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Bernard, C.

Publications and source records attributed to Bernard, C..

71 records · Page 4Linked to original sources

Epidynamics characterize and navigate the map of seizure dynamics

Seizures are a disruption of normal brain activity present across a vast range of species, diseases, and conditions. Here we introduce an organizing principle that leads to the first objective Taxonomy of Seizure Dynamics (TSD) based on bifurcation theory, and applied it to the analysis of EEG data. The "dynamotype" of a seizure is the part of its dynamic composition that defines its observable characteristics, including how it starts, evolves and terminates. Analyzing over 2000 focal-onset seizures recorded from 7 epilepsy centers on five continents, we find evidence of all 16 dynamotypes predicted in TSD. We demonstrate that patients dynamotypes evolve during their lifetime and display complex but systematic variations including hierarchy (certain dynamotypes are more common), non-bijectivity (a patient may display multiple dynamotypes) and pairing preference (multiple dynamotypes may occur during one seizure). TSD not only provides a way to stratify patients in complement to present practical classifications but also guides biophysically based mechanistic approaches and provides a language to describe the most critical features of seizure dynamics. Impact statementTaxonomy of Seizure Dynamics (TSD) provides a rigorous method for classifying and quantifying seizures and a principled framework for understanding seizure initiation and propagation.

bioinformatics↗

Dynamic core-periphery structure of information sharing networks in entorhinal cortex and hippocampus

Neural computation is associated with the emergence, reconfiguration and dissolution of cell assemblies in the context of varying oscillatory states. Here, we describe the complex spatio-temporal dynamics of cell assemblies through temporal network formalism. We use a sliding window approach to extract sequences of networks of information sharing among single units in hippocampus and enthorinal cortex during anesthesia and study how global and node-wise functional connectivity properties evolve along time and as a function of changing global brain state (theta vs slow-wave oscillations). First, we find that information sharing networks display, at any time, a core-periphery structure in which an integrated core of more tightly functionally interconnected units link to more loosely connected network leaves. However the units participating to the core or to the periphery substantially change across time-windows, with units entering and leaving the core in a smooth way. Second, we find that discrete network states can be defined on top of this continuously ongoing liquid core-periphery reorganization. Switching between network states results in a more abrupt modification of the units belonging to the core and is only loosely linked to transitions between global oscillatory states. Third, we characterize different styles of temporal connectivity that cells can exhibit within each state of the sharing network. While inhibitory cells tend to be central, we show that, otherwise, anatomical localization only poorly influences the patterns of temporal connectivity of the different cells. Furthermore, cells can change temporal connectivity style when the network changes state. Altogether, these findings reveal that the sharing of information mediated by the intrinsic dynamics of hippocampal and enthorinal cortex cell assemblies have a rich spatiotemporal structure, which could not have been identified by more conventional time- or state-averaged analyses of functional connectivity. AUTHOR SUMMARYIt is generally thought that computations performed by local brain circuits rely on complex neural processes, associated to the flexible waxing and waning of cell assemblies, i.e. ensemble of cells firing in tight synchrony. Although cell assembly formation is inherently and unavoidably dynamical, it is still common to find studies in which essentially "static" approaches are used to characterize this process. In the present study, we adopt instead a temporal network approach. Avoiding usual time averaging procedures, we reveal that hub neurons are not hardwired but that cells vary smoothly their degree of integration within the assembly core. Furthermore, our temporal network framework enables the definition of alternative possible styles of "hubness". Some cells may share information with a multitude of other units but only in an intermittent manner, as "activists" in a flash mob. In contrast, some other cells may share information in a steadier manner, as resolute "lobbyists". Finally, by avoiding averages over pre-imposed states, we show that within each global oscillatory state a rich switching dynamics can take place between a repertoire of many available network states. We thus show that the temporal network framework provides a natural and effective language to rigorously describe the rich spatiotemporal patterns of information sharing instantiated by cell assembly evolution.

neuroscience↗

Testing Finch’s hypothesis: the role of organismal modularity on the escape from actuarial senescence

