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Item Parkinson's disease-associated LRRK2 interferes with astrocyte-mediated alpha-synuclein clearance(Molecular Neurobiology, 2021) Streubel-Gallasch, Linn; Giusti, Veronica; Sandre, Michele; Tessari, Isabella; Plotegher, Nicoletta; Giusto, Elena; Masato, Anna; Iovino, Ludovica; Battisti, Ilaria; Arrigoni, Giorgio; Shimshek, Derya; Greggio, Elisa; Tremblay, Marie-Eve; Bubacco, Luigi; Erlandsson, Anna; Civiero, LauraParkinson's disease (PD) is a neurodegenerative, progressive disease without a cure. To prevent PD onset or at least limit neurodegeneration, a better understanding of the underlying cellular and molecular disease mechanisms is crucial. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene represent one of the most common causes of familial PD. In addition, LRRK2 variants are risk factors for sporadic PD, making LRRK2 an attractive therapeutic target. Mutations in LRRK2 have been linked to impaired alpha-synuclein (α-syn) degradation in neurons. However, in which way pathogenic LRRK2 affects α-syn clearance by astrocytes, the major glial cell type of the brain, remains unclear. The impact of astrocytes on PD progression has received more attention and recent data indicate that astrocytes play a key role in α-syn-mediated pathology. In the present study, we aimed to compare the capacity of wild-type astrocytes and astrocytes carrying the PD-linked G2019S mutation in Lrrk2 to ingest and degrade fibrillary α-syn. For this purpose, we used two different astrocyte culture systems that were exposed to sonicated α-syn for 24 h and analyzed directly after the α-syn pulse or 6 days later. To elucidate the impact of LRRK2 on α-syn clearance, we performed various analyses, including complementary imaging, transmission electron microscopy, and proteomic approaches. Our results show that astrocytes carrying the G2019S mutation in Lrrk2 exhibit a decreased capacity to internalize and degrade fibrillar α-syn via the endo-lysosomal pathway. In addition, we demonstrate that the reduction of α-syn internalization in the Lrrk2 G2019S astrocytes is linked to annexin A2 (AnxA2) loss of function. Together, our findings reveal that astrocytic LRRK2 contributes to the clearance of extracellular α-syn aggregates through an AnxA2-dependent mechanism.Item The implication of a diversity of non-neuronal cells in disorders affecting brain networks(Frontiers in Cellular Neuroscience, 2022) Carrier, Micaël; Dolhan, Kira; Bobotis, Bianca Caroline; Desjardins, Michèle; Tremblay, Marie-ÈveIn the central nervous system (CNS) neurons are classically considered the functional unit of the brain. Analysis of the physical connections and coactivation of neurons, referred to as structural and functional connectivity, respectively, is a metric used to understand their interplay at a higher level. A myriad of glial cell types throughout the brain composed of microglia, astrocytes and oligodendrocytes are key players in the maintenance and regulation of neuronal network dynamics. Microglia are the central immune cells of the CNS, able to affect neuronal populations in number and connectivity, allowing for maturation and plasticity of the CNS. Microglia and astrocytes are part of the neurovascular unit, and together they are essential to protect and supply nutrients to the CNS. Oligodendrocytes are known for their canonical role in axonal myelination, but also contribute, with microglia and astrocytes, to CNS energy metabolism. Glial cells can achieve this variety of roles because of their heterogeneous populations comprised of different states. The neuroglial relationship can be compromised in various manners in case of pathologies affecting development and plasticity of the CNS, but also consciousness and mood. This review covers structural and functional connectivity alterations in schizophrenia, major depressive disorder, and disorder of consciousness, as well as their correlation with vascular connectivity. These networks are further explored at the cellular scale by integrating the role of glial cell diversity across the CNS to explain how these networks are affected in pathology.Item Editorial: Women in neuroscience(Frontiers in Integrative Neuroscience, 2022) Maffei, Arianna; Chiappalone, Michela; Fattore, Liana; Torres, Elizabeth B.; Tremblay, Marie-Ève; Wierenga, Corette J.The “Matilda effect” is an expression coined in 1993 by Margaret Rossiter, a prominent science historian, to describe the faint recognition of the contribution of women to the scientific enterprise. The expression derived from the realization that just like the work of Matilda Gage, a suffragist who also wrote about