Faculty Publications (Medical Sciences)

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Articles from BioMed Central Click on this link to see Work published with BioMed Central, Chemistry Central and SpringerOpen by researchers at University of Victoria.


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    Containment of neuroimmune challenge by diosgenin confers amelioration of neurochemical and neurotrophic dysfunctions in ketamine-induced schizophrenia in mice
    (Brain Disorders, 2024) Ben-Azu, Benneth; Adebayo, Olusegun G.; Fokoua, Aliance R.; Onuelu, Jackson E.; Asiwe, Jerome N.; Moke, Emuesiri G.; Omogbiya, Itivere A.; Okpara, Oghenemarho L.; Okoro, Jennifer E.; Oghenevwerutevwe, Omadevuaye M.; Uruaka, Christian I.
    Inhibition of neuroinflammation through N-methyl-D-aspartate receptor (NMDAR) regulation can provide normalization of neurochemical homeostasis and neurotrophic support in the pathogenesis of psychiatric disorders with complex symptoms such as schizophrenia. Accordingly, the preventive and reversal effects, and potential mechanisms of diosgenin, a phyto-steroidal sapogenin with anti-inflammatory functions, was evaluated in ketamine (an NMDAR antagonist) model of schizophrenia in mice. Adult male mice were allotted into 5 groups. In the preventive protocol, mice received saline (10 mL/kg), diosgenin (25 and 50 mg/kg) and risperidone (0.5 mg/kg) orally for 14 days, with additional injection of ketamine (20 mg/kg/day/i.p.) from days 8–14. In the reversal protocol, mice took ketamine injection consecutively for 14 days prior to diosgenin and risperidone treatments from days 8–14. Thereafter, schizophrenia-like behavior, therapeutic extrapyramidal adverse effect, neuroimmune, neurochemical and neurotrophic consequences in important brain areas affected in the disorder were assayed. Diosgenin prevented and reversed stereotypy behavior, cognitive impairment, and psychotic-depression relative to ketamine groups. Complementarily, diosgenin prevents and reverses ketamine-induced dopamine and serotonin alterations in the striatum, prefrontal-cortex, and hippocampus relative to ketamine groups. Except for the cortical regions, diosgenin prevented and reversed glutamic acid decarboxylase depletion in these brain regions by ketamine, suggesting improved GABAergic system. Additionally, ketamine-induced elevation of neuroinflammatory markers: myeloperoxidase, tumor necrosis factor-alpha and interleukin-6, were inhibited in the striatum, prefrontal-cortex, and hippocampus. Also, diosgenin improved the levels of neurotrophic factor in the three brain regions in both protocols respectively. Among other mechanisms, the antipsychotic effect of diosgenin might be associated with attenuation of neurochemical and neuroimmune alterations.
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    Alterations in intrinsic and synaptic properties of hippocampal CA1 VIP interneurons during aging
    (Fronteirs in Cellular Neuroscience, 2020) Francavilla, Ruggiero; Guet-McCreight, Alexandre; Amalyan, Sona; Hui, Chin Wai; Topolnik, Dimitry; Michaud, Félix; Marino, Beatrice; Tremblay, Marie-Eve; Skinner, Frances K.; Topolnik, Lisa
    Learning and memory deficits are hallmarks of the aging brain, with cortical neuronal circuits representing the main target in cognitive deterioration. While GABAergic inhibitory and disinhibitory circuits are critical in supporting cognitive processes, their roles in age-related cognitive decline remain largely unknown. Here, we examined the morphological and physiological properties of the hippocampal CA1 vasoactive intestinal peptide/calretinin-expressing (VIP+/CR+) type 3 interneuron-specific (I-S3) cells across mouse lifespan. Our data showed that while the number and morphological features of I-S3 cells remained unchanged, their firing and synaptic properties were significantly altered in old animals. In particular, the action potential duration and the level of steady-state depolarization were significantly increased in old animals in parallel with a significant decrease in the maximal firing frequency. Reducing the fast-delayed rectifier potassium or transient sodium conductances in I-S3 cell computational models could reproduce the age-related changes in I-S3 cell firing properties. However, experimental data revealed no difference in the activation properties of the Kv3.1 and A-type potassium currents, indicating that transient sodium together with other ion conductances may be responsible for the observed phenomena. Furthermore, I-S3 cells in aged mice received a stronger inhibitory drive due to concomitant increase in the amplitude and frequency of spontaneous inhibitory currents. These age-associated changes in the I-S3 cell properties occurred in parallel with an increased inhibition of their target interneurons and were associated with spatial memory deficits and increased anxiety. Taken together, these data indicate that VIP+/CR+ interneurons responsible for local circuit disinhibition survive during aging but exhibit significantly altered physiological properties, which may result in the increased inhibition of hippocampal interneurons and distorted mnemonic functions.
