Biology subjects

Pope, M.

Publications and source records attributed to Pope, M..

11 recordsLinked to original sources

bioRxiv2026

Structural signatures of synergy and redundancy in human brain function

A fundamental goal in neuroscience is to understand how the brains physical architecture supports complex functional dynamics. While the relationship between structural connectivity and pairwise functional connectivity has been extensively studied, the anatomical basis of higher-order interactions remains poorly understood. In this study, we use multivariate information theory -specifically the O-information- to investigate how the human connectome constrains subsets of brain regions characterized by predominantly redundant or synergistic information sharing. By analyzing the topology and community embedding of these subsets, we reveal two different structural profiles. Redundant subsets are characterized by high internal connection density and strong weights. Their nodes have high clustering and occupy globally less central positions. In contrast, synergistic subsets consist of globally central nodes with high betweenness centrality. We further demonstrate that leveraging these structural features, in particular node centrality, significantly improves the identification of synergistic subsets compared to random sampling. Together, these results demonstrate that the human connectome imposes specific constraints on higher-order information sharing, extending structure-function relationships beyond pairwise interactions and providing new insight into the structural origins of multivariate functional organization.

neuroscience↗

bioRxiv2025

Altered Relaxation and Mitochondria-Endoplasmic Reticulum Contact Sites Precede Major (Mal)adaptations in Aging Skeletal Muscle and are Prevented by Exercise

Sarcopenia, or age-related muscle dysfunction, contributes to morbidity and mortality. Besides decreases in muscle force, sarcopenia is associated with atrophy and fast-to-slow fiber type switching, which is typically secondary to denervation in humans and rodents. However, very little is known about cellular changes preceding these important (mal)adaptations. To this matter, mitochondria and the sarcoplasmic reticulum are critical for tension generation in myofibers. They physically interact at the boundaries of sarcomeres forming subcellular hubs called mitochondria-endo/sarcoplasmic reticulum contacts (MERCs). Yet, whether changes at MERCs ultrastructure and proteome occur early in aging is unknown. Here, studying young adult and older mice we reveal that aging slows muscle relaxation leading to longer excitation-contraction-relaxation (ECR) cycles before maximal force decreases and fast-to-slow fiber switching takes place. We reveal that muscle MERC ultrastructure and mitochondria-associated ER membrane (MAM) protein composition are also affected early in aging and are closely associated with rate of muscle relaxation. Additionally, we demonstrate that regular exercise preserves muscle relaxation rate and MERC ultrastructure in early aging. Finally, we profile a set of muscle MAM proteins involved in energy metabolism, protein quality control, Ca2+ homeostasis, cytoskeleton integrity and redox balance that are inversely regulated early in aging and by exercise. These may represent new targets to preserve muscle function in aging individuals.

physiology↗

bioRxiv2024

Neonatal systemic gene therapy restores cardiorespiratory function in a rat model of Pompe disease

Absence of functional acid--glucosidase (GAA) leads to early-onset Pompe disease with cardiorespiratory and neuromuscular failure. A novel Pompe rat model (Gaa-/-) was used to test the hypothesis that neonatal gene therapy with adeno-associated virus serotype 9 (AAV9) restores cardiorespiratory neuromuscular function across the lifespan. Temporal vein administration of AAV9-DES-GAA or sham (saline) injection was done on post-natal day 1; rats were studied at 6-12 months old. Whole-body plethysmography showed that reduced inspiratory tidal volumes in Gaa-/-rats were corrected by AAV-GAA treatment. Matrix- assisted laser desorption/ionization mass spectrometry imaging (MALDI) revealed that AAV-GAA treatment normalized diaphragm muscle glycogen as well as glycans. Neurophysiological recordings of phrenic nerve output and immunohistochemical evaluation of the cervical spinal cord indicated a neurologic benefit of AAV-GAA treatment. In vivo magnetic resonance imaging demonstrated that impaired cardiac volumes in Gaa-/- rats were corrected by AAV-GAA treatment. Biochemical assays showed that AAV treatment increased GAA activity in the heart, diaphragm, quadriceps and spinal cord. We conclude that neonatal AAV9-DES-GAA therapy drives sustained, functional GAA expression and improved cardiorespiratory function in the Gaa-/- rat model of Pompe disease.

physiology↗

bioRxiv2024

Leveraging multivariate information for community detection in functional brain networks

Embedded in neuroscience is the concept that brain functioning is underpinned by specialized systems whose integration enables cognition and behavior. Modeling the brain as a network of interconnected brain regions, allowed us to capitalize on network science tools and identify these segregated systems (modules, or communities) by optimizing the weights of pairwise connections within them. However, just knowing how strongly two brain areas are connected does not paint the whole picture. Brain dynamics is also engendered by interactions involving more areas at the same time, namely, higher-order interactions. In this paper, we propose a community detection algorithm that accounts for higher-order interactions and finds modules of brain regions whose brain activity is maximally redundant. Compared to modules identified with methods based on bivariate interactions, our redundancy-dominated modules are more symmetrical between the hemispheres, they overlap with canonical systems at the level of the sensory cortex, but describe a new organization of the transmodal cortex. By detecting redundant modules across spatial scales, we identified a sweet spot of maximum balance between segregation and integration of information as that scale where redundancy within modules and synergy between modules peaked. Moreover, we defined a local index that distinguishes brain regions in segregators and integrators based on how much they participate in the redundancy of their modules versus the redundancy of the whole system. Finally, we applied the algorithm to a lifespan dataset and tracked how redundant subsystems change across time. The results of this paper serve as educated guesses on how the brain organizes itself into modules accounting for higher-order interactions of its fundamental units, and pave the way for further investigation that could link them to cognition, behavior, and disease.

