This past decade has witnessed a revolution in our understanding of microglia, the resident immune cells of the brain. Specifically, these cells were shown to originate from the embryonic yolk sac (rather than being derived from circulating precursors) and to mediate crucial physiological functions across brain development, maintenance, and plasticity. In her postdoctoral work, Marie-Ève Tremblay demonstrated that 94% of all microglial processes directly contact synaptic elements during normal physiological conditions. Microglia-synapse interactions are regulated by sensory and behavioral experiences, and eliminate a subset of pre-synaptic axon terminals and post-synaptic dendritic spines, as well as entire synapses, by means of phagocytosis. Very recently altered microglial phagocytosis of synaptic elements was strongly linked to the risk of developing schizophrenia in humans. Despite these advances, the underlying molecular mechanisms remain largely undetermined.
A series of discoveries spanning the last decade has challenged our view of microglia, the brain's immune cells, showing their essential but previously unexpected contribution to the remodeling of neuronal circuits. In this emergent field of investigation, research in the laboratory of Marie-Ève Tremblay aims to determine how this newly-defined fundamental mechanism could be implicated in the loss of neuronal connections that best correlates with the impairment of learning and memory across chronic stress, depression, schizophrenia, aging, and Alzheimer's disease.
The goal of our research is to design novel therapeutic strategies that specifically target microglia in order to promote stress resilience, healthy aging, and improve cognitive functions in individuals suffering from neurodegenerative diseases.
Marie-Ève Tremblay, Ph.D.
Nathalie Vernoux, Ph.D.
Julie Savage, Ph.D.
Hassan El Hajj
Considering that synaptic loss is the best pathological correlate of cognitive decline across the significance of this newly defined cellular mechanism –microglial phagocytosis of synaptic elements– in the pathogenesis of brain disorders. The Neuroimmune Plasticity lab investigates the role of microglia as vectors for effecting targeted changes in neuronal circuits in order to spare memory, learning and other cognitive functions that can be compromised during chronic stress, aging, and neurodegenerative disease. Since chronic stress accelerates cellular aging, potentiates oxidative stress, neuroinflammation, and predisposes to various diseases across the lifespan, therapeutic interventions promoting resilience –of the brain immune cells– to stress could be crucial for healthy aging (in vulnerable individuals).
Microglia are extremely sensitive to environmental challenges, including chronic stress, which is associated with a substantial remodeling of neuronal circuits and elimination of synapses. Our recent work revealed that neuron-microglia communication underlies adaptation of the brain and behavior to chronic stress, and that neuronal signaling between the chemokine fractalkine (CX3CL1) and its unique receptor CX3CR1, mainly expressed by microglia, plays a crucial role in this process. Fractalkine receptor deficiency (in CX3CR1 knockout mice) prevents the effects of chronic unpredictable stress on the phagocytosis of synaptic elements by microglia, short- and long-term neuronal plasticity, as well as depressive-like behavior. In CX3CR1 knockout mice, microglial phagocytosis of terminals and spines is basally elevated, targeting synaptic elements in a non-specific manner, and is not modulated by chronic stress. These findings indicate that microglia-regulated mechanisms could underlie the differential susceptibility to chronic stress and consequently the vulnerability to disorders, including major depression, triggered by stressful events.
In parallel, we also uncovered the existence of an ultrastructurally distinct microglial phenotype that is predominantly associated with pathological states. These cells are rare in steady state conditions, but become prevalent upon chronic stress, aging, or Alzheimer’s disease (AD) pathology, and account for almost 50% of the microglial population in CX3CR1 knockout mice. They exhibit several signs of oxidative stress including a condensed, electron-dense cytoplasm and nucleoplasm giving them a ‘dark’ appearance similar to mitochondria, accompanied by endoplasmic reticulum dilation (the best characterized sign of oxidative stress at the ultrastructural level), mitochondrial disruption, and heterochromatin remodeling associated with epigenetic alteration. The physiological significance of these dark microglia has yet to be elucidated but they appear extremely active, frequently reaching for synaptic clefts, while extensively encircling terminals, spines, and entire synapses with their highly ramified and thin processes. They strongly express CD11b, which forms complement receptor 3 involved in synaptic pruning, specifically in their processes encircling synaptic elements, and myeloid-cell specific TREM2 when associated with amyloid-β plaques. In AD pathology, TREM2 positive cells were recently shown to express the phagocytic effectors MERTK and AXL. These findings indicate that dark microglia could represent a subset of cells that become stressed as a result of their hyperactivity under adaptive pressure, leading to abnormal (or perhaps specialized) interactions with synapses.
We are now testing the hypothesis that stressed microglia are specifically implicated in the loss of synapses that impairs learning, memory, and other cognitive functions along the aging trajectory. These experiments are conducted during chronic stress and aging, the greatest risk factors for AD, in preclinical mouse models that we have developed. We use an integrative approach that combines non-invasive imaging (two-photon, super-resolution, and 3D-scanning electron microscopy) with whole-transcriptomics and behavioral assessments. We also validate our findings in human brain samples from healthy individuals, young vs aged, and AD patients.
Leadership & Outreach
The discovery that microglia actively remodel neuronal circuits during normal physiological conditions led to the development of a new field of research investigating their roles in the healthy brain. The mini-symposium “The role of microglia in the healthy brain” that Marie-Ève Tremblay organized and chaired at the 2011 Society for Neuroscience meeting contributed to the launch of this new field and was enthusiastically received by the scientific community with over 800 people attending. It was accompanied by a review article [J Neurosci (IF=5.9)] cited 519 times (Google Scholars; as of June 2018). Since then, the field has experienced an explosive growth.