women in science, the discoveries and inventions of many women scientists had been forgotten over the course of history. Indeed, women’s contributions to science have been often misappropriated, forgotten or, in some cases, even actively removed from the records. This resulted in a misplaced historic assumption that women lack the intellectual ability and interest for scientific disciplines, and left younger generations of women with very few role models to look up to. Over the past few years, the awareness of this lack of recognition has increased and, despite encountering some resistance, active efforts have been made to make science a more inclusive enterprise. Neuroscience is a multidisciplinary field that encompasses all scientific disciplines including biology, psychology, cognitive sciences, physics, engineering, and mathematics. While women to this day represent a minority of neuroscience faculty, they contribute to all aspects of the field. The goal of the Women in neuroscience Research Topic is to oppose the “Matilda effect” by bringing together excellent research by women, or in collaboration with women. The Research Topic brings together 33 articles in which the first or last author are women. The formats include mini-reviews and reviews of the exceptional work done by past and present women neuroscientists, an opinion article, perspectives and specific Research Topic reviews highlighting scholarship and innovative frameworks, and original research articles that push the field forward.Item Ultrastructural characterization of dark microglia during aging in a mouse model of Alzheimer's disease pathology and in human post-mortem brain samples(Journal of Neuroinflammation, 2022) St-Pierre, Marie-Kim; Carrier, Micaël; González Ibáñez, Fernando; Šimončičová, Eva; Wallman, Marie‑Josée; Vallières, Luc; Parent, Martin; Tremblay, Marie-ÈveA diverse heterogeneity of microglial cells was previously described in Alzheimer’s disease (AD) pathology, including dark microglia, a state characterized by ultrastructural markers of cellular stress. To provide novel insights into the roles of dark microglia during aging in the context of AD pathology, we performed a quantitative density and ultrastructural analysis of these cells using high-throughput scanning electron microscopy in the ventral hippocampus CA1 stratum lacunosum-moleculare of 20-month-old APP-PS1 vs C57BL/6J male mice. The density of dark microglia was significantly higher in APP-PS1 vs C57BL/6J mice, with these cells accounting for nearly half of all microglia observed near amyloid-beta (Aβ) plaques. This dark microglial state interacted more with dystrophic neurites compared to other APP-PS1 microglia and possessed glycogen granules, associated with a metabolic shift toward glycolysis, which provides the first ultrastructural evidence of their presence in microglia. Dark microglia were further observed in aging human post-mortem brain samples showing similar ultrastructural features as in mouse. Overall, our results provide a quantitative ultrastructural characterization of a microglial state associated with cellular stress (i.e., dark microglia) that is primarily restricted near Aβ plaques and dystrophic neurites. The presence of this microglial state in the aging human post-mortem brain is further revealed.Item A 3D analysis revealed complexe mitochondria morphologies in porcine cumulus cells(Scientific Reports, 2022) Lounas, Amel; Lebrun, Ariane; Laflamme, Isabelle; Vernoux, Nathalie; Savage, Julie; Tremblay, Marie-Ève; Germain, Marc; Richard, François J.In the ovarian follicle, a bilateral cell-to-cell communication exists between the female germ cell and the cumulus cells which surround the oocyte. This communication allows the transit of small size molecules known to impact oocyte developmental competence. Pyruvate derivatives produced by mitochondria, are one of these transferred molecules. Interestingly, mitochondria may adopt a variety of morphologies to regulate their functions. In this study, we described mitochondrial morphologies in porcine cumulus cells. Active mitochondria were stained with TMRM (Tetramethylrhodamine, Methyl Ester, Perchlorate) and observed with 2D confocal microscopy showing mitochondria of different morphologies such as short, intermediate, long, and very long. The number of mitochondria of each phenotype was quantified in cells and the results showed that most cells contained elongated mitochondria. Scanning electron microscopy (SEM) analysis confirmed at nanoscale resolution the different mitochondrial morphologies including round, short, intermediate, and long. Interestingly, 3D visualisation by focused ion-beam scanning