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    Synaptic loss in Alzheimer's disease: Mechanistic insights provided by two-photon imaging of transgenic mouse models
    (Frontiers in Cellular Neuroscience, 2020) Subramanian, Jaichandar; Savage, Julie C.; Tremblay, Marie-Eve
    Synapse loss is the strongest correlate for cognitive decline in Alzheimer's disease. The mechanisms underlying synapse loss have been extensively investigated using mouse models expressing genes with human familial Alzheimer's disease mutations. In this review, we summarize how multiphoton imaging has improved our understanding of synapse loss mechanisms associated with excessive amyloid in the living animal brain. We also discuss evidence obtained from these imaging studies for the role of cell-intrinsic calcium dyshomeostasis and cell-extrinsic activities of microglia, which are the immune cells of the brain, in mediating synapse loss.
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    The inflamed brain in schizophrenia: The convergence of genetic and environmental risk factors that lead to uncontrolled neuroinflammation
    (Frontiers in Cellular Neuroscience, 2020) Comer, Ashley L.; Carrier, Micaël; Tremblay, Marie-Eve; Cruz-Martín, Alberto
    Schizophrenia is a disorder with a heterogeneous etiology involving complex interplay between genetic and environmental risk factors. The immune system is now known to play vital roles in nervous system function and pathology through regulating neuronal and glial development, synaptic plasticity, and behavior. In this regard, the immune system is positioned as a common link between the seemingly diverse genetic and environmental risk factors for schizophrenia. Synthesizing information about how the immune-brain axis is affected by multiple factors and how these factors might interact in schizophrenia is necessary to better understand the pathogenesis of this disease. Such knowledge will aid in the development of more translatable animal models that may lead to effective therapeutic interventions. Here, we provide an overview of the genetic risk factors for schizophrenia that modulate immune function. We also explore environmental factors for schizophrenia including exposure to pollution, gut dysbiosis, maternal immune activation and early-life stress, and how the consequences of these risk factors are linked to microglial function and dysfunction. We also propose that morphological and signaling deficits of the blood-brain barrier, as observed in some individuals with schizophrenia, can act as a gateway between peripheral and central nervous system inflammation, thus affecting microglia in their essential functions. Finally, we describe the diverse roles that microglia play in response to neuroinflammation and their impact on brain development and homeostasis, as well as schizophrenia pathophysiology.
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    A diversity of cell types, subtypes and phenotypes in the central nervous system: The importance of studying their complex relationships
    (Fronteirs in Cellular Neuroscience, 2020) Tremblay, Marie-Eve
    All the cell types in the central nervous system (CNS) cooperate to mediate proper development, function, and plasticity. Similarly, brain repair and neuroprotection, but also demyelination, synaptic loss and neurodegeneration, were increasingly shown to involve non-neuronal cells— both glial cells and peripheral immune cells—among the CNS parenchyma. Adding another degree of complexity, the non-neuronal cell populations are emerging as comprised of different subtypes, endowed with unique properties and functions at steady-state, and which can adopt various phenotypes upon exposure to homeostatic challenges. As a consequence, studying the multidirectional relationships between these different cell types, subtypes and phenotypes in the CNS is now required to provide insights into the mechanisms underlying physiological processes such as neuronogenesis, axon guidance,myelination, vascular formation and remodeling, regulation of neuronal activity, as well as synaptic formation, function and plasticity, and behavioral outputs, among other essential CNS functions.