O_LIUntil recently, senescence was assumed to be a universal phenomenon. Evolutionary theories of senescence predict that no organism may escape the physiological decline that results in an increase in mortality risk and/or decline in fertility with age. However, evidence both in animals and plants has emerged in the last decade defying such predictions. Researchers are currently seeking mechanistic explanations for the observed variation in ageing trajectories.\nC_LIO_LIWe argue that the historical view on the inevitability of senescence is due, in part, to the development of its classical theories, which targeted primarily unitary organisms. In unitary species, the integration of resources and functions is high, and adult size is determined. In contrast, the architecture of modular organisms is indeterminate and built upon repeated modules. The isolation of mortality risk in species like hydra (Hydra spp.) or creosote brush (Larrea tridentata) may explain their null or even negative senescence.\nC_LIO_LICaleb Finch hypothesised three decades ago that species with the ability to compartmentalise risk may escape senescence. Here, we first review the evidence on organisms that slow down or even avoid senescence in the context of their architecture, along a continuum of unitarity-modularity. Then, we use open-access databases to comparatively analyse various moments of senescence and link longevity to the degree of anatomic modularity. Our analysis compares 138 plants and 151 animals. Our comparative analysis reveals that plant species that are more modular do indeed tend to escape from senescence more often than those that are unitary. The role of modularity in animal senescence is less clear.\nC_LIO_LIIn light of novel support for Finchs hypothesis across a large diversity of plant species, and with less conclusive findings in animals, we identify new research directions. We highlight opportunities related to age-dependent mortality factors. Other areas for further research include the role of modularity in relation to endocrine actions, and the costs of modular anatomies.\nC_LI O_QD\"The actinozooid is a living thing which knows no time of youthful vigour, no waxing to a period of adult life, no waxing to senility - it knows no age - it practically knows no natural death.\" - Wood-Jones (1912)\n\nC_QD

ecology↗

In vivo characterization of neurophysiological diversity in the lateral supramammillary nucleus during hippocampal sharp-wave ripples of adult rats

The extent of the networks that control the genesis and modulation of hippocampal sharp wave ripples (SPW-Rs), which are involved in memory consolidation, remains incompletely understood. Here, we performed a detailed in vivo analysis of single cell firing in the lateral supramammillary nucleus (lSuM) during theta and slow oscillations, including SPW-Rs, in anesthetized rats. We classified neurons as SPW-R-active and SPW-R unchanged according to whether or not they increased their firing during SPW-Rs. We show that lSuM SPW-R-active neurons increase their firing prior SPW-Rs peak power and prior hippocampal pyramidal cell activation. Moreover, lSuM SPW-R-active neurons show increased firing activity during theta and slow oscillations as compared to unchanged-neurons. SPW-R-active neurons are more active during high peak power SPW-Rs, whereas SPW-R-unchanged neurons are more active during long SPW-Rs. These results suggest that a sub-population of lSuM neurons can interact with the hippocampus during SPW-Rs, raising the possibility that the lSuM may modulate memory consolidation.

neuroscience↗

Caffeine consumption during pregnancy accelerates the development of cognitive deficits in offspring in a model of tauopathy

Psychoactive drugs used during pregnancy can affect the development of the brain of offspring, directly triggering neurological disorders or increasing the risk for their occurrence. Caffeine is the most widely consumed psychoactive drug, including during pregnancy. In Wild type mice, early life exposure to caffeine renders offspring more susceptible to seizures. Here, we tested the long-term consequences of early life exposure to caffeine in THY-Tau22 transgenic mice, a model of Alzheimers disease-like Tau pathology. Caffeine exposed mutant offspring developed cognitive earlier than water treated mutants. Electrophysiological recordings of hippocampal CA1 pyramidal cells in vitro revealed that early life exposure to caffeine changed the way the glutamatergic and GABAergic drives were modified by the Tau pathology. We conclude that early-life exposure to caffeine affects the Tau phenotype and we suggest that caffeine exposure during pregnancy may constitute a risk-factor for early onset of Alzheimers disease-like pathology.

