Biology subjects

Olivier, C.

Publications and source records attributed to Olivier, C..

9 recordsLinked to original sources

bioRxiv2026

Distinct roles of the human cuneiform and pedunculopontine nuclei in gait initiation and freezing of gait

Freezing of gait in Parkinsons disease (PD) is a major cause of disability, often resistant to dopaminergic therapy and deep brain stimulation (DBS). Its underlying mechanisms remain unclear, mainly because the roles of the human mesencephalic locomotor region (MLR) nuclei are not well understood. Here, we combined rare local field potentials (LFP) recordings from the cuneiform (CuN) and pedunculopontine nuclei (PPN) with biomechanical markers of gait initiation (GI) in four PD patients. We identified functional differences: increases in CuN alpha-band activity precede anticipatory postural adjustments (APA) and correlate with the rhythm of upcoming steps, whereas decreases in PPN beta-band activity occur during APA just before the lead foot lifts off. Imminent freezing is characterized by a breakdown of this organization, marked by mistimed alpha-band surges across the MLR and abnormal PPN beta-band modulation. CuN stimulation selectively improved the stepping rhythm, while PPN stimulation worsened pace or forward vigor. Furthermore, exaggerated mesencephalic alpha-band power was associated with poor clinical responses. These results clarify the individual roles of MLR nuclei in human locomotion and identify pathological alpha dynamics as a biomarker for advancing adaptive neurostimulation.

neuroscience↗

bioRxiv2025

Subthalamic Signature of Freezing of Gait in Parkinson Disease

Freezing of gait (FOG) is a significant disability in Parkinsons disease (PD). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) only partially alleviates it, with approximately one-third of patients experiencing worsening FOG within a year after surgery. The precise role of STN dysfunction in gait disabilities and FOG remains not fully elucidated. To investigate this, we recorded gait and STN local field potential (LFP) activity in 38 PD patients, both Off and On dopamine medication. Our analysis focused on the relationship between gait performance and STN neuronal activity, particularly examining differences in LFP activity across the posterior-sensorimotor and central-associative regions of the STN. When Off dopamine medication, 12 patients experienced FOG during recordings, with a total of 263 FOG episodes documented. Even in trials without FOG episodes, these patients exhibited altered gait initiation strategies, prioritizing stepping rhythm to manage balance and initiate walking. In contrast, non-FOG patients maintained a higher walking pace. STN activity patterns revealed key differences. In FOG patients, weaker STN alpha/low beta band activity in the STN was associated with walking pace, while stronger decreased low beta band activity correlated with rhythm and balance control. This low beta band association extended from the posterior-sensorimotor to the central-associative STN. In contrast, non-FOG patients showed a more restricted relationship between low beta band activity and gait performance, confined to the posterior STN. As stepping rhythm deteriorated further in FOG patients, FOG episodes occurred. FOG episodes were preceeded by a significant positive relationship between high beta power and rhythm restricted to the posterior STN, with a reverse negative relationship with pace, and a disruption in low beta desynchronization across both posterior and central STN regions. Dopamine medication significantly improved gait patterns, and partially restored STN neuronal activity, reducing differences between FOG and non-FOG patients. These findings differentiate two FOG states, i.e. predisposition and occurrence, each associated with distinct gait initiation strategies and STN activity patterns. They suggest distinct pathophysiological roles of low and high beta band STN activity within specific STN regions in regulating gait and FOG. These findings provide key insights for refining targeted DBS therapies.

