Biology subjects

Canals, S.

Publications and source records attributed to Canals, S..

13 recordsLinked to original sources

bioRxiv2026

Multimodal neuroimaging-microbiota integration identifies Akkermansia as a modulator of alcohol-induced gut-liver-brain pathology

Alcohol use disorder (AUD) disrupts the gut-liver-brain axis, yet mechanistically grounded and therapeutically actionable targets within this network remain poorly defined. To identify microbial modulators of alcohol-induced tissue pathology, longitudinal advanced diffusion MRI and fecal 16S rRNA profiling were integrated across Marchigian Sardinian alcohol-preferring rats evaluated at baseline, after four weeks of voluntary alcohol intake, and following six weeks of abstinence. Machine learning, specifically random forest models combining neuroimaging and microbiota data, improved phase classification and identified Akkermansia as the microbial feature most strongly associated with alcohol-related white matter microstructural abnormalities. Alcohol exposure induced widespread white matter alterations alongside gut dysbiosis characterized by reduced microbial diversity. To evaluate functional relevance, Akkermansia muciniphila was administered during the abstinence phase. Supplementation with A. muciniphila restored intestinal mucus, reduced liver injury markers, and elevated myelin basic protein levels within affected white matter regions. Collectively, these findings highlight Akkermansia as a critical modulator of alcohol-induced gut-liver-brain pathology and provide experimental support for a causal contribution of specific gut bacteria to persistent white matter damage in AUD. More broadly, this work establishes a robust multimodal framework for microbiome-based target discovery with clear translational relevance for disorders characterized by dysfunction along the gut-liver-brain axis. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSAlcohol use disorder (AUD) is associated with gut dysbiosis, impaired intestinal barrier function, liver injury, and persistent white matter abnormalities. Previous studies in patients and animal models have linked alcohol exposure to reduced microbial diversity, altered gut permeability, and white matter microstructural damage, particularly during abstinence. Other work has shown that microbiota-derived interventions can ameliorate peripheral consequences of alcohol exposure, especially in the gut and liver. However, the specific microbial features linked to alcohol-induced brain pathology remain poorly defined, and no prior study has integrated longitudinal microbiota and neuroimaging data to identify candidate microbial modulators of alcohol-related white matter damage and then functionally test them in vivo across the gut-liver-brain axis. Added value of this studyWe developed a multimodal framework that integrates longitudinal advanced diffusion MRI with fecal microbiota profiling and machine learning in alcohol-preferring rats. This approach identified Akkermansia as the microbial feature most strongly associated with alcohol-induced white matter abnormalities. Guided by this result, we administered Akkermansia muciniphila during abstinence and observed coordinated beneficial effects across multiple organs, including restoration of intestinal mucus, reduction of liver injury markers, and recovery of myelin basic protein in affected white matter regions. To our knowledge, this is the first study to combine longitudinal microbiota-MRI integration with experimental validation of a microbiota-based intervention that mitigates alcohol-induced pathology across the gut-liver-brain axis while restoring central white matter integrity. Implications of all the available evidenceOur findings support a mechanistic contribution of specific gut bacteria to persistent alcohol-induced tissue damage and identify Akkermansia as a candidate modulator of gut-liver-brain axis dysfunction in AUD. More broadly, this study establishes a generalizable strategy for integrating microbiota and neuroimaging data to discover biologically meaningful and therapeutically actionable targets in complex disorders involving coordinated peripheral and central pathology.

neuroscience↗

bioRxiv2026

Longitudinal MRI reveals hormone-dependent brain remodeling supporting preserved cognition in aged females

