Biology subjects

Lejeune, F.-X.

Publications and source records attributed to Lejeune, F.-X..

16 recordsLinked to original sources

bioRxiv2026

Differential endothelial cell remodeling in Down syndrome and APP duplication drives distinct blood brain barrier dysfunction

An extra copy of the amyloid precursor protein gene (APP) is present in Down syndrome (DS) and APP duplication (APPdup), increasing the risk of Alzheimer disease (AD) and cerebral amyloid angiopathy (CAA). However, we reported greater vascular A{beta} deposition in APPdup than in DS with AD, suggesting that other triplicated chromosome 21 genes may mitigate CAA severity. We investigated endothelial cell (EC) function and blood brain barrier (BBB) integrity in DS and APPdup using human induced pluripotent stem cell-derived ECs (iECs), assessing their morphology, junctional proteins, A{beta} peptide secretion, barrier function, and transcriptomic profiles. Both DS and APPdup iECs secreted more A{beta}40 A{beta}42 compared with their respective isogenic controls but exhibited distinct A{beta} peptide profiles. DS iECs showed increased junctional protein expression and reduced permeability, whereas APPdup iECs displayed increased permeability. Transcriptomic analysis revealed extensive dysregulation in DS iECs, with enrichment of junctional, adhesion, angiogenic, immune, and apoptosis pathways, and reduced cell-cycle, proliferative, and membrane-targeting signatures. APPdup iECs showed milder changes, including impaired protein targeting and reduced adhesion-related pathways. Despite comparable APP dosage, DS iECs maintained greater junctional integrity and lower permeability than APPdup iECs, potentially contributing to differential CAA vulnerability. However, impaired proliferation and altered angiogenesis may reduce BBB resilience during ageing.

neuroscience↗

bioRxiv2026

Spontaneous slow waves index multiple dimensions of recovery in Disorders of Consciousness

Whether and how residual awareness is expressed in patients with Disorders of Consciousness (DoC) depends on the severity of brain damage and the transient functional state of the cortex at assessment. Classically, DoC are associated with electroencephalographic (EEG) slowing, marked by high-amplitude slow waves, even during the day. Yet, slow waves are also a hallmark of healthy sleep, where they are thought to serve restorative functions and to help maintain network homeostasis. Here, we asked whether slow waves in DoC can provide insights into the severity of cortical dysfunction or, conversely, into the preservation of residual awareness and recovery potential, by characterizing their spatial, temporal and morphological properties. We analyzed 256-channel EEG recorded during the Local-Global auditory paradigm in 236 DoC patients, including 123 in Unresponsive Wakefulness Syndrome (UWS), 62 in a Minimally Conscious State minus (MCS-) and 29 in MCS plus (MCS+). High-amplitude slow waves were detected as local events, and their density, amplitude and slopes were quantified scalp-wide and channel-wise, by mean level and temporal variability across the recording. Slow-wave features were related to concurrent (Coma Recovery Scale-Revised - CRS-R, Local-Global paradigm) and follow-up (one-year Glasgow Outcome Scale-Extended - GOS-E) assessments of consciousness and functional recovery. Associations with MRI-derived measures of cortical integrity and structural connectivity, and differences between anoxic and traumatic etiologies, were also examined. Slow waves were more frequent in less severe DoC patients (i.e., MCS) compared to UWS. Slow-wave slopes were also steeper frontally and increased at a faster rate in patients exhibiting higher levels of consciousness and/or markers of conscious access during the Local-Global paradigm. More frequent and steeper slow waves at baseline further predicted recovery of consciousness and of functional independence at one year. At the individual level, slow-wave features classified states of consciousness above chance (AUC = 0.62 and 0.71 for MCS- and MCS+ versus UWS), whereas outcome prediction remained modest (0.56-0.58). These clinical associations had a structural basis: slow-wave occurrence was greater after traumatic than anoxic injury and scaled with the integrity of subcortico-cortical projection fibers and consciousness-related cortical networks. Contrary to the classical view of delta activity as a non-specific marker of impaired consciousness, prominent spontaneous slow waves indexed behavioral and neurophysiological signs of awareness and better recovery. Beyond reflecting a propensity for pathological bistability, they may also signal the integrity of the networks required to generate them, together with their residual capacity for dynamic regulation.

