHighlightsO_LIThe putative firing of grid cells (i.e., the grid code) can be examined using fMRI\nC_LIO_LINecessary steps for grid code analysis are reviewed\nC_LIO_LIThe Matlab-based grid code analysis toolbox (GridCAT) is introduced\nC_LIO_LIAutomated grid code analysis can be conducted either via a graphical user interface or open-source code\nC_LIO_LIA detailed manual and an example dataset are provided\nC_LI

neuroscience↗