Adaptive plasticity, the brains capacity to counteract structural decline and preserve performance with age, is a hallmark of successful aging, yet its biological underpinnings remain poorly understood. Here, we combined longitudinal magnetic resonance imaging (MRI) spanning the entire lifespan with electrophysiology, immunohistochemistry, and behavioral assays in female and male rats to identify key region- and systems-level mechanisms underlying this process. Resting-state functional MRI revealed a striking sex-specific pattern of connectivity reorganization in anterior brain regions, emerging in midlife and more pronounced in females. Microstructural MRI and histological analyses linked increased connectivity to prolonged white matter preservation and downstream maintenance of neuronal function in the female prefrontal cortex, while electrophysiological recordings demonstrated enhanced effective connectivity in the same region in aged females. Behaviorally, enhanced anterior connectivity was associated with superior memory performance. Ovariectomy at a critical time point for white matter maturation compromised this female-specific neuroprotection, disrupting microstructural integrity and functional reorganization, thereby highlighting the role of sex hormones in shaping these trajectories. Together, these findings identify a novel sexually dimorphic pattern of functional reorganization in anterior brain regions and point to estrogen availability during critical periods as a key modulator of brain aging.

neuroscience↗

bioRxiv2025

A sensitivity-consistency trade-off in memory formation regulated by dentate gyrus inhibition

A core computational challenge for memory systems is the need to balance two opposing demands: (1) sensitivity to subtle input differences for flexible encoding, and (2) consistency to preserve stable, interference-resistant representations. How the brain dynamically regulates this trade-off remains unclear. Here, we show that modulating parvalbumin-expressing (PV+) interneurons in the dentate gyrus regulates this balance by shifting hippocampal computation between sensitivity and consistency regimes. Combining cell-type-specific pharmacogenetics, behavioral assays, and computational modeling, we found that reducing PV+-mediated inhibition during encoding enhanced the subsequent discrimination of similar inputs but it increased vulnerability to interference. In contrast, increased inhibition stabilized memory representations at the cost of discriminability. Together, the results establish PV+ interneurons as key modulators of hippocampal memory processing, enabling the system to prioritize either flexible updating or robust retention based on inhibitory tone at the time of encoding. This sensitivity-consistency continuum may reflect a fundamental organizing principle of memory computation.

neuroscience↗

bioRxiv2025

The Role of Feedforward and Feedback Inhibition in Modulating Theta-Gamma Cross-Frequency Interactions

Interactions among brain rhythms play a crucial role in organizing neuronal firing sequences during specific cognitive functions. In memory formation, the coupling between the phase of the theta rhythm and the amplitude of gamma oscillations has been extensively studied in the hippocampus. Prevailing perspectives suggest that the phase of the slower oscillation modulates the fast activity. However, recent metrics, such as Cross-Frequency Directionality (CFD), indicate that these electrophysiological interactions can be bidirectional. Using a computational model, we demonstrate that feedforward inhibition modeled by a theta-modulated ING (Interneuron Network Gamma) mechanism induces fast-to-slow interactions, while feedback inhibition through a PING (Pyramidal Interneuron Network Gamma) model drives slow-to-fast interactions. Importantly, in circuits combining both feedforward and feedback motifs, as commonly found experimentally, directionality is flexibly modulated by synaptic strength within biologically realistic ranges. A signature of this interaction is that fast-to-slow dominance in feedforward motifs is associated with gamma oscillations of higher frequency, and vice versa. Using previously acquired electrophysiological data from the hippocampus of rats freely navigating in a familiar environment or in a novel one, we show that CFD is dynamically regulated and linked to the frequency of the gamma band, as predicted by the model. Finally, the model attributes each theta-gamma interaction scheme, determined by the balance between feedforward and feedback inhibition, to distinct modes of information transmission and integration, adding computational flexibility. Our results offer a plausible neurobiological interpretation for cross-frequency directionality measurements associated with the activation of different underlying motifs that serve distinct computational needs. Author SummaryThis study investigates the interaction between various types of brain oscillations and their potential relationship with the connectivity of underlying neural networks. Brain activity encompasses slow oscillations, such as theta, alpha, and delta, as well as faster oscillations, including gamma. These oscillations interact through Cross-Frequency Coupling (CFC), a mechanism essential for cognitive processes like memory, learning, and attention. Given the higher spectral power and broader spatial propagation of slow oscillations, it has been proposed that CFC arises when slow oscillations modulate faster activity. However, recent evidence suggests that gamma oscillations can also predict the phase of slower oscillations, indicating a bidirectional and more intricate relationship. To explore this complexity, we developed a computational model that reproduces both forms of interaction observed experimentally. Our results demonstrate that while slow oscillations originating from distant regions can induce gamma activity, local connectivity and specific cell-type dynamics allow gamma oscillations to anticipate slow oscillations in certain conditions. The balance of inhibitory circuits modulates fast-slow oscillation interactions, creating distinct dynamical modes with varying computational properties and enhancing system flexibility. This work integrates competing hypotheses on oscillation interactions and offers a conceptual framework for linking these dynamics to the structural organization of neural circuits.