electron microscopy (FIB-SEM) revealed different complex mitochondrial morphologies including connected clusters of different sizes, branched mitochondria, as well as individual mitochondria. Since mitochondrial dynamics is a key regulator of function, the description of the mitochondrial network organisation will allow to further study mitochondrial dynamics in cumulus cells in response to various conditions such as in vitro maturation.Item All roads lead to heterogeneity: The complex involvement of astrocytes and microglia in the pathogenesis of Alzheimer’s disease(Frontiers in Cellular Neuroscience, 2022) St-Pierre, Marie-Kim; VanderZwaag, Jared; Loewen, Sophia; Tremblay, Marie-ÈveIn recent years, glial cells have been acknowledged as key players in the pathogenesis of Alzheimer’s disease (AD), a neurodegenerative condition in which an accumulation of intracellular neurofibrillary tangles and extracellular fibrillar amyloid beta is notably observed in the central nervous system. Genome-wide association studies have shown, both in microglia and astrocytes, an increase in gene variants associated with a higher risk of developing late-onset AD. Microglia, the resident innate immune cells of the brain, and astrocytes, glial cells crucial for vascular integrity and neuronal support, both agglomerate near amyloid beta plaques and dystrophic neurites where they participate in the elimination of these harmful parenchymal elements. However, their role in AD pathogenesis has been challenging to resolve due to the highly heterogeneous nature of these cell populations, i.e., their molecular, morphological, and ultrastructural diversity, together with their ever-changing responsiveness and functions throughout the pathological course of AD. With the recent expansions in the field of glial heterogeneity through innovative advances in state-of-the-art microscopy and -omics techniques, novel concepts and questions arose, notably pertaining to how the diverse microglial and astrocytic states interact with each other and with the AD hallmarks, and how their concerted efforts/actions impact the progression of the disease. In this review, we discuss the recent advances and findings on the topic of glial heterogeneity, particularly focusing on the relationships of these cells with AD hallmarks (e.g., amyloid beta plaques, neurofibrillary tangles, synaptic loss, and dystrophic neurites) in murine models of AD pathology and post-mortem brain samples of patients with AD.Item A light-inducible protein clustering system for in vivo analysis of α-synuclein aggregation in Parkinson disease(PLoS Biology, 2022) Bérard, Morgan; Sheta, Razan; Malvaut, Sarah; Rodriguez-Aller, Raquel; Teixeira, Maxime; Idi, Walid; Turmel, Roxanne; Alpaugh, Melanie; Dubois, Marilyn; Dahmene, Manel; Salesse, Charleen; Lamontage-Proulx, Jérôme; St-Pierre, Marie-Kim; Tavassoly, Omid; Luo, Wen; Del Cid-Pellitero, Esther; Qazi, Raza; Jeong, Jae-Woong; Durcan, Thomas M.; Vallières, Luc; Tremblay, Marie-Eve; Soulet, Denis; Lévesque, Martin; Cicchetti, Francesca; Fon, Edward A.; Saghatelyan, Armen; Oueslati, AbidNeurodegenerative disorders refer to a group of diseases commonly associated with abnormal protein accumulation and aggregation in the central nervous system. However, the exact role of protein aggregation in the pathophysiology of these disorders remains unclear. This gap in knowledge is due to the lack of experimental models that allow for the spatiotemporal control of protein aggregation, and the investigation of early dynamic events associated with inclusion formation. Here, we report on the development of a light-inducible protein aggregation (LIPA) system that enables spatiotemporal control of α-synuclein (α-syn) aggregation into insoluble deposits called Lewy bodies (LBs), the pathological hallmark of Parkinson disease (PD) and other proteinopathies. We demonstrate that LIPA-α-syn inclusions mimic key biochemical, biophysical, and ultrastructural features of authentic LBs observed in PD-diseased brains. In vivo, LIPA-α-syn aggregates compromise nigrostriatal transmission, induce neurodegeneration and PD-like motor impairments. Collectively, our findings provide a new tool for the generation, visualization, and dissection of the role of α-syn aggregation in PD.Item Early stress-induced impaired microglial pruning of excitatory synapses on immature CRH-expressing neurons provokes aberrant adult stress responses(Cell Reports, 2022) Bolton, Jessica L.; Short, Annabel K.; Othy, Shivashankar; Kooiker, Cassandra L.; Shao, Manlin; Gunn, Benjamin G.; Beck, Jaclyn; Bai, Xinglong; Law, Stephanie M.; Savage, Julie C.; Lambert, Jeremy J.; Belelli, Delia; Tremblay, Marie-Ève; Cahalan, Michael