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    A systematic, open-science framework for quantification of cell-types in mouse brain sections using fluorescence microscopy
    (Frontiers in Neuroanatomy, 2021) Sanchez-Arias, Juan C.; Carrier, Micaël; Frederiksen, Simona D.; Shevtsova, Olga; McKee, Chloe; van der Slagt, Emma; Gonçalves de Andrade, Elisa; Nguyen, Hai Lam; Young, Penelope A.; Tremblay, Marie-Ève; Swayne, Leigh Anne
    The ever-expanding availability and evolution of microscopy tools has enabled ground-breaking discoveries in neurobiology, particularly with respect to the analysis of cell-type density and distribution. Widespread implementation of many of the elegant image processing tools available continues to be impeded by the lack of complete workflows that span from experimental design, labeling techniques, and analysis workflows, to statistical methods and data presentation. Additionally, it is important to consider open science principles (e.g., open-source software and tools, user-friendliness, simplicity, and accessibility). In the present methodological article, we provide a compendium of resources and a FIJI-ImageJ-based workflow aimed at improving the quantification of cell density in mouse brain samples using semi-automated open-science-based methods. Our proposed framework spans from principles and best practices of experimental design, histological and immunofluorescence staining, and microscopy imaging to recommendations for statistical analysis and data presentation. To validate our approach, we quantified neuronal density in the mouse barrel cortex using antibodies against pan-neuronal and interneuron markers. This framework is intended to be simple and yet flexible, such that it can be adapted to suit distinct project needs. The guidelines, tips, and proposed methodology outlined here, will support researchers of wide-ranging experience levels and areas of focus in neuroscience research.
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    Editorial: The metabolism of the neuron-glia unit
    (Fronteirs in Cellular Neuroscience, 2021) Poitelon, Yannick; Johnson, Lance A.; Tremblay, Marie-Ève
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    Psychological stress as a risk factor for accelerated cellular aging and cognitive decline: The involvement of microglia-neuron crosstalk
    (Frontiers in Molecular Neuroscience, 2021) Carrier, Micaël; Šimončičová, Eva; St-Pierre, Marie-Kim; McKee, Chloe; Tremblay, Marie-Ève
    The relationship between the central nervous system (CNS) and microglia is lifelong. Microglia originate in the embryonic yolk sac during development and populate the CNS before the blood-brain barrier forms. In the CNS, they constitute a self-renewing population. Although they represent up to 10% of all brain cells, we are only beginning to understand how much brain homeostasis relies on their physiological functions. Often compared to a double-edged sword, microglia hold the potential to exert neuroprotective roles that can also exacerbate neurodegeneration once compromised. Microglia can promote synaptic growth in addition to eliminating synapses that are less active. Synaptic loss, which is considered one of the best pathological correlates of cognitive decline, is a distinctive feature of major depressive disorder (MDD) and cognitive aging. Long-term psychological stress accelerates cellular aging and predisposes to various diseases, including MDD, and cognitive decline. Among the underlying mechanisms, stress-induced neuroinflammation alters microglial interactions with the surrounding parenchymal cells and exacerbates oxidative burden and cellular damage, hence inducing changes in microglia and neurons typical of cognitive aging. Focusing on microglial interactions with neurons and their synapses, this review discusses the disrupted communication between these cells, notably involving fractalkine signaling and the triggering receptor expressed on myeloid cells (TREM). Overall, chronic stress emerges as a key player in cellular aging by altering the microglial sensome, notably via fractalkine signaling deficiency. To study cellular aging, novel positron emission tomography radiotracers for TREM and the purinergic family of receptors show interest for human study.
