Biology subjects

Barbosa, J.

Publications and source records attributed to Barbosa, J..

11 recordsLinked to original sources

bioRxiv2025

Patient-derived organoids to study glycosylation dynamics during gastric disease

BACKGROUND AND AIMSAberrant cellular glycosylation remains a key event that accompanies and actively sustains gastric neoplastic transformation. Patient-derived organoids (PDOs) have recently emerged as a promising ex vivo model to study human gastric disorders. Since the PDOs glycosylation landscape remains unknown, this study aims to evaluate PDOs as potential avatars of in vivo tissue glycosylation profiles in the gastric context. METHODSFresh gastric mucosa samples derived from non-tumoral obese patients (n=11), adjacent tumor mucosa samples (n=29), and tumor tissue samples derived from gastric cancer (GC) patients (n=30) were used to establish a biobank of gastric PDOs (n=56). The N- and O-glycophenotypes of normal, adjacent, and tumor PDOs and respective in vivo tissues were thoroughly characterized by immunostaining. Additionally, a comparative glycan analysis was performed over time, upon PDO biobanking and xenografting in mice. The binding of two Helicobacter pylori (H. pylori) isogenic strains with distinct glycan-binding affinities was assessed in parental gastric mucosa tissues and compared with the respective PDOs before and after modulation of their glycan landscape. RESULTSOur results show that PDOs mimic different phenotypes of the carcinogenic cascade and recapitulate parental gastric tissues glycosylation profile. Tumor PDOs recapitulate the inter- and intra-heterogeneity features observed in GC, which is maintained over time, upon biobanking and xenografting. We demonstrated that the expression of type I and type II Lewis antigens is dynamically controlled by PDOs differentiation status, which results in differential binding to H. pylori strains displaying distinct glycan-binding adhesins, mirroring the gastric epithelium tissue interactions. CONCLUSIONSThis study established PDOs as invaluable ex vivo tools to study the complex glycan dynamics in both gastric physiological and pathological settings.

cell biology↗

bioRxiv2025

Redundant, weakly connected prefrontal hemispheres balance precision and capacity in spatial working memory

The prefrontal hemispheres must coordinate dynamically to maintain a unified representation of visual space. Recently, two opposing theories using distinct storage strategies have been proposed: A high-capacity specialized architecture, where each hemisphere governs contralateral behavior, and a fail-safe redundant one, where both hemispheres jointly guide behavior across the visual space. Here, we analyzed simultaneous bilateral prefrontal cortex recordings from three macaque monkeys performing a visuo-spatial working memory task. Both hemispheres equally predicted behavioral imprecision, decoding errors were weakly correlated between hemispheres, and serial dependence remained local within hemispheres, suggesting a redundant, weakly coupled organization. Attractor network simulations showed that redundancy improved precision when task demands were below memory capacity, while weak interhemispheric coupling increased capacity in more demanding tasks by allowing hemispheric specialization. These predicted patterns were validated in human and monkey data, reconciling previous findings and revealing a versatile interhemispheric architecture that adapts to varying cognitive demands.

animal behavior and cognition↗

bioRxiv2025

Quantifying Differences in Neural Population Activity With Shape Metrics

Quantifying differences across species and individuals is fundamental to many fields of biology. However, it remains challenging to draw detailed functional comparisons between large populations of interacting neurons. Here, we introduce a general framework for comparing neural population activity in terms of shape distances. This approach defines similarity in terms of explicit geometric transformations, which can be flexibly specified to obtain different measures of population-level neural similarity. Moreover, differences between systems are defined by a distance that is symmetric and satisfies the triangle inequality, enabling downstream analyses such as clustering and nearest-neighbor regression. We demonstrate this approach on datasets spanning multiple behavioral tasks (navigation, passive viewing of images, and decision making) and species (mice and non-human primates), highlighting its potential to measure functional variability across subjects and brain regions, as well as its ability to relate neural geometry to animal behavior.