D.; Baram, Tallie Z.Several mental illnesses, characterized by aberrant stress reactivity, often arise after early-life adversity (ELA). However, it is unclear how ELA affects stress-related brain circuit maturation, provoking these enduring vulnerabilities. We find that ELA increases functional excitatory synapses onto stress-sensitive hypothalamic corticotropin-releasing hormone (CRH)-expressing neurons, resulting from disrupted developmental synapse pruning by adjacent microglia. Microglial process dynamics and synaptic element engulfment were attenuated in ELA mice, associated with deficient signaling of the microglial phagocytic receptor MerTK. Accordingly, selective chronic chemogenetic activation of ELA microglia increased microglial process dynamics and reduced excitatory synapse density to control levels. Notably, selective early-life activation of ELA microglia normalized adult acute and chronic stress responses, including stress-induced hormone secretion and behavioral threat responses, as well as chronic adrenal hypertrophy of ELA mice. Thus, microglial actions during development are powerful contributors to mechanisms by which ELA sculpts the connectivity of stress-regulating neurons, promoting vulnerability to stress and stress-related mental illnesses.Item N-3 PUFA deficiency affects the ultrastructural organization and density of white matter microglia in the developing brain of male mice(Frontiers in Cellular Neuroscience, 2022) Decoeur, Fanny; Picard, Katherine; St-Pierre, Marie-Kim; Greenhalgh, Andrew D.; Delpech, Jean-Christophe; Sere, Alexandra; Layé, Sophie; Tremblay, Marie-Eve; Nadjar, AgnèsOver the last century, westernization of dietary habits has led to a dramatic reduction in dietary intake of n-3 polyunsaturated fatty acids (n-3 PUFAs). In particular, low maternal intake of n-3 PUFAs throughout gestation and lactation causes defects in brain myelination. Microglia are recognized for their critical contribution to neurodevelopmental processes, such as myelination. These cells invade the white matter in the first weeks of the post-natal period, where they participate in oligodendrocyte maturation and myelin production. Therefore, we investigated whether an alteration of white matter microglia accompanies the myelination deficits observed in the brain of n-3 PUFA-deficient animals. Macroscopic imaging analysis shows that maternal n-3 PUFA deficiency decreases the density of white matter microglia around post-natal day 10. Microscopic electron microscopy analyses also revealed alterations of microglial ultrastructure, a decrease in the number of contacts between microglia and myelin sheet, and a decreased amount of myelin debris in their cell body. White matter microglia further displayed increased mitochondrial abundance and network area under perinatal n-3 PUFA deficiency. Overall, our data suggest that maternal n-3 PUFA deficiency alters the structure and function of microglial cells located in the white matter of pups early in life, and this could be the key to understand myelination deficits during neurodevelopment.Item Differential effects of early or late exposure to prenatal maternal immune activation on mouse embryonic neurodevelopment(PNAS, 2022) Guma, Elisa; Bordeleau, Maude; González Ibáñez, Fernando; Picard, Katherine; Snook, Emily; Desrosiers-Grégoire, Gabriel; Spring, Shoshana; Lerch, Jason P.; Nieman, Brian J.; Devenyi, Gabriel A.; Tremblay, Marie-Eve; Chakravarty, M. MallarExposure 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 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 the putative neuroanatomical underpinnings of MIA timing in the hippocampus 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 neurons and glia with ultrastructural features reflective of 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.Item Editorial: Role of neuroinflammation in the neuropsychiatric and neurological aspects of COVID-19(Frontiers in Cellular Neuroscience, 2022) Tremblay, Marie-Eve; Madore, Charlotte; Tian, Li; Verkhratsky, AlexeiItem Maternal high-fat diet in mice induces cerebrovascular, microglial and long-term behavioural alterations in offspring(Communications Biology, 2022) Bordeleau, Maude; Comin, Cesar H.; de Cossío, Lourdes Fernández; Lacabanne, Chloé; Freitas-Andrade, Moises; González Ibáñez, Fernando; Raman-Nair, Joanna; Wakem, Michael; Chakravarty, Mallar; da F. Costa, Luciano; Lacoste, Baptiste; Tremblay, Marie-ÈveVarious environmental exposures during pregnancy, like maternal diet, can compromise, at critical periods of development, the neurovascular maturation of the offspring. Foetal exposure to maternal high-fat diet (mHFD), common