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    Microglial functional alteration and increased diversity in the challenged brain: Insights into novel targets for intervention
    (Brain, Behavior, & Immunity - Health, 2021) Tremblay, Marie-Ève
    Microglia are the resident immune cells of the central nervous system (CNS) parenchyma, which perform beneficial physiological roles across life. These immune cells actively maintain CNS health by clearing toxic debris and removing dysfunctional or degenerating cells. They also modify the wiring of neuronal circuits, by acting on the formation, modification, and elimination of synapses-the connections between neurons. Microglia furthermore recently emerged as highly diverse cells comprising several structural and functional states, indicating a far more critical involvement in orchestrating brain development, plasticity, behaviour, and cognition. Various environmental factors, together with the individual genetic predispositions, confer an increased risk for neurodevelopmental and neuropsychiatric disorders, as well as neurodegenerative diseases that include autism spectrum disorders, schizophrenia, major depressive disorder, and Alzheimer's disease, across life. Microglia are highly sensitive to chronic psychological stress, inadequate diet, viral/bacterial infection, pollution, and insufficient or altered sleep, especially during critical developmental periods, but also throughout life. These environmental challenges can compromise microglial physiological functions, resulting notably in defective neuronal circuit wiring, altered brain functional connectivity, and the onset of behavioral deficits into adolescence, adulthood, and aging. This short review provides a historical and technical perspective, notably focused on my contribution to the field, on how environmental challenges affect microglia, particularly their physiological functions, and increase their diversity, which provides novel targets for intervention.
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    Maternal high-fat diet modifies myelin organization, microglial interactions, and results in social memory and sensorimotor gating deficits in adolescent mouse offspring
    (Brain, Behavior, & Immunity - Health, 2021) Bordeleau, Maude; Fernández de Cossío, Lourdes; Lacabanne, Chloé; Savage, Julie C.; Vernoux, Nathalie; Chakravarty, Mallar; Tremblay, Marie-Ève
    Prenatal exposure to maternal high-fat diet (mHFD) acts as a risk factor for various neurodevelopmental alterations in the progeny. Recent studies in mice revealed that mHFD results in both neuroinflammation and hypomyelination in the exposed offspring. Microglia, the brain-resident macrophages, play crucial roles during brain development, notably by modulating oligodendrocyte populations and performing phagocytosis of myelin sheaths. Previously, we reported that mHFD modifies microglial phenotype (i.e., morphology, interactions with their microenvironment, transcripts) in the hippocampus of male and female offspring. In the current study, we further explored whether mHFD may induce myelination changes among the hippocampal-corpus callosum-prefrontal cortex pathway, and result in behavioral outcomes in adolescent offspring of the two sexes. To this end, female mice were fed with control chow or HFD for 4 weeks before mating, during gestation, and until weaning of their litter. Histological and ultrastructural analyses revealed an increased density of myelin associated with a reduced area of cytosolic myelin channels in the corpus callosum of mHFD-exposed male compared to female offspring. Transcripts of myelination-associated genes including -a growth factor released by microglia- were also lower, specifically in the hippocampus (without changes in the prefrontal cortex) of adolescent male mouse offspring. These changes in myelin were not related to an altered density, distribution, or maturation of oligodendrocytes, instead we found that microglia within the corpus callosum of mHFD-exposed offspring showed reduced numbers of mature lysosomes and increased synaptic contacts, suggesting microglial implication in the modified myelination. At the behavioral level, both male and female mHFD-exposed adolescent offspring presented loss of social memory and sensorimotor gating deficits. These results together highlight the importance of studying oligodendrocyte-microglia crosstalk and its involvement in the long-term brain alterations that result from prenatal mHFD in offspring across sexes.