neuroscience↗

Individual structural features constrain the functional connectome

Whole brain dynamics intuitively depends upon the internal wiring of the brain; but to which extent the individual structural connectome constrains the corresponding functional connectome is unknown, even though its importance is uncontested. After acquiring structural data from individual mice, we virtualized their brain networks and simulated in silico functional MRI data. Theoretical results were validated against empirical awake functional MRI data obtained from the same mice. We demonstrate that individual structural connectomes predict the functional organization of individual brains. Using a virtual mouse brain derived from the Allen Mouse Brain Connectivity Atlas, we further show that the dominant predictors of individual structure-function relations are the asymmetry and the weights of the structural links. Model predictions were validated experimentally using tracer injections, identifying which missing connections (not measurable with diffusion MRI) are important for whole brain dynamics in the mouse. Individual variations thus define a specific structural fingerprint with direct impact upon the functional organization of individual brains, a key feature for personalized medicine.\n\nSIGNIFICANCE STATEMENTThe structural connectome is a key determinant of brain function and dysfunction. The connectome-based model approach aims to understand the functional organization of the brain by modeling the brain as a dynamical system and then studying how the functional architecture rises from the underlying structural skeleton. Here, taking advantage of mice studies, we systematically investigated the informative content of different structural features in explaining the emergence of the functional ones. We demonstrate that individual variations define a specific structural fingerprint with a direct impact upon the functional organization of individual brains stressing the importance of using individualized models to understand brain function. We show how limitations of connectome reconstruction with the diffusion-MRI method restrict our comprehension of the structural-functional relation.

neuroscience↗

The GABA-Glutamate supramammillary-dorsal Dentate Gyrus pathway controls theta and gamma oscillations in the DG during paradoxical sleep

Several studies suggest that neurons from the lateral region of the SuM (SuML) innervating the dorsal dentate gyrus (DG) display a dual GABAergic and glutamatergic transmission and are specifically activated during paradoxical (REM) sleep (PS). The objective of the present study is to fully characterize the anatomical, neurochemical and electrophysiological properties of the SuML-DG projection neurons and to determine how they control DG oscillations and neuronal activation during PS and other vigilance states. For this purpose, we combine structural connectivity techniques using neurotropic viral vectors (rabies virus, AAV), neurochemical anatomy (immunohistochemistry, in situ hybridization) and imaging (light, electron and confocal microscopy) with in vitro (patch clamp) and in vivo (LFP, EEG) optogenetic and electrophysiological recordings performed in transgenic VGLUT2-cre male mice. At the cellular level, we show that the SuML-DG neurons co-release GABA and glutamate on dentate granule cells and increase the activity of a subset of DG granule cells. At the network level, we show that activation of the SuML-DG pathway increases theta power and frequency during PS as well as gamma power during PS and waking in the DG. At the behavioral level, we show that the activation of this pathway does not change animal behavior during PS, induces awakening during slow wave sleep and increases motor activity during waking. These results suggest that the SuML-DG pathway is capable of supporting the increase of theta and gamma power in the DG observed during PS and plays an important modulatory role of DG network activity during this state.\n\nSignificant statementAn increase of theta and gamma power in the dentate gyrus (DG) is an hallmark of paradoxical (REM) sleep (PS) and is suggested to promote learning and memory consolidation by synchronizing hippocampal networks and increasing its outputs to cortical targets. However the neuronal networks involved in such control of DG activity during PS are poorly understood. The present study identifies a population of GABA/Glutamate neurons in the lateral supramammllary nucleus (SuML) innervating the DG that could support such control during PS. Indeed, we show that activation of these SuML-DG projections increase theta power and frequency as well as gamma power in the DG specifically during PS and modulate activity of a subset of DG granule cells.