to Western societies, has been shown to disturb neurovascular development in neonates and long-term permeability of the neurovasculature. Nevertheless, the effects of mHFD on the offspring’s cerebrovascular health remains largely elusive. Here, we sought to address this knowledge gap by using a translational mouse model of mHFD exposure. Three-dimensional and ultrastructure analysis of the neurovascular unit (vasculature and parenchymal cells) in mHFD-exposed offspring revealed major alterations of the neurovascular organization and metabolism. These alterations were accompanied by changes in the expression of genes involved in metabolism and immunity, indicating that neurovascular changes may result from abnormal brain metabolism and immune regulation. In addition, mHFD-exposed offspring showed persisting behavioural alterations reminiscent of neurodevelopmental disorders, specifically an increase in stereotyped and repetitive behaviours into adulthood.Item Microglia control glutamatergic synapses in the adult mouse hippocampus(Glia, 2022) Basilico, Bernadette; Ferrucci, Laura; Ratano, Patrizia; Golia, Maria T.; Grimaldi, Alfonso; Rosito, Maria; Ferretti, Valentina; Reverte, Ingrid; Sanchini, Caterina; Marrone, Maria C.; Giubettini, Maria; De Turris, Valeria; Salerno, Debora; Garofalo, Stefano; St-Pierre, Marie-Kim; Carrier, Micael; Renzi, Massimiliano; Pagani, Francesca; Modi, Brijesh; Tremblay, Marie-Ève; Caprioli, Daniele; Maggi, Laura; Limatola, Cristina; Di Angelantonio, Silvia; Ragozzino, DavideMicroglia cells are active players in regulating synaptic development and plasticity in the brain. However, how they influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological microglia depletion, 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 and higher levels of plasticity. Microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. These events were accompanied by hippocampal astrogliosis, although in the absence of neuroinflammatory condition. PLX-induced synaptic changes were absent in Cx3cr1 / mice, highlighting the role of CX3CL1/CX3CR1 axis in microglia control of synaptic functioning. Remarkably, microglia 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 organization and activity of glutamatergic synapses.Item Microglia as a hub for suicide neuropathology: Future investigation and prevention targets(Frontiers in Cellular Neuroscience, 2022) Gonçalves de Andrade, Elisa; González Ibáñez, Fernando; Tremblay, Marie-ÈveSuicide is a complex public health challenge associated worldwide with one death every 40 s. Research advances in the neuropathology of suicidal behaviors (SB) have defined discrete brain changes which may hold the key to suicide prevention. Physiological differences in microglia, the resident immune cells of the brain, are present in postmortem tissue samples of individuals who died by suicide. Furthermore, microglia are mechanistically implicated in the outcomes of important risk factors for SB, including early-life adversity, stressful life events, and psychiatric disorders. SB risk factors result in inflammatory and oxidative stress activities which could converge to microglial synaptic remodeling affecting susceptibility or resistance to SB. To push further this perspective, in this Review we summarize current areas of opportunity that could untangle the functional participation of microglia in the context of suicide. Our discussion centers around microglial state diversity in respect to morphology, gene and protein expression, as well as function, depending on various factors, namely brain region, age, and sex.Item Density of TMEM119‑positive microglial cells in postmortem cerebrospinal fluid as a surrogate marker for assessing complex neuropathological processes in the CNS(International Journal of Legal Medicine, 2022) Bohnert, Simone; Trella, Stefanie; Preiß, Ulrich; Heinsen, Helmut; Bohnert, Michael; Zwirner, Johann; Tremblay, Marie‑Ève; Monoranu, Camelia-Maria; Ondruschka, BenjaminRoutine coronal paraffin-sections through the dorsal frontal and parieto-occipital cortex of a total of sixty cases with divergent causes of death were immunohistochemically (IHC) stained with an antibody against TMEM119. Samples of cerebrospinal fluid (CSF) of the same cases were collected by suboccipital needle-puncture, subjected to centrifugation and processed as cytospin preparations stained with TMEM119. Both, cytospin preparations and sections were subjected to computer-assisted density measurements. The density of microglial TMEM119-positive cortical profiles correlated with that of cytospin results and with the density of TMEM119-positive microglial profiles in the medullary