Biology subjects

Carrier, M.

Publications and source records attributed to Carrier, M..

5 recordsLinked to original sources

bioRxiv2025

Early micro and nanoscopic responses of microglia to blood-brain barrier modulation by transcranial-focused ultrasound

Modulation of the blood-brain barrier (BBB) using transcranial-focused ultrasound (FUS) has rapidly progressed to clinical trials. In combination with phospholipid microspheres, also known as microbubbles, administered in the bloodstream, ultrasound energy is guided by magnetic resonance imaging (MRI) to target specific brain regions with millimetric precision. At the targeted area, the interaction between FUS and microbubbles increases local BBB permeability for 4 to 6 hours, with an ensuing inflammation that resolves within days to weeks. Microglia, as the resident immune cells of the brain, are triggered by FUS-BBB modulation, although the time course of this response is unclear. Thus, the goal of this study was to characterize the early cellular (i.e., density, distribution, and morphology) and subcellular (i.e., ultrastructure) changes in microglial activities following FUS-BBB modulation. MethodsWe targeted the hippocampi of adult mice with FUS, in the presence of intravenous microbubbles and guided by MRI, and performed analyses 1 hour and 24 hours after FUS-BBB modulation. Microglia were investigated at the population, cellular and subcellular levels, where hippocampal BBB permeability was identified by the entry of endogenous immunoglobulin (Ig)G in the parenchyma. Respective outcome measures included i) the density and distribution of ionized calcium binding adaptor molecule-positive (Iba)1-positive (+) cells; ii) the morphology of the soma and processes of Iba1+ cells; and iii) the quantification of microglial organelles (e.g., phagosomes) and contacts with blood vessels and synapses using chip mapping scanning electron microscopy. ResultsNo significant changes in baseline density and distribution of microglia were found in IgG-positive hippocampal areas at 1 hour and 24 hours after FUS-BBB modulation. By contrast, FUS-BBB modulation was associated with more elongated microglial cell bodies at both time points. The relative distribution of morphologies at 1 hour shifted toward compact shapes with stubby processes, whereas at 24 hours, shapes were bigger, with fewer processes. At the nanoscale, microglia maintained their interactions with blood vessel elements, except vessels most affected by swollen endfeet, which occurred regardless of treatment. In the parenchyma, 24 hours after FUS-BBB modulation, microglia reduced the frequency of contacts with pre-synaptic elements and extracellular space pockets, while showing features of increased metabolic demand and reduced lysosomal activity. ConclusionAt 1 hour and 24 hours after FUS-BBB modulation, traits of microglial surveillance activity were largely maintained, with shifts in the shape of a subset of cells, which adopted a morphology associated with injury shielding. FUS-BBB modulation also appears to temporarily modify the digestive, but not the phagocytic activity, of microglia and to reduce pre-synaptic remodeling early after treatment.

neuroscience↗

bioRxiv2023

Ketogenic diet alters microglial morphology and changes the hippocampal lipidomic profile distinctively in stress susceptible versus resistant male mice upon repeated social defeat