neuroscience↗

bioRxiv2026

Obesity-related alterations in plasma metabolomics and fecal microbiota in Down syndrome Dp(16)1Yey mice

Background/ObjectivesIndividuals with Down syndrome (DS) are at increased risk of obesity and metabolic comorbidities, yet the mechanisms underlying these conditions remain unclear. Here we investigated how DS-associated genetic condition interacts with diet and metabolic pathways in the Dp(16)1Yey mouse model of DS. MethodsUntargeted plasma metabolomics was performed in Dp(16)1Yey and control mice, subjected to either control or high-fat diet (HFD). Raw data were processed, and features were annotated. Statistical analyses were conducted in R, and pathway analysis was performed with MetaboAnalyst v5.0. Fecal microbiome was obtained using 16SrRNAseq and analyzed using phyloseq in R. ResultsDiet exerted the strongest effect on mice plasma metabolome, followed by sex and genotype. Seventy-five diet-responsive metabolites were enriched in amino acid and nucleotide metabolism. Genotype-driven changes affected 34 metabolites, notably impacting amino acid and taurine-hypotaurine metabolism. Fifty-six sex-associated metabolites highlighted disruptions in aromatic amino acid biosynthesis and pyrimidine metabolism. A significant Diet*Genotype interaction was observed for five metabolites, including a marked reduction in the microbiota-derived metabolite 3-indolepropionic acid (IPA) in Dp(16)1Yey mice on HFD. Both genotype and diet exerted pronounced effects on fecal microbiome with selective depletion of the IPA-producing Clostridia in Dp1Yey mice under HFD. ConclusionSegmental trisomy in Dp(16)1Yey mice modulates the host metabolic response to dietary fat, partly through microbiota-derived metabolites such as IPA. These findings highlight the importance of genotype, diet, and microbiome interactions in shaping metabolic disease risk in DS and point toward microbiota-targeted dietary interventions.

neuroscience↗

bioRxiv2026

High neuron-microglia interaction at the node of Ranvier predicts recovery in an inflammatory model of Multiple Sclerosis

Microglia, the resident immune cells of the central nervous system, dynamically respond to their environment in health, injury and disease. They contact axons at the nodes of Ranvier in an activity-dependent manner, a process which contributes to repair, but how adaptive immunity in Multiple Sclerosis (MS) impacts this neuron-microglia crosstalk remains unknown. Using an inflammatory MS model, we identify strengthened microglia-node interactions at remission onset, with marked interindividual variability. Increased engagement correlates with a Th2-related cytokine signature, and IL13/IL4 are sufficient to enhance microglia-node contacts. High interaction levels associate with more pro-regenerative microglia, improved tissue repair and better functional recovery. Low-intensity physical exercise at remission onset further promotes microglia-node interaction, pro-regenerative microglia and improves recovery. Consistently, high microglia-node contact in MS tissue is associated with more extensive remyelination, underscoring this interaction as a key process in repair.

neuroscience↗

bioRxiv2026

Functional cerebellar connectomes interfacing motor adaptation and reinforcement feedback

Motor adaptation is driven by sensory prediction errors, yet reinforcement feedback can alter the speed and retention of adaptive behaviors. The cerebellum is central in motor adaptation, but posterior lobules, especially Lobule VI (CB6) and Crus I (CBcrus1), also participate in reinforcement-related signaling. Serotoninergic and dopaminergic systems, key modulators of motivational processes, directly influence cerebellar activity. However, how these neuromodulatory systems contribute to cerebellar network organization and to reinforcement-based adaptation in humans remains unclear. We employed a multimodal framework (Receptor-Enriched Analysis of functional Connectivity by Targets; REACT) using PET-derived Serotonin/Dopamine Transporter (SERT/DAT) templates to enrich resting-state functional Magnetic Resonance Imaging (rs-fMRI). We estimated SERT- and DAT-enriched functional connectivity from CB6 and CBcrus1 within motor-adaptation and reinforcement-learning networks, and tested their correlations with performance in a visuomotor adaptation task completed under reward and punishment. Our findings show lobule-specific neuromodulatory organization within the cerebellum. CB6 exhibited predominantly DAT- and SERT-enriched connectivity with motor adaptation networks, while CBcrus1 showed stronger SERT-enriched communication extending to both motor and reinforcement networks. Crucially, distinct cerebello-cortical neuromodulatory networks predicted individual differences in adaptation rate. DAT-enriched CBcrus1 connectivity was linked to punishment-driven adaptation, whereas SERT-enriched cerebello-orbitofrontal connectivity predicted faster adaptation across both reward and punishment contingencies. Furthermore, we observed overlaps between SERT- and DAT-enriched networks in the medial orbitofrontal area for Crus I, which predicted retention following punishment, underscoring the role of convergent neuromodulation in stabilizing adapted movements. We conclude that partially segregated yet convergent cerebello-cortical networks support interactions between motor and motivational behaviors, with combined and opposing effects of serotonergic and dopaminergic neuromodulation accounting for the speed and retention of adaptive behaviors.

