Biology subjects

Dhenain, M.

Publications and source records attributed to Dhenain, M..

10 recordsLinked to original sources

bioRxiv2026

APPNL-F knock-in Alzheimer's Disease model mice reveal etiological convergence of aging and amyloidosis

Alzheimers disease (AD) is the leading cause of dementia worldwide, with a steadily increasing prevalence. Despite the advent of some plaque-degrading therapies, early intervention strategies are still suboptimal, largely due to an incomplete understanding of how early pathological events of amyloid-{beta} (A{beta}) plaque deposition entail or accompany the neuroinflammatory processes that ensue. The APPNL-F mouse line is a second-generation endogenous-promoter knock-in AD model that represents a valuable tool to dissect disease mechanisms and evaluate therapeutic strategies. However, the early prodromal stage remains poorly characterized. Here we performed in-depth analyses in both homozygous (APPNL-F/NL-F) and heterozygous (APPNL-F/WT) mice at 3, 6, 9 and 12 months of age. Among a battery of behavioural tests, the first phenotype was observed at 9 months with defects in spatial memory. Using hypersensitive MSD-ELISA technology assays we quantified distinct A{beta} species and found that A{beta}42 oligomers, protofibrils, and fibrillar aggregates were detectable as early as 6 months of age in homozygous APPNL-F/NL-F mice. By 9 months, their A{beta}42 levels increased markedly and overt A{beta} plaques were detected, histologically associated with recruited glial cells. Targeted RT-qPCR analysis of neuroinflammation-related genes in the cortex also identified 9 months as a molecular tipping point in these middle aged APPNL-F mice. To characterize the etiological signal transduction at the cellular level, we isolated microglia, the brain resident immune cells, whose contribution to AD pathogenesis is now well established. Sequencing around 5,000 individual cells from both 12-month-old APPNL-F/NL-F and APPWT/WT CD11b+ myeloid cells revealed that the buildup of amyloidosis was associated with an accelerated shift of microglia from a homeostatic toward a senescent-like state. Together, these findings highlight the 6-12 month period of the APPNL-F/NL-F model as a powerful system to study the interdependence between microglial senescence and amyloidosis in driving AD progression.

neuroscience↗

bioRxiv2026

Astrocyte diversity and aging in the mouse lemur primate brain

Astrocytes play key roles in maintaining brain homeostasis, metabolism, and neurovascular integrity, yet their diversity and age-related modulation remain insufficiently understood, particularly across primate lineages. While rodent studies have generated extensive knowledge, notable species differences highlight the need for comparative analyses in non-human primates. The gray mouse lemur (Microcebus murinus), a small primate widely used in aging research, offers a valuable but underexplored model for studying astroglial aging. In this study, we characterized astrocyte distribution, morphology, and reactivity in 17 mouse lemurs aged 1.0-11.5 years using GFAP and vimentin immunohistochemistry. We identified marked regional and morphological heterogeneity, with dense astrocytic labeling in white matter, hippocampus, and sparse but diverse cortical populations. Distinct astrocyte subtypes--including fibrous, protoplasmic, projection, pial and subpial interlaminar, radial glia-like cells, tanycytes--were documented. Varicosity-bearing processes were common across multiple astroglial subtypes and may indicate altered physiological states. Quantitative analyses revealed pronounced age-related increases in astrocytic reactivity, particularly in white matter and interlaminar astrocytes. Cortical and hippocampal changes were comparatively modest. These findings indicate region-specific astrocytic vulnerability during aging and support the translational value of the mouse lemur for investigating glial aging in primates. Main PointsO_LIThe mouse lemur is the smallest primate on earth with a key role to understand primate brain characteristics. C_LIO_LIWe characterized seven different astrocyte subtypes: from fibrous to primate-specific astrocyte as interlaminar astrocytes in different brain regions of this primate. C_LIO_LIVaricosities were reported in different astrocyte subtypes found close to brain borders. C_LIO_LIMain age-related changes concerned fibrous astrocytes in the white matter and interlaminar astrocytes at the cortical border. C_LI

neuroscience↗

bioRxiv2025

Increased white matter microglial reaction and perivascular macrophages in the aging microcebe primate