neuroscience↗

bioRxiv2024

Alpha phase-coding supports feature binding during working memory maintenance

The ability to successfully retain and manipulate information in working memory (WM) requires that objects individual features are bound into cohesive representations; yet, the mechanisms supporting feature binding remain unclear. Binding (or swap) errors, where memorized features are erroneously associated with the wrong object, can provide a window into the intrinsic limits in capacity of WM that represent a key bottleneck in our cognitive ability. We tested the hypothesis that binding in WM is accomplished via neural phase synchrony and that swap errors result from perturbations in this synchrony. Using magnetoencephalography data collected from human subjects in a task designed to induce swap errors, we showed that swaps are characterized by reduced phase-locked oscillatory activity during memory retention, as predicted by an attractor model of spiking neural networks. Further, we found that this reduction arises from increased phase coding variability in the alpha-band over a distributed network of sensorimotor areas. Our findings demonstrate that feature binding in WM is accomplished through phase coding dynamics that emerge from the competition between different memories. SignificanceWe investigate the neural basis of working memory, focusing on how feature binding is accomplished and how binding or swap errors arise. Using magnetoencephalography, we found that stable phase-locking of alpha oscillations supports correct feature binding, while swap errors correlate with reduced alpha phase preservation, localized to specific brain areas. These findings align with a biologically-plausible computational model predicting that temporal synchrony in neuronal firing underpins feature binding. This work advances our understanding of the neural mechanisms of working memory, providing empirical support for theories of time-based binding and demonstrating the utility of biophysically-realistic models in human neuroimaging studies.

neuroscience↗

bioRxiv2022

Flexible selection of task-relevant features through across-area population gating

Brains can gracefully weed out irrelevant stimuli to guide behavior. This feat is believed to rely on a progressive selection of task-relevant stimuli across the cortical hierarchy, but the specific across-area interactions enabling stimulus selection are still unclear. Here, we propose that population gating, occurring within A1 but controlled by top-down inputs from mPFC, can support across-area stimulus selection. Examining single-unit activity recorded while rats performed an auditory context-dependent task, we found that A1 encoded relevant and irrelevant stimuli along a common dimension of its neural space. Yet, the relevant stimulus encoding was enhanced along an extra dimension. In turn, mPFC encoded only the stimulus relevant to the ongoing context. To identify candidate mechanisms for stimulus selection within A1, we reverse-engineered low-rank RNNs trained on a similar task. Our analyses predicted that two context-modulated neural populations gated their preferred stimulus in opposite contexts, which we confirmed in further analyses of A1. Finally, we show in a two-region RNN how population gating within A1 could be controlled by top-down inputs from PFC, enabling flexible across-area communication despite fixed inter-areal connectivity.

neuroscience↗

bioRxiv2021

Across-area synchronization supports feature integration in working memory

Working memory function is severely limited. One key limitation that constrains the ability to maintain multiple items in working memory simultaneously is so-called swap errors. These errors occur when an inaccurate response is in fact accurate relative to a non-target stimulus, reflecting the failure to maintain the appropriate association or "binding" between the features that define one object (e.g., color and location). The mechanisms underlying feature binding in working memory remain unknown. Here, we tested the hypothesis that features are bound in memory through synchrony across feature-specific neural assemblies. We built a biophysical neural network model composed of two one-dimensional attractor networks - one for color and one for location - simulating feature storage in different cortical areas. Within each area, gamma oscillations were induced during bump attractor activity through the interplay of fast recurrent excitation and slower feedback inhibition. As a result, different memorized items were held at different phases of the networks oscillation. These two areas were then reciprocally connected via weak cortico-cortical excitation, accomplishing binding between color and location through the synchronization of pairs of bumps across the two areas. Encoding and decoding of color-location associations was accomplished through rate coding, overcoming a long-standing limitation of binding through synchrony. In some simulations, swap errors arose: "color bumps" abruptly changed their phase relationship with "location bumps". This model, which leverages the explanatory power of similar attractor models, specifies a plausible mechanism for feature binding and makes specific predictions about swap errors that are testable at behavioral and neurophysiological levels.

neuroscience↗

bioRxiv2019

Disrupted serial dependence suggests deficits in synaptic potentiation in anti-NMDAR encephalitis and schizophrenia

We report markedly reduced working memory-related serial dependence with preserved memory accuracy in anti-NMDAR encephalitis and schizophrenia. We argue that NMDAR-related changes in cortical excitation, while quickly destabilizing persistent neural activity, cannot fully account for a reduction of memory-dependent biases. Rather, our modeling results support a disruption of a memory mechanism operating on a longer timescale, such as short-term potentiation.