neuroscience↗

bioRxiv2024

Inhibitory control of gait initiation in humans: an electroencephalography study

Response inhibition is a crucial component of executive control. Although mainly studied in upper limb tasks, it is fully implicated in gait initiation. Here, we assessed the influence of proactive and reactive inhibitory control during gait initiation in healthy adult participants. For this purpose, we measured kinematics and electroencephalography (EEG) activity (event-related potential [ERP] and time-frequency data) during a modified Go/NoGo gait initiation task in 23 healthy adults. The task comprised Go-certain, Go-uncertain, and NoGo conditions. Each trial included preparatory and imperative stimuli. Our results showed that go-uncertainty resulted in delayed reaction time (RT), without any difference for the other parameters of gait initiation. Proactive inhibition, i.e. Go uncertain versus Go certain conditions, influenced EEG activity as soon as the preparatory stimulus. Moreover, both proactive and reactive inhibition influenced the amplitude of the ERPs (central P1, occipito-parietal N1, and N2/P3) and theta and alpha/low beta band activities in response to the imperative--Go-uncertain versus Go-certain and NoGo versus Go-uncertain--stimuli. These findings demonstrate that the uncertainty context induced proactive inhibition, as reflected in delayed gait initiation. Proactive and reactive inhibition elicited extended and overlapping modulations of ERP and time-frequency activities. This study shows protracted influence of inhibitory control in gait initiation.

neuroscience↗

bioRxiv2023

Low concentrations of ethylene bisdithiocarbamate pesticides maneb and mancozeb impair manganese and zinc homeostasis to induce oxidative stress and caspase-dependent apoptosis in human hepatocytes

The worldwide and intensive use of phytosanitary compounds results in environmental and food contamination by chemical residues. Human exposure to multiple pesticide residues is a major health issue. Considering that the liver is not only the main organ for metabolizing pesticides but also a major target of toxicities induced by xenobiotics, we studied the effects of a mixture of 7 pesticides (chlorpyrifos-ethyl, dimethoate, diazinon, iprodione, imazalil, maneb, mancozeb) often detected in food samples. Effects of the mixture was investigated using metabolically competent HepaRG cells and human hepatocytes in primary culture. We report the strong cytotoxicity of the pesticide mixture towards hepatocytes-like HepaRG cells and human hepatocytes upon acute and chronic exposures at low concentrations extrapolated from the Acceptable Daily Intake (ADI) of each compound. Unexpectedly, we demonstrated that the manganese (Mn)-containing dithiocarbamates (DTCs) maneb and mancozeb were solely responsible for the cytotoxicity induced by the mixture. The mechanism of cell death involved the induction of oxidative stress, which led to cell death by intrinsic apoptosis involving caspases 3 and 9. Importantly, this cytotoxic effect was found only in cells metabolizing these pesticides. Herein, we unveil a novel mechanism of toxicity of the Mn-containing DTCs maneb and mancozeb through their metabolization in hepatocytes generating the main metabolite ethylene thiourea (ETU) and the release of Mn leading to intracellular Mn overload and depletion in zinc (Zn). Alteration of the Mn and Zn homeostasis provokes the oxidative stress and the induction of apoptosis, which can be prevented by Zn supplementation. Our data demonstrate the hepatotoxicity of Mn-containing fungicides at very low doses and unveil their adverse effect in disrupting Mn and Zn homeostasis and triggering oxidative stress in human hepatocytes.

pharmacology and toxicology↗

bioRxiv2022

Virtual histology of Alzheimer's Disease: why are amyloid-β plaques visible with X-ray phase-contrast imaging?