Psychological stress confers an increased risk for several diseases including psychiatric conditions. The susceptibility to psychological stress is modulated by various factors, many of them being modifiable lifestyle choices. The ketogenic diet (KD) has emerged as a dietary regime that offers positive outcomes on mood and health status. Psychological stress and elevated inflammation are common features of neuropsychiatric disorders such as certain types of major depressive disorder. KD has been attributed anti-inflammatory properties that could underlie its beneficial consequences on the brain and behavior. Microglia are the main drivers of inflammation in the central nervous system. They are known to respond to both dietary changes and psychological stress, notably by modifying their production of cytokines and relationships among the brain parenchyma. To assess the interactions between KD and the stress response, including effects on microglia, we examined adult male mice on control diet (CD) versus KD that underwent 10 days of repeated social defeat (RSD) or remained non-stressed (controls; CTRLs). Through a social interaction test, stressed mice were classified as susceptible (SUS) or resistant (RES) to RSD. The mouse population fed a KD tended to have a higher proportion of individuals classified as RES following RSD. Microglial morphology and ultrastructure were then analyzed in the ventral hippocampus CA1, a brain region known to present structural alterations as a response to psychological stress. Distinct changes in microglial soma and arborization linked to the KD, SUS and RES phenotypes were revealed. Ultrastructural analysis by electron microscopy showed a clear reduction of cellular stress markers in microglia from KD fed animals. Furthermore, ultrastructural analysis showed that microglial contacts with synaptic elements were reduced in the SUS compared to the RES and CTRL groups. Hippocampal lipidomic analyses lastly identified a distinct lipid profile in SUS animals compared to CTRLs. These key differences, combined with the distinct microglial responses to diet and stress, indicate that unique metabolic changes may underlie the stress susceptibility phenotypes. Altogether, our results reveal novel mechanisms by which a KD might improve the resistance to psychological stress. HighlightsO_LIKetogenic diet tends to promote resistance to psychological stress C_LIO_LIHippocampal microglia show morphological adaptations to stress and diet C_LIO_LIMicroglia of stress-susceptible mice make less synaptic contacts C_LIO_LIMicroglia of ketogenic diet-fed mice show less signs of cellular stress C_LIO_LILipids are differentially regulated in the hippocampi of susceptible mice C_LI

neuroscience↗

bioRxiv2023

Astroglial Hmgb1 regulates postnatal astrocyte morphogenesis and cerebrovascular maturation.

Astrocytes are intimately linked with brain vessels, a relationship that is critical for neuronal health and function. However, astroglial factors driving these physical and functional associations during postnatal brain development have yet to be identified. We characterized structural and transcriptional changes in mouse cortical astrocytes and microvessels during the first two postnatal weeks and found that high-mobility group box 1 (Hmgb1), normally upregulated with injury and involved in adult cerebrovascular repair, was highly expressed in astrocytes at birth and then decreased rapidly. Astrocyte-selective ablation of Hmgb1 at birth affected astrocyte morphology and endfoot placement, altered distribution of endfoot proteins connexin43 and aquaporin-4, induced transcriptional changes in astrocytes related to cytoskeleton remodeling, and profoundly disrupted endothelial ultrastructure. While lack of astroglial Hmgb1 did not affect the blood-brain barrier or angiogenesis postnatally, it impaired neurovascular coupling and behavior in adult mice. These findings identify astroglial Hmgb1 as a key player in postnatal gliovascular maturation.

developmental biology↗

bioRxiv2021

Microglia control glutamatergic synapses in the adult mouse hippocampus

Microglial cells are active players in regulating synaptic development and plasticity in the brain. However, how these cells influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological depletion of microglia, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features accompanied by higher levels of plasticity. In addition, microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. Remarkably, microglial repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in synaptic organization and activity of glutamatergic synapses.

neuroscience↗

bioRxiv2020

Cross-sectional evaluation of humoral responses against SARS-CoV-2 Spike

The SARS-CoV-2 virus is responsible for the current worldwide coronavirus disease 2019 (COVID-19) pandemic, infecting millions of people and causing hundreds of thousands of deaths. The Spike glycoprotein of SARS-CoV-2 mediates viral entry and is the main target for neutralizing antibodies. Understanding the antibody response directed against SARS-CoV-2 is crucial for the development of vaccine, therapeutic and public health interventions. Here we performed a cross-sectional study on 106 SARS-CoV-2-infected individuals to evaluate humoral responses against the SARS-CoV-2 Spike. The vast majority of infected individuals elicited anti-Spike antibodies within 2 weeks after the onset of symptoms. The levels of receptor-binding domain (RBD)-specific IgG persisted overtime, while the levels of anti-RBD IgM decreased after symptoms resolution. Some of the elicited antibodies cross-reacted with other human coronaviruses in a genus-restrictive manner. While most of individuals developed neutralizing antibodies within the first two weeks of infection, the level of neutralizing activity was significantly decreased over time. Our results highlight the importance of studying the persistence of neutralizing activity upon natural SARS-CoV-2 infection.

microbiology↗