neuroscience↗

bioRxiv2025

NAc-DBS selectively enhances memory updating without effect on retrieval

Deep brain stimulation (DBS) has emerged as a widely used therapeutic option when pharmacological treatments prove ineffective or refractory for psychiatric patients. The nucleus accumbens (NAc) represents a frequently targeted site in DBS interventions due to its demonstrated safety profile and therapeutic efficacy in obsessive-compulsive disorder, major depression, and anorexia nervosa. However, limited mechanistic understanding hampers its broader clinical applicability. This study sought to delineate the distinct behavioural dimensions modulated by NAc-DBS, its impact on distinct facets of memory, and to elucidate the underlying brain-network mechanism of action. We developed a novel spatial navigation task for rats and employed a high-dimensional behavioural analysis complemented by fMRI to dissect the cognitive, behavioural and neurobiological effects of NAc-DBS. Active NAc-DBS produced a selective enhancement of long-term memory encoding without affecting memory recall or working memory. We found no effect of NAc-DBS on motor, appetitive or stress-related behaviours. Sustained neuronal activation in the NAc, septum, entorhinal and insular cortex demonstrated no desensitization to chronic NAc-DBS, which triggered a functional reorganization among dopaminergic-related structures. These findings suggest that NAc-DBS induces a functional reorganization in the mesocorticolimbic system, potentially mimicking a dopaminergic novelty signal to enhance memory updating. This provides a mechanistic basis for the therapeutic use of NAc-DBS, particularly in improving cognitive flexibility in psychiatric disorders.

neuroscience↗

bioRxiv2024

Influence of temporal information gaps on decision making: describing the dynamics of working memory

Decision making involves evaluating options and predicting their likely outcomes. Traditional laboratory studies of decision making often employ tasks involving the discrimination of perceptual evidence, where sensory information is constant and presented continuously. However, during natural behavior, decision making usually involves intermittent information streams, punctuated by periods with no input. To investigate decision making under such conditions, we designed a perceptual task where participants observed tokens sequentially jumping from a central circle to one of two peripheral targets, disappearing shortly after. Participants were required to report which target they believed would have received most tokens by the trials end. Half of the trials included a temporal gap, during which no information was displayed. To better understand decision-making dynamics, we introduced specific patterns of token jumps. We found that participants made choices with less available information and disproportionally weighted the information presented immediately after the gap more heavily than they did when no gap was present. Traditional computational models, which assume uniform or gradual decay or increase of weighting of information over time, could not account for this effect. A control task with randomly presented information further confirmed that the disproportionate weighting of post-gap information is a robust feature of the decision-making process. These findings highlight the importance of studying decision making in environments with intermittent information and temporal gaps, where the timing and structure of inputs critically shape behavior. Significance statementDecision making in real-world environments often involves intermittent information, where key evidence might be separated by temporal gaps. Our study demonstrate that people disproportionately rely on information received immediately after such gaps, weighting the same information more heavily than when no gap is present. Traditional decision-making models do not account for this effect, as they lack mechanisms to capture how temporal disruptions shape evidence weighting. By understanding how gaps influence decision making, this research provides insights into how people adapt their decisions in fluctuating environments, with implications for fields ranging from neuroscience to artificial intelligence.