neuroscience↗

Computing Hubs in the Hippocampus and Cortex

Neural computation, which relies on the active storage and sharing of information, occurs within large neuron networks in the highly dynamic context of varying brain states. Whether such functions are performed by specific subsets of neurons and whether they occur in specific dynamical regimes remain poorly understood. Using high density recordings in the hippocampus, medial entorhinal and medial prefrontal cortex of the rat, we identify computing microstates, or discreet epochs, in which specific computing hub neurons perform well defined storage and sharing operations in a brain state-dependent manner. We retrieve a multiplicity of distinct computing microstates within each global brain state, such as REM and nonREM sleep. Half of recorded neurons act as computing hubs in at least one microstate, suggesting that functional roles are not firmly hardwired but dynamically reassigned at the second timescale. We identify sequences of microstates whose temporal organization is dynamic and stands between order and disorder. We propose that global brain states constrain the language of neuronal computations by regulating the syntactic complexity of these microstate sequences.

neuroscience↗

Spatio-temporal organization of cell assemblies in Nucleus Reuniens during slow oscillations

The nucleus reuniens (NR) is an important anatomical and functional relay between the medial prefrontal cortex (mPFC) and the hippocampus (HPC). Whether the NR controls neuronal assemblies, a hallmark of information exchange between the HPC and mPFC for memory transfer/consolidation, is not known. Using simultaneous LFP and unit recordings in NR, HPC and mPFC in rats during slow oscillations under anesthesia, we identified a reliable sequential activation of NR neurons at the beginning of UP states, which preceded mPFC ones. NR sequences were spatially organized, from dorsal to ventral NR. Chemical inactivation of the NR disrupted mPFC sequences at the onset of UP states as well as HPC sequences present during sharp-wave ripples. We conclude that the NR contributes to the coordination and stabilization of mPFC and HPC neuronal sequences during slow oscillations, possibly via the early activation of its own sequences. Significance StatementNeuronal assemblies are believed to be instrumental to code/encode/store information. They can be recorded in different brain regions, suggesting that widely distributed networks of networks are involved in such information processing. The prefrontal cortex, the hippocampus and the thalamic nucleus reuniens constitute a typical example of a complex network involved in memory consolidation. In this study, we show that spatially organized cells assemblies are recruited in the nucleus reuniens at the UP state onset during slow oscillations. Nucleus reuniens activity appears to be necessary to the stability of prefrontal cortex and hippocampal cell assembly formation during slow oscillations. This result further highlights the role of the Nucleus Reuniens as a functional hub for exchanging and processing memories.

neuroscience↗

Subcellular localization of microcystin in the liver and the gonad of medaka fish acutely exposed to microcystin-LR

Among the diverse toxic components produced by cyanobacteria, microcystins (MCs) are one of the most toxic and notorious cyanotoxin groups. Besides their potent hepatotoxicity, MCs have been revealed to induce potential reproductive toxicity in various animal studies. However, little is still known regarding the distribution of MCs in the reproductive organ, which could directly affect reproductive cells. In order to respond to this question, an acute study was conducted in adult medaka fish (model animal) gavaged with 10 {micro}g.g-1 body weight of pure MC-LR. The histological and immunohistochemical examinations reveal an intense distribution of MC-LR within hepatocytes along with a severe liver lesion in the toxin-treated female and male fish. Besides being accumulated in the hepatocytes, MC-LR was also found in the connective tissue of the ovary and the testis, as well as in oocytes and degenerative spermatocyte-like structures. Both liver and gonad play important roles in the reproductive process of oviparous vertebrates. This observation constitutes the first observation of the presence of MC-LR in the reproductive cell of a vertebrate model with in vivo study. Our results, which provide intracellular localization of MC-LR in the gonad, advance our understanding of the potential reproductive toxicity of MC-LR in fish.

cell biology↗

Specific metabolic signatures of fish exposed to cyanobacterial blooms

With the increasing impact of the global warming, occurrences of cyanobacterial blooms in aquatic ecosystems are becoming a main ecological concern around the world. Due to their capacity to produce potential toxic metabolites, interactions between the cyanobacteria/cyanotoxin complex and the other freshwater organisms have been widely studied in the past years. Non-targeted metabolomic analyses have the powerful capacity to study a high number of metabolites at the same time and thus to understand in depth the molecular interactions between various organisms in different environmental scenario and notably during cyanobacterial blooms. In this way during summer 2015, liver metabolomes of two fish species, sampled in peri-urban lakes of the ile-de-France region containing or not high concentrations of cyanobacteria, were studied. The results suggest that similar metabolome changes occur in both fish species exposed to cyanobacterial blooms compared to them not exposed. Metabolites implicated in protein synthesis, protection against ROS, steroid metabolism, cell signaling, energy storage and membrane integrity/stability have shown the most contrasted changes. Furthermore, it seems that metabolomic studies will provide new information and research perspectives in various ecological fields and notably concerning cyanobacteria/fish interactions but also a promising tool for environmental monitoring of water pollutions.