As populations age, the incidence of neurodegenerative disorders is rising. Early age-related neuropathological changes are the breeding ground for the development of these disorders. Microglia are the resident macrophages of the central nervous system. They play crucial roles in maintaining brain homeostasis, yet their age-related changes remain not fully understood. While age-related microglia changes have been strongly characterized in rodents, studies in non-human primates are scarce. The microcebe primate (mouse lemur (Microcebus murinus)) is widely used as a model for cerebral aging and to investigate age-related neurodegenerative processes. HLA-DR is a major histocompatibility class II cell surface receptor which presents antigens to cells of the immune response. It is a major marker of microglia reaction. In this study, we explored microglia in the whole brains of middle-aged and old microcebes using HLA-DR immunolabeling. We analyzed microglial morphology and quantified HLA-DR+ cell density and protein expression. A wide range of microglial morphologies was observed in the white matter, including thin processes microglia, "rod-like" elongated and polarized shape, hypertrophic, and amoeboid microglia. Aging was associated with increased HLA-DR+ microglial expression in the white matter while very few HLA-DR+ microglia were observed in the parenchyma of cortical gray matter regions. A second finding was the higher number of HLA-DR+ perivascular macrophages in old animals. This study in a primate outlines that, in the absence of neurodegenerative processes, the most prominent signs of age-related microglia/macrophage changes are region-specific and concern white matter and perivascular regions. This emphasizes the need to target these regions to prevent cerebral aging. Main PointsO_LIHLA-DR+ microglia in Microcebus murinus primate show diverse morphologies and increase with age in white matter. C_LIO_LIHLA-DR+ perivascular macrophage load increase in aged animals. C_LI Table of Contents Image (TOCI) O_FIG O_LINKSMALLFIG WIDTH=167 HEIGHT=200 SRC="FIGDIR/small/645519v2_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@edb574org.highwire.dtl.DTLVardef@23f606org.highwire.dtl.DTLVardef@ed2e0borg.highwire.dtl.DTLVardef@169f059_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Alteration of mean amplitude of low frequency fluctuations measured by fMRI at 11.7 T in the aging brain of mouse lemur primate

Non-human primates are a critical species for the identification of key biological mechanisms in normal and pathological aging. One of these primates, the mouse lemur, has been widely studied as a model of cerebral aging or Alzheimers disease. The amplitude of low-frequency fluctuations of blood oxygenation level-dependent (BOLD) can be measured with functional MRI. Within specific frequency bands (e.g. the 0.01-0.1 Hz), these amplitudes were proposed to indirectly reflect neuronal activity as well as glucose metabolism. Here, we first created whole brain maps of the mean amplitude of low frequency fluctuations (mALFF) in middle-aged mouse lemurs. Then, we extracted mALFF in old lemurs to identify age-related changes. A high level of mALFF was detected in the temporal cortex (Brodmann area 20), somatosensory areas (Brodmann area 5), insula (Brodmann area 13-6) and the parietal cortex (Brodmann area 7) of healthy middle-aged mouse lemurs. Aging was associated with alteration of mALFF in somatosensory areas (area 5) and the parietal cortex (area 7). Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=159 HEIGHT=200 SRC="FIGDIR/small/521367v2_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@15c9556org.highwire.dtl.DTLVardef@1505c78org.highwire.dtl.DTLVardef@e6f3fcorg.highwire.dtl.DTLVardef@9c6053_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIWe characterized mean amplitude of fluctuation at low frequencies (mALFF) in mouse lemurs. C_LIO_LImALFF was the highest in regions involved in visuo-somatosensory-motor function (Brodmann areas 5, 7, 20) and in more integrative functions (area 13-16). C_LIO_LImALFF was affected by aging in regions involved in visuo-somatosensory-motor function (parietal areas 5 and 7). C_LIO_LImALFF is a useful marker to investigate age-related cerebral dysfunction in animals. C_LI Significance StatementO_LIThe amplitude of low-frequency fluctuations (ALFF) is expected to reflect neuronal activity. It has been proposed as an MRI-based method to evaluate brain function. C_LIO_LIALFF has been used to investigate different cerebral pathologies in animal models but the regional differences of ALFF signal and the impact of cerebral aging on ALFF has never been characterized. C_LIO_LIHere, we highlight for the first time regional difference of ALFF. High signal was detected in regions involved in visuo-somatosensory-motor function as well as in more integrative functions. ALFF was reduced in regions involved in visuo-somatosensory-motor function during aging. ALFF is thus a useful marker to investigate age-related cerebral dysfunction. C_LI