layer. There was no statistically significant correlation between the density of medullary TMEM119-positive profiles and the cytospin data. Cortical microglial cells were primarily encountered in supragranular layers I, II, and IIIa and in infragranular layers V and VI, the region of U-fibers and in circumscribed foci or spread in a diffuse manner and high density over the white matter. We have evidence that cortical microglia directly migrate into CSF without using the glympathic pathway. Microglia in the medullary layer shows a strong affinity to the adventitia of deep vessels in the myelin layer. Selected rapidly fatal cases including myocardial infarcts and drowning let us conclude that microglia in cortex and myelin layer can react rapidly and its reaction and migration is subject to pre-existing external and internal factors. Cytospin preparations proved to be a simple tool to analyze and assess complex changes in the CNS after rapid fatal damage. There is no statistically significant correlation between cytospin and postmortem interval. Therefore, the quantitative analyses of postmortem cytospins obviously reflect the neuropathology of the complete central nervous system. Cytospins provide forensic pathologists a rather simple and easy to perform method for the global assessment of CNS affliction.Item Blocking immune cell infiltration of the central nervous system to tame neuroinflammation in amyotrophic lateral sclerosis(2022) Garofalo, Stefano; Cocozza, Germana; Bernardini, Giovanni; Savage, Julie; Raspa, Marcello; Aronica, Eleonora; Tremblay, Marie-Eve; Ransohoff, Richard M.; Santoni, Angela; Limatola, CristinaNeuroinflammation is one of the main hallmarks of amyotrophic lateral sclerosis (ALS). Recently, peripheral immune cells were discovered as pivotal players that promptly participate in this process, speeding up neurodegeneration during progression of the disease. In particular, infiltrating T cells and natural killer cells release inflammatory cytokines that switch glial cells toward a pro-inflammatory/detrimental phenotype, and directly attack motor neurons with specific ligand-receptor signals. Here, we assessed the presence of lymphocytes in the spinal cord of sporadic ALS patients. Furthermore, we demonstrate that blocking the extravasation of immune cells in the central nervous system using Natalizumab (NAT), an antibody for the α4 integrin, reduces the level of interferon-γ in the spinal cord of ALS mouse models, such as the hSOD1G93A and TDP43A315T mice, modifying microglia and astrocytes phenotype, increasing motor neuron number and prolonging the survival time. Taken together, our results establish a central role for the immune cells as drivers of inflammation in ALS.Item The pathobiology of myalgic encephalomyelitis/chronic fatigue syndrome: The case for neuroglial failure(Frontiers in Cellular Neuroscience, 2022) Renz-Polster, Herbert; Tremblay, Marie-Eve; Bienzle, Dorothee; Fischer, Joachim E.Although myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has a specific and distinctive profile of clinical features, the disease remains an enigma because causal explanation of the pathobiological matrix is lacking. Several potential disease mechanisms have been identified, including immune abnormalities, inflammatory activation, mitochondrial alterations, endothelial and muscular disturbances, cardiovascular anomalies, and dysfunction of the peripheral and central nervous systems. Yet, it remains unclear whether and how these pathways may be related and orchestrated. Here we explore the hypothesis that a common denominator of the pathobiological processes in ME/CFS may be central nervous system dysfunction due to impaired or pathologically reactive neuroglia (astrocytes, microglia and oligodendrocytes). We will test this hypothesis by reviewing, in reference to the current literature, the two most salient and widely accepted features of ME/CFS, and by investigating how these might be linked to dysfunctional neuroglia. From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.Item Single‑cell transcriptomics of the ventral posterolateral nucleus‑enriched thalamic regions from HSV‑1‑infected mice reveal a novel microglia/microglia‑like transcriptional response(Journal of Neuroinflammation, 2022) Uyar, Olus; Dominguez, Juan Manuel; Bordeleau, Maude; Lapeyre, Lina; González Ibáñez, Fernando; Vallières, Luc; Tremblay, Marie-Eve; Corbeil, Jacques; Boivin, GuyBackground: Microglia participate in the immune response upon central nervous system (CNS) infections. However, the role of these cells during herpes simplex encephalitis (HSE) has not been fully characterized. We sought to identify different