Biology subjects

Picard, K.

Publications and source records attributed to Picard, K..

6 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↗

bioRxiv2024

Dark Microglia Are Abundant in Normal Postnatal Development, where they Remodel Synapses via Phagocytosis and Trogocytosis, and Are Dependent on TREM2

This study examined dark microglia--a state linked to central nervous system pathology and neurodegeneration--during postnatal development in the mouse ventral hippocampus, finding that dark microglia interact with blood vessels and synapses and perform trogocytosis of pre-synaptic axon terminals. Furthermore, we found that dark microglia in development notably expressed C-type lectin domain family 7 member A (CLEC7a), lipoprotein lipase (LPL) and triggering receptor expressed on myeloid cells 2 (TREM2) and required TREM2, differently from other microglia, suggesting a link between their role in remodeling during development and central nervous system pathology. Together, these results point towards a previously under-appreciated role for dark microglia in synaptic pruning and plasticity during normal postnatal development.

neuroscience↗

bioRxiv2024

Abstinence from cocaine self-administration promotes microglia pruning of astrocytes which drives cocaine-seeking behavior

Rodent drug self-administration leads to compromised ability of astrocytes to maintain glutamate homeostasis within the brains reward circuitry, as well as reductions in surface area, volume, and synaptic colocalization of astrocyte membranes. However, the mechanisms driving astrocyte responses to cocaine are unknown. Here, we report that long-access cocaine self-administration followed by prolonged home cage abstinence results in decreased branching complexity of nucleus accumbens astrocytes, characterized by the loss of peripheral processes. Using a combination of confocal fluorescence microcopy and immuno-gold electron microscopy, we show that alterations in astrocyte structural features are driven by microglia phagocytosis, as labeled astrocyte membranes are found within microglia phagolysosomes. Inhibition of complement C3-mediated phagocytosis using the neutrophil inhibitory peptide (NIF) rescued astrocyte structure and decreased cocaine seeking behavior following cocaine self-administration and abstinence. Collectively, these results provide evidence for microglia pruning of accumbens astrocytes across cocaine abstinence which mediates cocaine craving.

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↗

bioRxiv2021

Differential effects of early or late exposure to prenatal maternal immune activation on mouse embryonic neurodevelopment

Exposure to maternal immune activation (MIA) in utero is a risk factor for neurodevelopmental and psychiatric disorders. MIA-induced deficits in adolescent and adult offspring have been well characterized, however, less is known about the effects of MIA-exposure on embryo development. To address this gap, we performed high-resolution ex vivo magnetic resonance imaging (MRI) to investigate the effects of early (gestational day [GD]9) and late (GD17) MIA-exposure on embryo (GD18) brain structure. We identify striking neuroanatomical changes in the embryo brain, particularly in the late exposed offspring. We further examined hippocampal neuroanatomy using electron microscopy and identified differential effects due to MIA-timing. An increase in apoptotic cell density was observed in the GD9 exposed offspring, while an increase in the density of dark neurons and glia, putative markers for increased neuroinflammation and oxidative stress, was observed in GD17 exposed offspring, particularly in females. Overall, our findings integrate imaging techniques across different scales to identify differential impact of MIA-timing on the earliest stages of neurodevelopment.

neuroscience↗

bioRxiv2020

Long-term single-cell imaging and simulations of microtubules reveal driving forces for wall pattering during proto-xylem development

Plants are the tallest organisms on Earth; a feature sustained by solute-transporting xylem vessels in the plant vasculature. The xylem vessels are supported by strong cell walls that are assembled in intricate patterns. Cortical microtubules direct wall deposition and need to rapidly re-organize during xylem cell development. We established long-term live-cell imaging of single Arabidopsis cells undergoing proto-xylem trans-differentiation, resulting in spiral wall patterns, to investigate the microtubule re-organization. The initial disperse microtubule array rapidly readjusted into well-defined microtubule bands, which required local de-stabilization of individual microtubules in band-interspersing gap regions. Using extensive microtubule simulations, we could recapitulate the process in silico and found that local recruitment of microtubule-bound nucleation is critical for pattern formation, which we confirmed in vivo. Our simulations further indicated that the initial microtubule alignment impact microtubule band patterning. We confirmed this prediction using katanin mutants, which have microtubule organization defects, and uncovered active KATANIN recruitment to the forming microtubule bands. Our combination of quantitative microscopy and modelling outlines a framework towards a comprehensive understanding of microtubule re-organization during wall pattern formation.

plant biology↗