neuroscience↗

bioRxiv2024

The role of dopaminergic, cholinergic and noradrenergic networks in hyposmia in Parkinson's disease

BackgroundOlfactory impairment is frequently observed in Parkinsons disease (PD) before motor symptom onset. Patients with isolated rapid eye movement sleep behaviour disorder (iRBD) are at risk to develop PD and present olfactory dysfunction. Subcortical neuromodulatory nuclei including the substantia nigra, the nucleus basalis of Meynert, and the locus coeruleus, may all contribute to olfactory dysfunction. ObjectiveThe objective of this study was to understand the network alterations underlying olfactory dysfunction in PD and in the early prodromal iRBD patients using multimodal MRI. MethodsPD (n = 107), iRBD patients (n = 35) and healthy controls (HC, n = 39) were recruited from the ICEBERG cohort for a cross-sectional study. We separated subjects in Healthy Controls, iRBD patients, and PD patients with or without RBD and with or without anosmia. Olfactory, motor, and cognitive scores were assessed and combined with multimodal imaging. ResultsWe found that olfaction positively correlated with (i) striatal DaT signal in PD patients; (ii) neuromelanin contrast in the locus coeruleus and (iii) Nucleus Basalis of Meynert grey matter (GM) volume in all patients. These signals were uncorrelated with motor and cognitive scores. Functional connectivity was reduced in regions of the cholinergic olfactory network in anosmic patients. Functional connectivity was also reduced in the noradrenergic network of patients with RBD. DiscussionOur results indicate the implication of the cholinergic network in PD patients with anosmia and a contribution of the noradrenergic network to olfactory dysfunction, only in patients with RBD.

neuroscience↗

bioRxiv2024

Longitudinal neuromelanin changes in prodromal and early Parkinson's disease in humans and rat model

Studies in animal models of Parkinsons disease (PD) suggested that the accumulation of the neuromelanin (NM), a pigment contained in nigral dopaminergic neurons, could trigger neurodegeneration above a pathogenic threshold. Here we investigated this hypothesis using NM-sensitive MRI in rodents and in patients with isolated rapid eye movement sleep disorders (iRBD) subjects, a prodromal phase of parkinsonism, and early PD. We first combined NM-sensitive MRI and histology to study NM accumulation and neurodegeneration in a humanized rat model of PD. NM-MRI signal changes were biphasic with an initial increase due to the accumulation of NM in dopaminergic neurons, followed signal decrease due to neurodegeneration. In healthy subjects and patients with iRBD, NM-MRI signal increased initially and then decreased similarly as in rodents after reaching a similar maximum signal intensity in both groups. In early PD and converted iRBD patients, NM-MRI signal drop was greater than in healthy individuals. Results in animals and humans show that NM-sensitive MRI is a marker of the intracellular NM accumulation up to a threshold then of neuronal degeneration beyond this threshold and agree with the hypothesis of a pathogenic threshold of NM triggering neurodegeneration.

neuroscience↗

bioRxiv2024

The UPRER governs the cell-specific response of human dopaminergic neurons to mitochondrial stress