Amyloid-{beta} (A{beta}) plaques from Alzheimers Disease (AD) can be visualized ex vivo in label-free brain samples using synchrotron X-ray phase-contrast tomography (XPCT). However, for XPCT to be useful as a screening method for amyloid pathology, it is essential to understand which factors drive the detection of A{beta} plaques. The current study was designed to test the hypothesis that A{beta}-related contrast in XPCT could be caused by the A{beta} fibrils and/or by metals trapped in the plaques. This study probed the fibrillar and elemental compositions of A{beta} plaques in brain samples from different types of AD patients and AD models to establish a relationship between XPCT contrast and A{beta} plaque characteristics. XPCT, micro-Fourier-Transform Infrared spectroscopy and micro-X-Ray Fluorescence spectroscopy were conducted on human samples (genetic and sporadic cases) and on four transgenic rodent strains (mouse: APPPS1, ArcA{beta}, J20; rat: TgF344). A{beta} plaques from the genetic AD patient were visible using XPCT, and had higher {beta}-sheet content and higher metal levels than the sporadic AD patient, which remained undetected by XPCT. A{beta} plaques in J20 mice and TgF344 rats appeared hyperintense on XPCT images, while they were hypointense with an hyperintense core in the case of APPPS1 and ArcA{beta} mice. In all four transgenic strains, {beta}-sheet content was similar, while metal levels were highly variable: J20 (zinc and iron) and TgF344 (copper) strains showed greater metal accumulation than APPPS1 and ArcA{beta} mice. Hence, a positive contrast formation of A{beta} plaques in XPCT images appeared driven by biometal entrapment. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=143 SRC="FIGDIR/small/509706v2_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@56e672org.highwire.dtl.DTLVardef@1336d85org.highwire.dtl.DTLVardef@15b6690org.highwire.dtl.DTLVardef@1aaa6cb_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIAmyloid-{beta} plaques in the different forms of Alzheimers Disease have various contrasts in X-ray phase-contrast tomography C_LIO_LIIn transgenic rodents, a core-restricted, positive contrast is driven by the level of metal entrapment within plaques C_LIO_LIIn humans, greater and more diffuse metal accumulation lead to a positive contrast in a genetic case of AD C_LI

biophysics↗

bioRxiv2022

The onset of whole-body regeneration in Botryllus schlosseri: morphological and molecular characterization

Colonial tunicates are the only chordates that regularly regenerate a fully functional whole body as part of their asexual life cycle, starting from specific epithelia and/or mesenchymal cells. In addition, in some species, whole-body regeneration (WBR) can also be triggered by extensive injuries, which deplete most of their tissues and organs and leave behind only small fragments of their body. In this manuscript, we characterized the onset of WBR in Botryllus schlosseri, one colonial tunicate long used as a laboratory model. We first analyzed the transcriptomic response to a WBR-triggering injury. Then, through morphological characterization, in vivo observations via time-lapse, vital dyes, and cell transplant assays, we started to reconstruct the dynamics of the cells triggering regeneration, highlighting an interplay between mesenchymal and epithelial cells. The dynamics described here suggest that WBR in B. schlosseri is initiated by extravascular tissue fragments derived from the injured individuals rather than particular populations of blood-borne cells, as has been described in closely related species. The morphological and molecular datasets here reported provide the background for future mechanistic studies of the WBR ontogenesis in B. schlosseri and allow to compare it with other regenerative processes occurring in other tunicate species and possibly independently evolved.

developmental biology↗

bioRxiv2021

Brain virtual histology with X-ray phase-contrast tomography Part I: whole-brain myelin mapping in white-matter injury models

White-matter injury leads to severe functional loss in many neurological diseases. Myelin staining on histological samples is the most common technique to investigate white-matter fibers. However, tissue processing and sectioning may affect the reliability of 3D volumetric assessments. The purpose of this study was to propose an approach that enables myelin fibers to be mapped in the whole rodent brain with microscopic resolution and without the need for strenuous staining. With this aim, we coupled inline (propagation-based) X-ray phase-contrast tomography (XPCT) to ethanol-induced brain sample dehydration. We here provide the proof-of-concept that this approach enhances myelinated axons in rodent and human brain tissue. In addition, we demonstrated that white-matter injuries could be detected and quantified with this approach, using three animal models: ischemic stroke, premature birth and multiple sclerosis. Furthermore, in analogy to diffusion tensor imaging (DTI), we retrieved fiber directions and DTI-like diffusion metrics from our XPCT data to quantitatively characterize white-matter microstructure. Finally, we showed that this non-destructive approach was compatible with subsequent complementary brain sample analysis by conventional histology. In-line XPCT might thus become a novel gold-standard for investigating white-matter injury in the intact brain. This is Part I of a series of two articles reporting the value of in-line XPCT for virtual histology of the brain; Part II shows how in-line XPCT enables the whole-brain 3D morphometric analysis of amyloid-{beta} (A{beta}) plaques. HighlightsO_LIX-ray phase-contrast tomography (XPCT) enables myelin mapping of the whole brain C_LIO_LIXPCT detects and quantifies white-matter injuries in a range of diseases C_LIO_LIFiber directions and anisotropy metrics can be retrieved from XPCT data C_LIO_LIXPCT is compatible with subsequent conventional histology of brain samples C_LIO_LIXPCT is a powerful virtual histology tool that requires minimal sample preparation C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=130 SRC="FIGDIR/small/436852v3_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@1b06ba6org.highwire.dtl.DTLVardef@16b8d4aorg.highwire.dtl.DTLVardef@91cfborg.highwire.dtl.DTLVardef@4dcbca_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Brain virtual histology with X-ray phase-contrast tomography Part II: 3D morphologies of amyloid-β plaques in Alzheimer's disease models