neuroscience↗

bioRxiv2024

Time-varying synergy/redundancy dominance in the human cerebral cortex

Recent work has emphasized the ubiquity of higher-order interactions in brain function. These interactions can be characterized as being either redundancy or synergy-dominated by the heuristic O-information [1]. Though the O-information can be decomposed into local values to measure the synergy-redundancy dominance at each point in a time series [2] no such analysis of fMRI dynamics has been carried out. Here we analyze the moment-to-moment synergy and redundancy dominance of the fMRI BOLD signal during rest for 95 unrelated subjects. We present results from several interaction sizes. The whole brain is rarely synergy-dominated, with some subjects never experiencing a whole-brain synergistic moment. Randomly sampled subsets of many sizes reveal that subsets that are the most redundancy dominated on average exhibit both the most synergistic and most redundant time points. Exhaustive calculation of the optimally synergistic and optimally redundant triads further emphasizes this finding, with recurrent nodes frequently belonging to a single coherent functional system. We find that when a triad is momentarily synergistic, it is often split between two instantaneously co-fluctuating communities, but is collectively co-fluctuating when it is momentarily redundant. After optimizing for synergy and redundancy in subsets of size five to seventy-five, we show that this effect is consistent across interaction sizes. Additionally, we find notable temporal structure in all optimized redundant and synergistic subsets: higher order redundant and synergistic interactions change smoothly in time and recur more than expected by chance.

neuroscience↗

bioRxiv2024

The ancient evolution of far-red light photoacclimation in cyanobacteria

Cyanobacteria oxygenated the atmosphere of early Earth and continue to be key players in global carbon and nitrogen cycles. A phylogenetically diverse subset of extant cyanobacteria can perform photosynthesis with far-red light through a process called far-red light photoacclimation, or FaRLiP. This phenotype is enabled by a cluster of [~]20 genes, and involves the synthesis of red-shifted chlorophylls f and d, together with paralogues of the ubiquitous photosynthetic machinery used in visible light. The FaRLiP gene cluster is present in diverse, environmentally important cyanobacterial groups but its origin, evolutionary history, and connection to early biotic environments have remained unclear. This study takes advantage of the recent increase in (meta)genomic data to clarify this issue; sequence data mining, metagenomic assembly, and phylogenetic tree networks were used to recover more than 600 new FaRLiP gene sequences, corresponding to 52 new gene clusters. These data enable high-resolution phylogenetics and - by relying on multiple gene trees, together with gene arrangement conservation - support FaRLiP appearing early in cyanobacterial evolution. Sampling information shows that considerable FaRLiP diversity can be observed in microbialites to the present day, and the process may have been associated with microbial mats and stromatolite formation in the early Paleoproterozoic. The ancestral FaRLiP cluster was reconstructed, revealing a conserved intergenic regulatory sequence that has been maintained for billions of years. Taken together, our results indicate that oxygenic photosynthesis using far-red light may have played a significant role in Earths early history.

evolutionary biology↗

bioRxiv2023

Modular subgraphs in large-scale connectomes underpin spontaneous co-fluctuation "events" in mouse and human brains

Previous studies have adopted an edge-centric framework to study fine-scale dynamics in human fMRI. To date, however, no studies have applied this same framework to data collected from model organisms. Here, we analyze structural and functional imaging data from lightly anesthetized mice through an edge-centric lens. We find evidence of "bursty" dynamics and events - brief periods of high-amplitude network connectivity. Further, we show that on a per-frame basis events best explain static FC and can be divided into a series of hierarchically-related clusters. The co-fluctuation patterns associated with each centroid link distinct anatomical areas and largely adhere to the boundaries of algorithmically detected functional brain systems. We then investigate the anatomical connectivity undergirding high-amplitude co-fluctuation patterns. We find that events induce modular bipartitions of the anatomical network of inter-areal axonal projections. Finally, we replicate these same findings in a human imaging dataset. In summary, this report recapitulates in a model organism many of the same phenomena observed in previously edge-centric analyses of human imaging data. However, unlike human subjects, the murine nervous system is amenable to invasive experimental perturbations. Thus, this study sets the stage for future investigation into the causal origins of fine-scale brain dynamics and high-amplitude co-fluctuations. Moreover, the cross-species consistency of the reported findings enhances the likelihood of future translation.