neuroscience↗

bioRxiv2024

SAMson: an automated brain extraction tool for rodents using SAM

Accurate brain extraction is a critical step in the analysis of rodent head magnetic resonance imaging (MRI) data. However, current methods often encounter difficulties in handling the diverse range of imaging setups, resolutions, and experimental conditions that are commonly found in this field. Based on the Segment Anything Model (SAM), we introduce here SAMson (SAM for Segmentation Of Neuroimages), an automated tool for robust rodent brain extraction. SAMson integrates a bounding box generator and a mask prediction pipeline, offering fully automated and semi-automated modes to address varying experimental complexities. The performance of SAMson was evaluated using three multi-centre rodent MRI datasets annotated at the pixel level, which differed in terms of acquisition parameters, resolution, and animal age groups. SAMson demonstrates superior performance to existing methods, including BET, RBM, and BEN, in terms of segmentation accuracy, with Jaccard indices exceeding 90% across datasets. The semi-automated mode demonstrates particular efficacy in challenging scenarios, including low-resolution images and cases requiring refined mask precision. In contrast to conventional volumetric techniques, SAMson identifies errors at the level of individual slices, thereby enabling rapid and targeted correction when needed. By providing open-source access, SAMson aims to support large-scale research workflows and advance translational neuroscience. The curated data can be downloaded from https://doi.org/10.20350/digitalCSIC/17000, and the code is available at https://github.com/CanalsLab/SAMson.

neuroscience↗

bioRxiv2023

Somatic disinhibition of granule cells improves information transmission and pattern separation in the dentate gyrus

Cortical circuits operate in a tight excitation/inhibition balance. This balance is relaxed during learning processes, but neither the mechanism nor its impact on network operations are well understood. In the present study, we combined in-vivo and in-vitro neuronal recordings with computational modelling and demonstrated that synaptic plasticity in the afferents from the entorhinal cortex (EC) to the dentate gyrus (DG), in addition to strengthening the glutamatergic inputs into granule cells (GCs), depressed perisomatic inhibition. Computational modelling revealed a functional reorganization in the inhibitory network that explained several experimental findings, including depression of the feed-forward inhibition. In vitro results confirmed a perisomatic dominance of the inhibitory regulation with important functional consequences. It favoured GCs burst firing, improved reliability of input/output transformations and enhanced separation and transmission of temporal and spatial patterns in the EC-DG-CA3 network.

neuroscience↗

bioRxiv2022

A translational MRI approach to validate acute axonal damage detection in multiple sclerosis

Axonal degeneration is a central pathological feature of neurodegenerative pathologies and is closely associated with irreversible clinical disability. Current noninvasive methods to detect axonal damage in vivo are limited in their specificity, clinical applicability, and lack of proper validation. We aimed to validate an MRI framework based on multicompartment modeling of the diffusion-weighted signal (AxCaliber) in rats in the presence of axonal pathology, achieved through injection of a neurotoxin damaging the neuronal terminal of axons. We then applied the same MRI protocol to map axonal integrity in the whole brain of multiple sclerosis relapsing-remitting patients and age-matched healthy controls, a pathology associated with a neurodegenerative component. AxCaliber is sensitive to microstructural axonal damage in rats, as demonstrated by a significant increase in the mean axonal caliber along the target tract, which correlated with the neurotoxin neurofilament staining. In humans, we uncovered a diffuse increase in mean axonal caliber in multiple sclerosis lesions and, importantly, in most areas of the normal-appearing white matter. Our results demonstrate that axonal diameter mapping is a sensitive and specific imaging biomarker able to link noninvasive imaging contrasts with the underlying biological substrate, supporting the key role of generalized axonal damage useful in diseases such as multiple sclerosis.

neuroscience↗

bioRxiv2020

Hippocampal dentate gyrus coordinates brain-wide communication and memory updating through an inhibitory gating

Distinct forms of memory processing are often causally identified with specific brain regions, but a key facet of memory processing includes linking separated neuronal populations. Using cell-specific manipulations of inhibitory neuronal activity, we discovered a key role of the dentate gyrus (DG) in coordinating dispersed neuronal populations during memory formation. In whole-brain fMRI and electrophysiological experiments, we found that parvalbumin (PV) interneurons in the DG control the functional coupling of the hippocampus within a wider network of neocortical and subcortical structures including the prefrontal cortex (PFC) and the nucleus accumbens (NAc). In a novel object-location task, regulation of PV interneuron activity enhanced or prevented memory encoding and, without effect upon the total number of task activated c-Fos+ cells, revealed a correlation between activated neuronal populations in the hippocampus-PFC-NAc network. These data suggest a critical regulatory role of PV interneurons in the dentate gyrus in brain-wide polysynaptic communication channels and the association of cell assemblies across multiple brain regions.