While numerous transgenic mouse strains have been produced to model the formation of amyloid-{beta} (A{beta}) plaques in the brain, efficient methods for whole-brain 3D analysis of A{beta} deposits are lacking. Moreover, standard immunohistochemistry performed on brain slices precludes any shape analysis of A{beta} plaques. The present study shows how in-line (propagation-based) X-ray phase-contrast tomography (XPCT) combined with ethanol-induced brain sample dehydration enables hippocampus-wide detection and morphometric analysis of A{beta} plaques. Performed in three distinct Alzheimer mouse strains, the proposed workflow identified differences in signal intensity and 3D shape parameters: 3xTg displayed a different type of A{beta} plaques, with a larger volume and area, greater elongation, flatness and mean breadth, and more intense average signal than J20 and APP/PS1. As a label-free non-destructive technique, XPCT can be combined with standard immunohistochemistry. XPCT virtual histology could thus become instrumental in quantifying the 3D spreading and the morphological impact of seeding when studying prion-like properties of A{beta} aggregates in animal models of Alzheimers disease. This is Part II of a series of two articles reporting the value of in-line XPCT for virtual histology of the brain; Part I shows how in-line XPCT enables 3D myelin mapping in the whole rodent brain and in human autopsy brain tissue. HighlightsO_LIX-ray phase-contrast tomography (XPCT) enables whole brain detection of A{beta} plaques C_LIO_LIMorphometric parameters of A{beta} plaques may be readily retrieved from XPCT data C_LIO_LINew shape parameters were successfully extracted from three Alzheimers disease models C_LIO_LIA Fiji-based "biologist-friendly" analysis workflow is proposed and shared C_LIO_LIXPCT is a powerful virtual histology tool that requires minimal sample preparation C_LI O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=120 SRC="FIGDIR/small/436908v2_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@7c3167org.highwire.dtl.DTLVardef@18f689eorg.highwire.dtl.DTLVardef@1d9c72org.highwire.dtl.DTLVardef@a027a_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

neuroscience↗

bioRxiv2019

Genetic variation influences pluripotent ground state stability in mouse embryonic stem cells through a hierarchy of molecular phenotypes

Mouse embryonic stem cells (mESCs) cultured under controlled conditions occupy a stable ground state where pluripotency-associated transcriptional and epigenetic circuitry are highly active. However, mESCs from some genetic backgrounds exhibit metastability, where ground state pluripotency is lost in the absence of ERK1/2 and GSK3 inhibition. We dissected the genetic basis of metastability by profiling gene expression and chromatin accessibility in 185 genetically heterogeneous mESCs. We mapped thousands of loci affecting chromatin accessibility and/or transcript abundance, including eleven instances where distant QTL co-localized in clusters. For one cluster we identified Lifr transcript abundance as the causal intermediate regulating 122 distant genes enriched for roles in maintenance of pluripotency. Joint mediation analysis implicated a single enhancer variant ~10kb upstream of Lifr that alters chromatin accessibility and precipitates a cascade of molecular events affecting maintenance of pluripotency. We validated this hypothesis using reciprocal allele swaps, revealing mechanistic details underlying variability in ground state metastability in mESCs.

genomics↗