Mitochondrial dysfunction is thought to be central to the pathophysiology of Parkinsons disease. The preferential vulnerability of dopaminergic (DA) neurons of the substantia nigra pars compacta to mitochondrial stress may underlie their massive degeneration and the occurrence of motor symptoms. Using LUHMES-derived DA neurons, we demonstrated that inhibition of the mitochondrial electron transport chain resulted in a severe alteration of mitochondrial turnover, pushing the balance towards mitochondrial loss, a reduction of the maturation status of the DA population and an increased proportion of apoptotic cells. PERK-mediated Unfolded Protein Response of the Endoplasmic Reticulum (UPRER) emerged as the key coordinator of the stress response, governing the inactivation of the mitochondrial UPR (UPRmt), the initiation of mitophagy and the cell-specific expression of long non-coding RNAs (lncRNAs). Importantly, we discovered novel lncRNAs specifically expressed in human DA neurons upon stress. Among them, we showed that lnc-SLC6A15-5 contributes to the resumption of translation after mitochondrial stress. SummaryThe Unfolded Protein Response of the Endoplasmic Reticulum is induced upon stress in human dopaminergic neurons and modulates mitochondrial homeostasis and transcriptional programs including expression of long non-coding RNAs (lncRNAs). We discovered a lncRNA involved in translation resumption after stress.

neuroscience↗

bioRxiv2024

Neuronal activity promotes axonal node-like clustering prior to myelination and remyelination in the central nervous system.

Nodes of Ranvier ensure the fast saltatory conduction along myelinated axons, through their enrichment in voltage-gated sodium and potassium channels. We and others have shown that node-like cluster assembly can occur before myelination. In multiple sclerosis, demyelination is associated with node of Ranvier disassembly, but node-like reassembly can occur prior to remyelination. Given the crucial role of neuronal activity in inducing (re)myelination, we asked whether neuronal activity could regulate node-like clustering. We show that node-like clustering is promoted by neuronal activity and decreased when excitatory glutamatergic receptors are inhibited. Altering glutamatergic neurotransmission leads to the downregulation of Nav1.1 expression, which we show to be critical for node-like clustering. Neuronal activity also promotes node-like clustering in remyelination. As node-like clusters modulate conduction velocity and myelination initiation along axons, we propose that activity-dependent node-like clustering could modulate neuronal network establishment, as well as myelination regulation and patterning during development, plasticity and repair.

neuroscience↗

bioRxiv2023

SCO-spondin knockout mice exhibit small brain ventricles and mild spine deformation

Reissners fiber (RF) is an extracellular polymer comprising the large monomeric protein SCO-spondin (SSPO) secreted by the subcommissural organ (SCO) that extends through cerebrospinal fluid (CSF)-filled ventricles into the central canal of the spinal cord. In zebrafish, RF and CSF-contacting neurons (CSF-cNs) form an axial sensory system that detects spinal curvature, instructs morphogenesis of the body axis, and enables proper alignment of the spine. In mammalian models, RF has been implicated in CSF circulation. However, challenges in manipulating Sspo, an exceptionally large gene of 15,719 nucleotides, with traditional approaches has limited progress. Here, we generated a Sspo knockout mouse model using CRISPR/Cas9-mediated genome-editing. Sspo knockout mice lacked RF-positive material in the SCO and fibrillar condensates in the brain ventricles. Remarkably, Sspo knockout brain ventricle sizes were reduced compared to littermate controls. Minor defects in thoracic spine curvature were detected in Sspo knockouts, which did not alter basic motor behaviors tested. Altogether, our work in mouse demonstrates that SSPO and RF regulate ventricle size during development but only moderately impact spine geometry.

neuroscience↗

bioRxiv2022

Lateral line hair cells integrate mechanical and chemical cues to orient navigation

The lateral line is a superficial sensory system responding to environmental hydrodynamic changes to orient locomotion of aquatic vertebrate species. Whether this system also detects chemical cues is unknown. We find that zebrafish lateral line hair cells express numerous chemoreceptors, including ionotropic receptors for serotonin. We show that the serotonin enriched in skin neuroepithelial cells is released upon injury and that environmental serotonin activates lateral line hair cells. We show that larval zebrafish exposed to serotonin in their environment rely on the lateral line to swim fast and away. These results uncover the sensory versatility of lateral line hair cells and how these properties modulate navigation in response to environmental stimuli.