neuroscience↗

bioRxiv2021

Whole brain mapping of glutamate in adult and old primates at 11.7T

Glutamate is the amino acid with the highest cerebral concentration. It plays a central role in brain metabolism. It is also the principal excitatory neurotransmitter in the brain and is involved in multiple cognitive functions. Alterations of the glutamatergic system may contribute to the pathophysiology of many neurological disorders. For example, changes of glutamate availability are reported in rodents and humans during Alzheimers and Huntingtons diseases, epilepsy as well as during aging. Most studies evaluating cerebral glutamate have used invasive or spectroscopy approaches focusing on specific brain areas. Chemical Exchange Saturation Transfer imaging of glutamate (gluCEST) is a recently developed imaging technique that can map glutamate distribution in the entire brain with higher sensitivity and at higher resolution than previous techniques. It thus has strong potential clinical applications to assess glutamate changes in the brain. High field is a key condition to perform gluCEST images with a meaningful signal to noise ratio. Thus, even if some studies started to evaluate gluCEST in humans, most studies focused on rodent models that can be imaged at high magnetic field. In particular, systematic characterization of gluCEST contrast distribution throughout the whole brain has never been performed in humans or non-human primates. Here, we characterized for the first time the distribution of the glutamate index in the whole brain and in large-scale networks of mouse lemur primates at 11.7 Tesla. Because of its small size, this primate can be imaged in high magnetic field systems. It is widely studied as a model of cerebral aging or Alzheimers disease. We observed high gluCEST contrast in cerebral regions such as the nucleus accumbens, septum, basal forebrain, cortical areas 24 and 25. Age-related alterations of this biomarker were detected in the nucleus accumbens, septum, basal forebrain, globus pallidus, hypophysis, cortical areas 24, 21, 6 and in olfactory bulbs. An age-related gluCEST contrast decrease was also detected in specific neuronal networks, such as fronto-temporal and evaluative limbic networks. These results outline regional differences of gluCEST contrast and strengthen its potential to provide new biomarkers of cerebral function in primates. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=85 SRC="FIGDIR/small/459778v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@d672a5org.highwire.dtl.DTLVardef@100e883org.highwire.dtl.DTLVardef@a0f827org.highwire.dtl.DTLVardef@3cad0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Identification of the key role of white matter alteration in the pathogenesis of Huntington's Disease

Pathogenesis of the inherited neurodegenerative disorder Huntingtons Disease (HD) is complex and progressive, with a long presymptomatic phase in which subtle changes occur in the brain of gene carriers up to 15 years before the onset of symptoms. Thus, there is a need of early, functional biomarker to better understand disease progression and to evaluate treatment efficacy far from onset. In particular, recent studies have shown that white matter may be affected early in HD. In this study, we scanned longitudinally Ki140CAG mice with structural MRI, Diffusion Tensor Imaging (DTI), Chemical Exchange Saturation Transfer of glutamate (gluCEST) and Magnetization Transfer (MT) imaging, in order to assess white matter integrity over the life of this very progressive mouse model. Our results show early defects of diffusion properties in the anterior part of the corpus callosum, preceding gluCEST defects in the same region (-10.8% at 8 months, -19% at 12 months) that spread to adjacent regions. At 12 months, frontal (-7.3%) and piriform (-16.7%) cortices showed reduced gluCEST, as well as the pallidum (-21.0%). MT imaging showed reduced signal in the septum (-21.7%) at 12 months. Cortical and striatal atrophy then appear at 18 months. Vulnerability of the striatum and motor cortex, combined with alterations of anterior corpus callosum, seems to point out the pivotal role of white matter, in the pathogenesis of HD and the pertinence of gluCEST and DTI as biomarkers in HD. Highlights- A knock-in mouse model of Huntingtons disease is longitudinally characterized - A multimodal MRI protocol is performed to identify biomarkers of the disease - The white matter plays a pivotal role in the pathogenesis of the disease - The cortico-striatal pathway seems particularly vulnerable in Huntingtons disease

neuroscience↗

bioRxiv2021

Alzheimer's brain inoculation in Aβ-plaque bearing mice: synaptic loss is linked to tau seeding and low microglial activity