ecology↗

Global metabolomic characterizations of Microcystis spp. highlights clonal diversity in natural bloom-forming populations and expands metabolite structural diversity

Cyanobacteria are photosynthetic prokaryotes that are able to synthetize a wild rang of secondary metabolites exhibiting noticeable bioactivity, comprising toxicity. Microcystis represents one of the most common cyanobacteria taxa constituting the intensive blooms that arise nowadays in freshwater ecosystems worldwide. They produce numerous cyanotoxins (toxic metabolites), which are potentially harmful to Human health and aquatic organisms. In order to better understand the variations in cyanotoxins production between clones of the Microcystis, we investigate the diversity of several strains isolated from the same blooms, from different populations in various geographical area.\n\nTwenty-four clonal strains were compared by genotyping with 16S-ITS fragment sequencing and metabolites chemotyping using LC ESI-qTOF mass spectrometry. While, genotyping can only discriminate between the different species, the global metabolomes reveal clear discriminant molecular profiles between strains. These profiles can be clustered primarily according to their global metabolite content, then to their genotype, and finally to their sampling localities. A global molecular network of all metabolites highlights the production of a wide set of chemically diverse metabolites, comprising only few microcystins, but many aeruginosins, cyanopeptolins and microginins, along with a large set of unknown molecules. They represent the molecular biodiversity that still remain to be investigated and characterized at their structure as well as at their potential bioactivity or toxicity levels.

microbiology↗

Clinical data specification and coding for cross-analyses with omics data in autoimmune disease trials

ObjectivesAutoimmune and inflammatory diseases (AIDs) form a continuum of autoimmune and inflammatory diseases, yet AIDs nosology is based on syndromic classification. The TRANSIMMUNOM trial (NCT02466217) was designed to re-evaluate AIDs nosology through clinic-biological and multi-omics investigations of patients with one of 19 selected AIDs. To allow cross-analyses of clinic-biological data together with omics data, we needed to integrate clinical data in a harmonized database.\n\nMaterials and MethodsWe assembled a clinical expert consortium (CEC) to select relevant clinic-biological features to be collected for all patients and a cohort management team comprising biologists, clinicians and computer scientists to design an electronic case report form (eCRF). The eCRF design and implementation has been done on OpenClinica, an open-source CFR-part 11 compliant electronic data capture system.\n\nResultsThe CEC selected 865 clinical and biological parameters. The CMT selected coded the items using CDISC standards into 5835 coded values organized in 28 structured eCRFs. Examples of such coding are check boxes for clinical investigation, numerical values with units, disease scores as a result of an automated calculations, and coding of possible treatment formulas, doses and dosage regimens per disease.\n\nDiscussion21 CRFs were designed using OpenClinica v3.14 capturing the 5835 coded values per patients. Technical adjustment have been implemented to allow data entry and extraction of this amount of data, rarely achieved in classical eCRFs designs.\n\nConclusionsA multidisciplinary endeavour offers complete and harmonized CRFs for AID clinical investigations that are used in TRANSIMMUNOM and will benefit translational research team.

clinical trials↗

On the difficulty to interpret results when animals are singly housed: experimental epilepsy as a prototypical example