microglia/microglia-like cells and describe the potential mechanisms and signaling pathways involved during HSE. Methods: The transcriptional response of CD11b+ immune cells, including microglia/microglia-like cells, was investigated using single-cell RNA sequencing (scRNA-seq) on cells isolated from the ventral posterolateral nucleus (VPL)-enriched thalamic regions of C57BL/6 N mice intranasally infected with herpes simplex virus-1 (HSV-1) (6 × 105 PFUs/20 μl). We further performed scanning electronic microscopy (SEM) analysis in VPL regions on day 6 post-infection (p.i.) to provide insight into microglial functions. Results: We describe a novel microglia-like transcriptional response associated with a rare cell population (7% of all analyzed cells), named “in transition” microglia/microglia-like cells in HSE. This new microglia-like transcriptional signature, found in the highly infected thalamic regions, was enriched in specific genes (Retnlg, Cxcr2, Il1f9) usually associated with neutrophils. Pathway analysis of this cell-type transcriptome showed increased NLRP3-inflammasomemediated interleukin IL-1β production, promoting a pro-inflammatory response. These cells’ increased expression of viral transcripts suggests that the distinct “in transition” transcriptome corresponds to the intrinsic antiviral immune signaling of HSV-1-infected microglia/microglia-like cells in the thalamus. In accordance with this phenotype, we observed several TMEM119+/ IBA-I+ microglia/microglia-like cells immunostained for HSV-1 in highly infected regions. Conclusions: A new microglia/microglia-like state may potentially shed light on how microglia could react to HSV-1 infection. Our observations suggest that infected microglia/microglia-like cells contribute to an exacerbated CNSItem Microglial transcriptional signatures in the central nervous system: Toward a future of unraveling their function in health and disease(Annual Review of Genetics, 2023) Vecchiarelli, Haley A.; Tremblay, Marie-ÈveMicroglia, the resident immune cells of the central nervous system (CNS), are primarily derived from the embryonic yolk sac and make their way to the CNS during early development. They play key physiological and immunological roles across the life span, throughout health, injury, and disease. Recent transcriptomic studies have identified gene transcript signatures expressed by microglia that may provide the foundation for unprecedented insights into their functions. Microglial gene expression signatures can help distinguish them from macrophage cell types to a reasonable degree of certainty, depending on the context. Microglial expression patterns further suggest a heterogeneous population comprised of many states that vary according to the spatiotemporal context. Microglial diversity is most pronounced during development, when extensive CNS remodeling takes place, and following disease or injury. A next step of importance for the field will be to identify the functional roles performed by these various microglial states, with the perspective of targeting them therapeutically.Item Astroglial Hmgb1 regulates postnatal astrocyte morphogenesis and cerebrovascular maturation(Nature Communications, 2023) Freitas-Andrade, Moises; Comin, Cesar H.; Van Dyken, Peter; Ouellette, Julie; Raman-Nair, Joanna; Blakeley, Nicole; Liu, Qing Yan; Leclerc, Sonia; Pan, Youlian; Liu, Ziying; Carrier, Micaël; Thakur, Karan; Savard, Alexandre; Rurak, Gareth M.; Tremblay, Marie-Ève; Salmaso, Natalina; da F. Costa, Luciano; Coppola, Gianfilippo; Lacoste, BaptisteAstrocytes are intimately linked with brain blood vessels, an essential relationship for neuronal function. However, astroglial factors driving these physical and functional associations during postnatal brain development have yet to be identified. By characterizing structural and transcriptional changes in mouse cortical astrocytes during the first two postnatal weeks, we find that high-mobility group box 1 (Hmgb1), normally upregulated with injury and involved in adult cerebrovascular repair, is highly expressed in astrocytes at birth and then decreases rapidly. Astrocyte-selective ablation of Hmgb1 at birth affects astrocyte morphology and endfoot placement, alters distribution of endfoot proteins connexin43 and aquaporin-4, induces transcriptional changes in astrocytes related to cytoskeleton remodeling, and profoundly disrupts endothelial ultrastructure. While lack of astroglial Hmgb1 does not affect the blood-brain barrier or angiogenesis postnatally, it impairs neurovascular coupling and behavior in adult mice. These findings identify astroglial Hmgb1 as an important player in postnatal gliovascular maturation.