Alzheimers disease (AD) is characterized by intracerebral accumulations of extracellular amyloid-{beta} (A{beta}) plaques and intracellular tau pathology that spread in the brain. Tau lesions occur in the form of neuropil threads, neurofibrillary tangles, and neuritic plaques i.e. tau aggregates within neurites surrounding A{beta} deposits. The cascade of events linking these lesions and synaptic or memory impairments are still debated. Intracerebral infusion of human AD brain extracts in A{beta} plaque-bearing mice that do not overexpress pathological tau proteins induces tau pathologies following heterotopic seeding of mouse tau protein. There is however little information regarding the downstream events including synaptic or cognitive repercussions of tau pathology induction in these models. In the current study, human AD brain extracts (ADbe) and control-brain extracts (Ctrlbe) were infused in the hippocampus of A{beta} plaque-bearing APPswe/PS1dE9 mice. Memory, synaptic density, as well as A{beta} plaque and tau aggregate loads, microgliosis, astrogliosis at the inoculation site and in connected regions (perirhinal/entorhinal cortex) were evaluated 4 and 8 months post-inoculation. ADbe inoculation induced memory deficit. It increased deposition of A{beta} plaques close to the inoculation site. Tau pathology was also induced in ADbe-inoculated mice. Neuropil threads and neurofibrillary tangles occurred next to the inoculation site and spread to connected regions notably the perirhinal/entorhinal cortex. Neuritic plaque pathology was detected in both ADbe- and Ctrlbe- inoculated animals but ADbe inoculation increased the severity close and at distance of the inoculation site. Finally, ADbe inoculation reduced synaptic density close to the inoculation site and in connected regions as the perirhinal/entorhinal cortex. Synaptic impairments were correlated with increased severity of neuritic plaques but not of other tau lesions or A{beta} lesions, which suggests that neuritic plaques are a culprit for synaptic loss. Synaptic density was also associated with microglial load. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=182 HEIGHT=200 SRC="FIGDIR/small/438654v4_ufig1.gif" ALT="Figure 1"> View larger version (46K): org.highwire.dtl.DTLVardef@791f29org.highwire.dtl.DTLVardef@1ecf87corg.highwire.dtl.DTLVardef@adb3a0org.highwire.dtl.DTLVardef@1ebef93_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2019

An Automated Open-Source Workflow for Standards-Compliant Integration of Small Animal Magnetic Resonance Imaging Data

Large-scale research integration is contingent on seamless access to data in standardized formats. Standards enable researchers to understand external experiment structures, pool results, and apply homogeneous preprocessing and analysis workflows. Particularly, they facilitate these features without the need for numerous potentially confounding compatibility add-ons. In small animal magnetic resonance imaging, an overwhelming proportion of data is acquired via the ParaVision software of the Bruker Corporation. The original data structure is predominantly transparent, but fundamentally incompatible with modern pipelines. Additionally, it sources metadata from free-field operator input, which diverges strongly between laboratories and researchers. In this article we present an open-source workflow which automatically converts and reposits data from the ParaVision structure into the widely supported and openly documented Brain Imaging Data Structure (BIDS). Complementing this workflow we also present operator guidelines for appropriate ParaVision data input, and a programmatic walk-through detailing how preexisting scans with uninterpretable metadata records can easily be made compliant after the acquisition.

neuroscience↗

bioRxiv2019

Resting state cerebral networks in mouse lemur primates: from multilevel validation to comparison with humans

Measures of resting-state functional connectivity allow the description of neuronal networks in humans and provide a window on brain function in normal and pathological conditions. Animal models are critical to further address experimentally the function of brain networks and their roles in pathologies. Here we describe for the first time brain network organization in the mouse lemur (Microcebus murinus), a small primate attracting increased attention as a model for neuroscience. Resting-state functional MR images were recorded at 11.7 Tesla. Forty-eight functional regions were identified and used to identify networks using graph theory, dictionary learning and seed-based analyses. Comparison of results issued from these three complementary methods allowed the description of the most robust networks from mouse lemurs. Large scale networks were then identified from resting-state functional MR images of humans using the same method as for lemurs. Strong homologies were outlined between cerebral networks in mouse lemurs and humans.

neuroscience↗

bioRxiv2019

Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis

Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories world-wide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a murine default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.

neuroscience↗