Many experimental approaches require housing rodents in individual cages, including in epilepsy research. However, rats and mice are social animals; and individual housing constitutes a stressful situation. The goal of the present study was to determine the effects of individual housing as compared to conditions maintaining social contact on stress markers and epilepsy. Control male mice socially housed during pretest and then transferred to individual cages for six weeks displayed anhedonia, increased anxiety and biological markers of stress as compared to pretest values or mice kept socially housed during six weeks. Pilocarpine-treated mice housed together showed increased levels of anhedonia, anxiety and stress markers as well as decreased cognitive performance as compared to the control group. The differences were more significant in pilocarpine-treated mice housed individually. Anxiety correlated linearly with cognitive performance and stress markers independently of the experimental conditions. In the male rat pilocarpine model, seizures were sixteen times more frequent in singly housed animals as compared to animals kept in pairs. Daily interactions with an experimenter in otherwise singly housed animals was sufficient to produce results identical to those found in animals kept in pairs. We propose that social isolation produces a severe phenotype in terms of stress and seizure frequency as compared to animals maintaining social contact (at least in these two models), a factor that needs to be taken into account for data interpretation, in particular for preclinical studies.\n\nSignificance StatementMany experimental approaches require housing rodents in individual cages, a stressful condition for social animals, even in an enriched environment context. Using the pilocarpine model of epilepsy in rats and mice, we report that singly housing animals develop a more severe phenotype in terms of stress and epilepsy as compared to animals maintaining social contact. We propose that social isolation adds a degree of complexity for the interpretation of data, which may be particularly relevant for preclinical studies.

neuroscience↗

The circadian hippocampus and its reprogramming in epilepsy: impact for chronotherapeutics

Gene and protein expression displays circadian oscillations in numerous body organs. These oscillations can be disrupted in diseases, thus contributing to the disease pathology. Whether the molecular architecture of cortical brain regions oscillates daily and whether these oscillations are modified in brain disorders is less understood. We identified 1200 daily oscillating transcripts in the hippocampus of control mice. More transcripts (1600) were oscillating in experimental epilepsy, with only one fourth oscillating in both conditions. Proteomics confirmed these results. Metabolic activity and targets of antiepileptic drugs displayed different circadian regulation in control and epilepsy. Hence, the hippocampus, and perhaps other cortical regions, shows a daily remapping of its molecular landscape, which would enable different functioning modes during the night/day cycle. The impact of this remapping in brain pathologies needs to be taken into account not only to study their mechanisms, but also to design drug treatments and time their delivery.

neuroscience↗

Non-cell autonomous Otx2 homeoprotein regulates visual cortex plasticity through Gadd45b

The non-cell autonomous transfer of OTX2 homeoprotein transcription factor into juvenile mouse cerebral cortex regulates parvalbumin interneuron maturation and critical period timing. By analyzing gene expression in primary visual cortex of wild-type and Otx2+/GFP mice at plastic and non-plastic ages, we identified several putative genes implicated in Otx2-dependent visual cortex plasticity for ocular dominance. Cortical OTX2 infusion in juvenile mice induced Gadd45b/g expression through direct regulation of transcription. Intriguingly, a reverse effect was found in the adult, where reducing cortical OTX2 resulted in Gadd45b/g up-regulation. Viral expression of Gadd45b in adult visual cortex directly induced ocular dominance plasticity with concomitant changes in MeCP2 foci within parvalbumin interneurons and in methylation states of several plasticity gene promoters, suggesting epigenetic regulation. This interaction provides a molecular mechanism for OTX2 to trigger critical period plasticity yet suppress adult plasticity.

neuroscience↗

The Virtual Mouse Brain: A Computational Neuroinformatics Platform To Study Whole Mouse Brain Dynamics

Connectome-based modeling of large-scale brain network dynamics enables causal in silico interrogation of the brains structure-function relationship, necessitating the close integration of diverse neuroinformatics fields.\n\nHere we extend the open-source simulation software The Virtual Brain to whole mouse brain network modeling based on individual diffusion Magnetic Resonance Imaging (dMRI)-based or tracer-based detailed mouse connectomes. We provide practical examples on how to use The Virtual Mouse Brain to simulate brain activity, such as seizure propagation and the switching behavior of the resting state dynamics in health and disease.\n\nThe Virtual Mouse Brain enables theoretically driven experimental planning and ways to test predictions in the numerous strains of mice available to study brain function in normal and pathological conditions.

neuroscience↗