neuroscience↗

bioRxiv2023

Path integration selectively predicts midlife risk of Alzheimer's disease

The entorhinal cortex (EC) is the first cortical region to exhibit neurodegeneration in Alzheimers disease (AD), associated with EC grid cell dysfunction. Given the role of grid cells in path integration, we predicted that path integration impairment would represent the first behavioural change in adults at-risk of AD. Using immersive virtual reality, we found that midlife path integration impairments predicted both hereditary and physiological AD risk, with no corresponding impairment on tests of episodic memory or other spatial behaviours. Impairments related to poorer angular estimation and were associated with hexadirectional grid-like fMRI signal in the posterior-medial EC. These results indicate that altered path integration may represent the transition point from at-risk state to disease onset in AD, prior to impairment in other cognitive domains.

neuroscience↗

bioRxiv2023

Co-Evolving Dynamics and Topology in a Coupled Oscillator Model of Resting Brain Function

Dynamic models of ongoing BOLD fMRI brain dynamics and models of communication strategies have been two important approaches to understanding how brain network structure constrains function. However, dynamic models have yet to widely incorporate one of the most important insights from communication models: the brain may not use all of its connections in the same way or at the same time. Here we present a variation of a phase delayed Kuramoto coupled oscillator model that dynamically limits communication between nodes on each time step. An active subgraph of the empirically derived anatomical brain network is chosen in accordance with the local dynamic state on every time step, thus coupling dynamics and network structure in a novel way. We analyze this model with respect to its fit to empirical time-averaged functional connectivity, finding that it significantly outperforms standard Kuramoto models with phase delays. We also perform analyses on the novel structural edge time series it produces, demonstrating a slowly evolving topology moving through intermittent episodes of integration and segregation. We hope to demonstrate that the exploration of novel modeling mechanisms and the investigation of dynamics of networks in addition to dynamics on networks may advance our understanding of the relationship between brain structure and function.

neuroscience↗

bioRxiv2022

Light activation of Orange Carotenoid Protein reveals initial C8'-C7' double bond trans/cis photoisomerization

Orange Carotenoid protein (OCP) is the only known photoreceptor which uses carotenoid for its activation. It is found exclusively in cyanobacteria, where it functions to control light-harvesting of the photosynthetic machinery. However, the photochemical reactions and structural dynamics of this unique photosensing process are not yet resolved. We present time-resolved crystal structures at second-to-minute delays under bright illumination, capturing the early photoproduct and structures of the subsequent reaction intermediates. The first stable photoproduct shows concerted isomerization of C9-C8 and C7-C6 single bonds in the bicycle-pedal (BP) manner and structural changes in the N-terminal domain with minute timescale kinetics. These are followed by a thermally-driven recovery of the BP isomer to the dark state carotenoid configuration. Structural changes propagate to the C-terminal domain, resulting, at later time, in the H-bond rupture of the carotenoid keto group with protein residues. The isomerization and its transient nature are confirmed in OCP crystals and solution by FTIR and UV/Vis spectroscopy. This study reveals the single bond isomerization of the carotenoid in the BP manner and subsequent thermal structural reactions as the basis of OCP photoreception. Understanding and potentially controlling the OCP dynamics offers the prospect of novel applications in biomass engineering as well as in optogenetics and bioimaging.

biophysics↗

bioRxiv2021

Modular origins of high-amplitude co-fluctuations in fine-scale functional connectivity dynamics

The topology of structural brain networks shapes brain dynamics, including the correlation structure of brain activity (functional connectivity) as estimated from functional neuroimaging data. Empirical studies have shown that functional connectivity fluctuates over time, exhibiting patterns that vary in the spatial arrangement of correlations among segregated functional systems. Recently, an exact decomposition of functional connectivity into frame-wise contributions has revealed fine-scale dynamics that are punctuated by brief and intermittent episodes (events) of high-amplitude co-fluctuations involving large sets of brain regions. Their origin is currently unclear. Here, we demonstrate that similar episodes readily appear in silico using computational simulations of whole-brain dynamics. As in empirical data, simulated events contribute disproportionately to long-time functional connectivity, involve recurrence of patterned co-fluctuations, and can be clustered into distinct families. Importantly, comparison of event-related patterns of co-fluctuations to underlying patterns of structural connectivity reveals that modular organization present in the coupling matrix shape patterns of event-related co-fluctuations. Our work suggests that brief, intermittent events in functional dynamics are partly shaped by modular organization of structural connectivity. Significance StatementBrain regions engage in complex patterns of activation and co-activation over time. Relating these patterns to rest or task-related neural processing is a central challenge in cognitive neuroscience. Recent work has identified brief intermittent bursts of brain-wide signal co-fluctuations, called events, and shown that events drive functional connectivity. The origins of events are still unclear. Here, we address this gap in knowledge by implementing computational models of neural oscillators coupled by anatomical connections derived from maps of the human cerebral cortex. Analysis of the emerging large-scale brain dynamics reveals brief episodes with high system-wide signal amplitudes. Simulated events closely correspond to those seen recently in empirical recordings. Notably, simulated events are significantly aligned with underlying structural modules, thus suggesting an important role of modular network organization.

neuroscience↗