neuroscience↗

bioRxiv2020

Imaging Microglia and Astrocytes non-invasively using Diffusion MRI

Glia, and particularly microglia, are increasingly implicated in the pathophysiology of psychiatric and neurodegenerative disorders. However, to date the only methods for imaging these cells in vivo involve either invasive procedures (e.g. multi-photon imaging in rodents) or TSPO-PET radiotracers, which afford low resolution and specificity, since TSPO expresses across multiple cell types. Here, we present a non-invasive diffusion-weighted MRI method to image changes in glia morphometry in vivo. Using two rat models of neuroinflammation, with and without neurodegeneration, we demonstrate that diffusion-weighted MRI carries the fingerprint of microglia and astrocytes activation, and that specific signatures from each population can be quantified non-invasively. We demonstrate that the method can further detect glia proliferation, and provide a quantitative account of neuroinflammation regardless of the existence of a concomitant neuronal loss. We prove the translational value of the approach showing significant correlations between MRI and histological microglia markers measured across different brain regions in humans. This framework holds the potential to transform basic and clinical research by providing a tool to clarify the role of inflammation in health and disease across the lifespan.

neuroscience↗

bioRxiv2019

Neuronal identity is maintained in the adult brain through KAT3-dependent enhancer acetylation

Very little is known about the mechanisms responsible for maintaining cell identity in mature tissues. The paralogous type 3 lysine acetyltransferases (KAT3) CBP and p300 are both essential during development, but their specific functions in nondividing differentiated cells remains unclear. Here, we show that when both proteins are simultaneously knocked-out in excitatory neurons of the adult brain, the mice express a rapidly progressing neurological phenotype associated with reduced dendritic complexity and electrical activity, the transcriptional shutdown of neuronal genes, and a dramatic loss of H3K27 acetylation and pro-neural transcription factor binding at neuronal enhancers. The neurons lacking both KAT3 rapidly acquire a molecularly undefined fate with no sign of dedifferentiation, transdifferentiation or death. Restoring CBP expression or lysine acetylation reestablished neuronal-specific transcription. Our experiments demonstrate that KAT3 proteins act as fate-keepers in excitatory neurons and other cell types by jointly safeguarding chromatin acetylation levels at cell type-specific enhancers throughout life.

cell biology↗

bioRxiv2018

Gamma oscillations coordinate different theta rhythms in the hippocampus

Hippocampal firing is organized in theta sequences controlled by internal memory-related processing and by external sensory cues. How these computations are segregated or integrated, depending on the cognitive needs, is not fully understood. Although theta activity in the hippocampus is most commonly studied as a unique coherent oscillation, it is the result of a complex interaction between different rhythm generators. Here we investigated the coordination between theta generators as a possible mechanism to couple or decouple internally and externally driven computations. We separated and quantified three different theta current generators from the hippocampus of freely behaving rats, one originating in CA3 with current sinks in CA1 str. radiatum and two with current sinks in CA1 str. lacunosum-moleculare and dentate molecular layer, mainly driven by entorhinal cortex (EC) layers 3 and 2, respectively. These theta generators followed non fully coherent dynamics and presented epochs of higher and lower phase coupling, suggesting a flexible interaction between them. Selective optogenetic inhibition in CA3 depressed the str. radiatum generator without affecting the EC-driven theta oscillations, indicating that theta rhythm generators can be modulated independently. In addition, band-specific gamma interactions with theta oscillations selectively occurred with the corresponding pathway-specific theta current generator, supporting the existence of different theta-gamma coding frameworks to organize neuronal firing in the hippocampus. Importantly, we found that epochs of highly synchronized theta rhythmicity across generators preferentially occurred during memory-guided exploration and mismatch novelty detection in familiar environments, two conditions in which internally generated memory representations need to be coordinated with the incoming sensory information about external cues. We propose a mechanism for segregating and integrating hippocampal computations based on the coexistence of different theta-gamma frameworks that flexibly couple or decouple accommodating the cognitive needs.

neuroscience↗