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    Microglial implications in SARS-CoV-2 Infection and COVID-19: Lessons from viral RNA neurotropism and possible relevance to Parkinson's disease
    (Frontiers in Cellular Neuroscience, 2021) Awogbindin, Ifeoluwa O.; Ben-Azu, Benneth; Olusola, Babatunde A.; Akinluyi, Elizabeth T.; Adeniyi, Philip A.; Di Paolo, Therese; Tremblay, Marie-Eve
    Since December 2019, humankind has been experiencing a ravaging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak, the second coronavirus pandemic in a decade after the Middle East respiratory syndrome coronavirus (MERS-CoV) disease in 2012. Infection with SARS-CoV-2 results in Coronavirus disease 2019 (COVID-19), which is responsible for over 3.1 million deaths worldwide. With the emergence of a second and a third wave of infection across the globe, and the rising record of multiple reinfections and relapses, SARS-CoV-2 infection shows no sign of abating. In addition, it is now evident that SARS-CoV-2 infection presents with neurological symptoms that include early hyposmia, ischemic stroke, meningitis, delirium and falls, even after viral clearance. This may suggest chronic or permanent changes to the neurons, glial cells, and/or brain vasculature in response to SARS-CoV-2 infection or COVID-19. Within the central nervous system (CNS), microglia act as the central housekeepers against altered homeostatic states, including during viral neurotropic infections. In this review, we highlight microglial responses to viral neuroinfections, especially those with a similar genetic composition and route of entry as SARS-CoV-2. As the primary sensor of viral infection in the CNS, we describe the pathogenic and neuroinvasive mechanisms of RNA viruses and SARS-CoV-2 vis-à-vis the microglial means of viral recognition. Responses of microglia which may culminate in viral clearance or immunopathology are also covered. Lastly, we further discuss the implication of SARS-CoV-2 CNS invasion on microglial plasticity and associated long-term neurodegeneration. As such, this review provides insight into some of the mechanisms by which microglia could contribute to the pathophysiology of post-COVID-19 neurological sequelae and disorders, including Parkinson's disease, which could be pervasive in the coming years given the growing numbers of infected and re-infected individuals globally.
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    Novel microglia-mediated mechanisms underlying synaptic loss and cognitive impairment after traumatic brain injury
    (Brain Behavior and Immunity, 2021) Krukowski, Karen; Nolan, Amber; Becker, McKenna; Picard, Katherine; Vernoux, Nathalie; Frias, Elma S.; Feng, Xi; Rosi, Susanna; Tremblay, Marie-Eve
    Traumatic brain injury (TBI) is one of the leading causes of long-term neurological disability in the world. Currently, there are no therapeutics for treating the deleterious consequences of brain trauma; this is in part due to a lack of complete understanding of cellular processes that underlie TBI-related pathologies. Following TBI, microglia, the brain resident immune cells, turn into a "reactive" state characterized by the production of inflammatory mediators that contribute to the development of cognitive deficits. Utilizing multimodal, state-of-the-art techniques that widely span from ultrastructural analysis to optogenetic interrogation of circuit function, we investigated the reactive microglia phenotype one week after injury when learning and memory deficits are also measured. Microglia displayed increased: (i) phagocytic activity in vivo, (ii) synaptic engulfment, (iii) increased neuronal contact, including with dendrites and somata (termed 'satellite microglia'). Functionally, satellite microglia might impact somatic inhibition as demonstrated by the associated reduction in inhibitory synaptic drive. Cumulatively, here we demonstrate novel microglia-mediated mechanisms that may contribute to synaptic loss and cognitive impairment after traumatic brain injury.
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    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, Laura
    Parkinson'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.
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    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-Ève
    In 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.
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    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.
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    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-Ève
    A 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.
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    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.
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    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-Ève
    In 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.
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    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, Abid
    Neurodegenerative 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.
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    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.
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