neuroscience↗

bioRxiv2019

Interplay between persistent activity and activity-silent dynamics in prefrontal cortex during working memory

Persistent neuronal spiking has long been considered the mechanism underlying working memory, but recent proposals argue for alternative, \"activity-silent\" substrates for memory. Using monkey and human electrophysiology, we show here that attractor dynamics that control neural spiking during mnemonic periods interact with activity-silent mechanisms in PFC. This interaction allows memory reactivation, which enhance serial biases in spatial working memory. Stimulus information was not decodable between trials, but remained present in activity-silent traces inferred from spiking synchrony in PFC. Just prior to the new stimulus, this latent trace was reignited into activity that recapitulated the previous stimulus representation. Importantly, the reactivation strength correlated with the strength of serial biases in both monkeys and humans, as predicted by a computational model integrating activity-based and activity-silent mechanisms. Finally, single-pulse TMS applied to human prefrontal cortex prior to trial start enhanced serial biases, demonstrating the causal role of prefrontal reactivations in determining working memory behavior.

neuroscience↗

bioRxiv2019

Mps1 releases Mad1 from nuclear pores to ensure a robust mitotic checkpoint and accurate chromosome segregation

The strength of the Spindle Assembly Checkpoint (SAC) depends on the amount of the Mad1-C-Mad2 heterotetramer at kinetochores but also on its binding to Megator/Tpr at nuclear pore complexes (NPCs) during interphase. However, the molecular underpinnings controlling the spatiotemporal redistribution of Mad1-C-Mad2 as cells progress into mitosis remain elusive. Here, we show that Mps1-mediated phosphorylation of Megator/Tpr abolishes its interaction with Mad1 in vitro and in Drosophila cells. Timely activation of Mps1 during prophase triggers Mad1 release from NPCs, which we find to be required for competent kinetochore recruitment of Mad1-C-Mad2 and robust checkpoint response. Importantly, preventing Mad1 binding to Megator/Tpr rescues the fidelity of chromosome segregation and aneuploidy in larval neuroblasts of Drosophila mps1-null mutants. Our findings demonstrate that the subcellular localization of Mad1 is stringently coordinated with cell cycle progression by kinetochore-extrinsic activity of Mps1. This ensures that both NPCs in interphase and kinetochores in mitosis can generate anaphase inhibitors to efficiently preserve genomic stability.

cell biology↗

bioRxiv2018

Build-up of serial dependence in color working memory

Serial dependence, how recent experiences bias our current estimations, has been described experimentally during delayed-estimation of many different visual features, with subjects tending to make estimates biased towards previous ones. It has been proposed that these attractive biases help perception stabilization in the face of correlated natural scene statistics as an adaptive mechanism, although this remains mostly theoretical. Color, which is strongly correlated in natural scenes, has never been studied with regard to its serial dependencies. Here, we found significant serial dependence in 6 out of 7 datasets with behavioral data of humans (total n=111) performing delayed-estimation of color with uncorrelated sequential stimuli. Consistent with a drifting memory model, serial dependence was stronger when referenced relative to previous report, rather than to previous stimulus. In addition, it built up through the experimental session, suggesting metaplastic mechanisms operating at a slower time scale than previously proposed (e.g. short-term synaptic facilitation). Because, in contrast with natural scenes, stimuli were temporally uncorrelated, this build-up casts doubt on serial dependencies being an ongoing adaptation to the stable statistics of the environment.

neuroscience↗

bioRxiv2017

Neonatal Zika virus infection causes epileptic seizures, viral persistence and long-term behavioral impairment

A causal relationship between congenital Zika virus (ZIKV) exposure and microcephaly and other neurological disorders have been established, but long-term consequences of infection are still unknown. We evaluated acute and late neuropathological and behavioral consequences of ZIKV infection in a neonatal immunocompetent mouse model. ZIKV showed brain tropism, causing post-natal microcephaly and several behavioral dysfunctions. During the acute phase of infection, mice developed very frequent epileptic seizures, which are consistently reduced by TNF- neutralization. Although adult animals recover from seizures, they become more susceptible to chemically-induced crises. Intriguingly, the virus remained actively replicating in adult animals, which show persistent necrosis and calcifications in the mice brain. Altogether the results reveal late consequences of neonatal ZIKV exposure and suggest the early inhibition of neuroinflammation as a potential treatment.

neuroscience↗