neuroscience↗

bioRxiv2021

Spinal sensory neurons project onto hindbrain to stabilize posture and enhance locomotor speed

In the spinal cord, cerebrospinal fluid-contacting neurons (CSF-cNs) are GABAergic interoceptive sensory neurons that detect spinal curvature via a functional coupling with the Reissner fiber. This mechanosensory system has recently been found involved in spine morphogenesis and postural control but the underlying mechanisms are not fully understood. In zebrafish, CSF-cNs project an ascending and ipsilateral axon reaching two to six segments away. Rostralmost CSF-cNs send their axons ipsilaterally into the hindbrain, a brain region containing motor nuclei and reticulospinal neurons (RSNs), which send descending motor commands to spinal circuits. Until now, the synaptic connectivity of CSF-cNs has only been investigated in the spinal cord where they synapse onto motor neurons and premotor excitatory interneurons. The identity of CSF-cN targets in the hindbrain and the behavioral relevance of these sensory projections from spinal cord to hindbrain are unknown. Here, we provide anatomical and molecular evidence that rostralmost CSF-cNs synapse onto the axons of large RSNs including the Mauthner cells and early born chx10+ neurons. Functional anatomy and optogenetic-assisted mapping reveal that rostral CSF-cNs also synapse onto the soma and dendrites of cranial motor neurons innervating hypobranchial muscles. During acousto-vestibular evoked escape responses, ablation of rostralmost CSF-cNs results in a weaker escape response with a decreased C-bend amplitude, lower speed and a deficient postural control. Our study demonstrates that spinal sensory feedback enhances speed and stabilizes posture, and reveals a novel spinal gating mechanism acting on the output of descending commands sent from the hindbrain to the spinal cord. eTOCCerebrospinal fluid-contacting neurons are mechanosensory cells that detect spinal curvature. Wu et al. show here that rostralmost CSF-cNs synapse in the hindbrain onto cranial motor neurons and the descending axons of reticulospinal neurons, and enhance speed and power as well as postural control during active locomotion. HighlightsO_LICerebrospinal fluid-contacting neurons (CSF-cNs) in rostral spinal cord form inhibitory synapses onto cranial motor neurons C_LIO_LIRostral CSF-cNs synapse onto descending axons of reticulospinal neurons C_LIO_LICSF-cN sensory feedback in the rostral spinal cord enhance speed and power of locomotion C_LIO_LIRostral CSF-cNs projecting to the hindbrain contribute to postural control C_LI

neuroscience↗

bioRxiv2020

Microglia-neuron communication at nodes of Ranvier depends on neuronal activity through potassium release and contributes to myelin repair.

Microglia, the resident immune cells of the central nervous system, are key players in healthy brain homeostasis and plasticity. In neurological diseases, such as Multiple Sclerosis, activated microglia either promote tissue damage or favor neuroprotection and myelin regeneration. The mechanisms for microglia-neuron communication remain largely unkown. Here, we identify nodes of Ranvier as a direct and stable site of interaction between microglia and axons, in both mouse and human tissue. Using dynamic imaging, we highlight the preferential interaction of microglial processes with nodes of Ranvier along myelinated fibers. We show that microglianode interaction is modulated by neuronal activity and associated potassium release, with THIK-1 ensuring their microglial read-out. Disrupting axonal K+ flux following demyelination polarizes microglia towards a pro-inflammatory phenotype and decreases remyelination rate. Taken together, these findings identify the node of Ranvier as a major site for microglia-neuron communication, participating in the pro-remyelinating effect of microglia after myelin injury.

neuroscience↗

bioRxiv2020

Early diversity in the firing pattern of embryonic Renshaw cells: just a synergy between two opposite voltage-dependent currents

Renshaw cells (V1R) are excitable as soon as they reach their final location next to the spinal motoneurons and are functionally heterogeneous. Using multiple experimental approaches, in combination with biophysical modeling and dynamical systems theory, we analyzed, for the first time, the mechanisms underlying the electrophysiological properties of V1R during early embryonic development of the spinal cord locomotor networks (E11.5-E16.5). We found that these interneurons are subdivided into several functional clusters from E11.5 and then display an unexpected transitory involution process during which they lose their ability to sustain tonic firing. We demonstrated that the essential factor controlling the diversity of the discharge pattern of embryonic V1R is the ratio of a persistent sodium conductance to a delayed rectifier potassium conductance. Taken together, our results reveal how a simple mechanism, based on the synergy of two voltage-dependent conductances that are ubiquitous in neurons, can produce functional diversity in V1R and control their early developmental trajectory.

neuroscience↗

bioRxiv2019

Sensory neurons contacting the cerebrospinal fluid require the Reissner fiber to detect spinal curvature in vivo

Recent evidence indicate active roles for the cerebrospinal fluid (CSF) on body axis development and morphogenesis of the spine implying CSF-contacting neurons (CSF-cNs) in the spinal cord. CSF-cNs project a ciliated apical extension into the central canal that is enriched in the channel PKD2L1 and enables the detection of spinal curvature in a directional manner. Dorsolateral CSF-cNs ipsilaterally respond to lateral bending while ventral CSF-cNs respond to longitudinal bending. Historically, the implication of the Reissner fiber (RF), a long extracellular thread in the CSF, to CSF-cN sensory functions has remained a subject of debate. Here, we reveal using electron microscopy in zebrafish larvae that the RF is in close vicinity with cilia and microvilli of ventral and dorsolateral CSF-cNs. We investigate in vivo the role of cilia and the Reissner fiber in the mechanosensory functions of CSF-cNs by combining calcium imaging with patch-clamp recordings. We show that disruption of cilia motility affects CSF-cN sensory responses to passive and active curvature of the spinal cord without affecting the Pkd2l1 channel activity. Since ciliary defects alter the formation of the Reissner fiber, we investigated whether the Reissner fiber contributes to CSF-cN mechanosensitivity in vivo. Using a hypomorphic mutation in the scospondin gene that forbids the aggregation of SCO-spondin into a fiber, we demonstrate in vivo that the Reissner fiber per se is critical for CSF-cN mechanosensory function. Our study uncovers that neurons contacting the cerebrospinal fluid functionally interact with the Reissner fiber to detect spinal curvature in the vertebrate spinal cord. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/861344v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@3c7baaorg.highwire.dtl.DTLVardef@db094forg.highwire.dtl.DTLVardef@4041c6org.highwire.dtl.DTLVardef@9e3dae_HPS_FORMAT_FIGEXP M_FIG C_FIG eToCThe role of the Reissner fiber, a long extracellular thread running in the cerebrospinal fluid (CSF), has been since its discovery in 1860 a subject of debate. Orts-DelImmagine et al. report that the Reissner fiber plays a critical role in the detection of spinal curvature by sensory neurons contacting the CSF. HighlightsO_LISince its discovery, the role of the Reissner fiber has long been a subject of debate C_LIO_LIMechanoreception in CSF-contacting neurons (CSF-cNs) in vivo requires the Reissner fiber C_LIO_LICSF-cN apical extension is in close vicinity of the Reissner fiber C_LIO_LICSF-cNs and the Reissner fiber form in vivo a sensory organ detecting spinal curvature C_LI

neuroscience↗

bioRxiv2019

An alternative mechanism of early nodal clustering and myelination onset in GABAergic neurons of the central nervous system

In vertebrates, fast saltatory conduction along myelinated axons relies on the node of Ranvier. How nodes assemble on CNS neurons is not yet fully understood. We recently highlighted that clusters similar to nodes can form prior to myelin deposition in hippocampal GABAergic neurons and are associated with increased conduction velocity. Here, we used a live imaging approach to characterize the intrinsic mechanisms underlying the assembly of these early clusters. We first demonstrated that their components can partially pre-assemble prior to membrane targeting and determined the molecular motors involved in their trafficking. We then demonstrated the key role of the protein {beta}2Nav for clustering initiation. We further unraveled the fate of these early clusters, by showing that they participate in node formation, but also have an unexpected role in guiding oligodendrocyte processes prior to myelin deposition. Altogether our results shed light on an alternative mechanism of nodal clustering and myelination onset.

neuroscience↗