A PubMed search using the term “microglia” results in only a few papers published on the topic before 1990, and then a steady increase until the end of the 20th century. There is a first inflexion point in 2005, following publication of the seminal studies by Nimmerjahn and Davalos regarding the extraordinary motility of microglia in the healthy brain. A second inflexion point is also evident around 2010, coincident with the influential paper by Ginhoux on the unique origin of microglia from the embryonic yolk sac, and also with Marie-Ève Tremblay’s findings about the roles of microglia-synapse interactions in the healthy brain. Since its publication in November 2010, the work describing her original discovery that 94% of all microglial processes direct contact synaptic elements in the healthy brain [PloS Biol (IF=9.8)] was cited 638 times and viewed 21,962 times. It was recommended by Faculty of 1000, publicized in Nature two times, in SFARI and AlzForum, etc., and explained to the general public in New Scientist and Médecine/Sciences. Her follow-up work published as a co-first author in GLIA (IF=6.2) in 2012 was also influential to the field having received 124 citations.
Since her integration to Université Laval in March 2013, Marie-Ève Tremblay co-edited (with Dr. Amanda Sierra, Spain) the book “Microglia in Health and Disease” published by Springer in November 2014. She organized a symposium on the roles of microglia-neuron interactions for the 2015 European meeting on Glial Cells and chaired at the first North American meeting on microglia (Keystone Symposium “Microglia in the Brain” organized by Beth Stevens and Richard Ransohoff) a session on “microglial surveillance: lessons from in vivo imaging”. She also organized a session entitled “Microglia actively maintain health” for the 2017 Spring Brain Conference, the symposium “Glial phagocytic clearance in health and disease” for the 2019 International Society for Neurochemistry and American Society for Neurochemistry meeting (with Dr. Laura Civiero, Italy), and the workshop “Studying microglial heterogeneity and its implication in brain disorders using complementary cutting-edge technologies” for the 2018 European meeting on Glial Cells. Additionally, she is acting as a Scientific Faculty of the Canadian Association for Neuroscience meetings, which allows her to direct the research agenda.
In parallel, she has built her research team, the Laboratory of Neuroimmune Plasticity, by recruiting 4 postdocs, 12 graduate students, 20 undergraduate students, a research assistant and 2 part-time laboratory technicians, as well as secured 14 research grants, 9 as principal investigator (CIHR Foundation Scheme, NARSAD, NSERC, ERANET-NEURON Neuroinflammation, ERANET-NEURON Synaptic Dysfunction, FRQS, FRQNT, Banting Foundation, Scottish Rite Charitable Foundation) and 4 as co-investigator (CIHR Operating Grants, FRQNT, Heart and Stroke Foundation of Canada), in addition to a CFI John R. Evans Leaders grant to acquire a state-of-the-art customized two-photon system for in vivo microscopy. She holds 63 publications: 39 research articles, 15 review articles, 4 addenda, 2 invited editorials, and 3 book chapters. Her publications were cited a total of 2,797 times, corresponding to an h-index of 26 (Google Scholars).
Marie-Ève Tremblay was invited to present her work 79 times around the world, with 70 lectures given so far, in Canada, Finland, France, Germany, Italy, Japan, Spain, United Kingdom, and United States, as seminars (notably at King’s College London, Case Western, Harvard University, and the University of Tübingen), and lectures in symposia, conferences, specialized courses (International Astrocyte School and IBRO-Network of European Neuroscience Schools Training Course), and meetings (including the prestigious Gordon Research Conference, Keystone Symposia, and FASEB Research Conference). Her research is internationally recognized, as supported by her contribution to collaborative studies in the fields of neuroscience, immunology, microbiology, and nutrition.
Lab Historic & Alumni
Samuel Boisjoly-Villeneuve, B.Sc. Student in Biomedical Sciences, Université Laval (2013-15) Co-supervised by Dr. Richard Kinkead
Samuel Comeau, B.Sc. Student in Biology, Université Laval (2013-14)
Maria Gabriela Sanchez, Postdoctoral Researcher (2014)
Cynthia Lecours, B.Sc. Student in Biomedical Sciences, Université Laval (2014-16)
Louis Samson, M.D. Student, Université Laval (2014-15)
Vanessa Théberge, B.Sc. Student in Biomedical Sciences, Université Laval (2014)
Valerio Messina, M.D. Exchange Student from Italy, International Federation of Medical Students’ Association (2015)
Danaja Plevel, M.D. Exchange Student from Slovenia, International Federation of Medical Students’ Association (2015)
Isabelle Girard, B.Sc. Student in Biomedical Sciences, Université Laval (2015)
Oihane Abiega, Ph.D. Exchange Student, University of Basque Country, Bilbao, Spain (2015) Co-supervised by Dr. Amanda Sierra
Steven Gagnon, M.D. Student, Université Laval (2015-2016)
Yvan Rémy, B.Sc. Exchange Student, Université Paul Sabatier, Toulouse, France (2016)
Clémentine Beucher, B.Sc. Student in Biomedical Sciences, Université Laval (2016)
Abygaël St-Pierre, B.Sc. Student in Biomedical Sciences, Université Laval (2016)
Katherine Picard, B.Sc. Student in Biomedical Sciences, Université Laval (2016-17)
Marie-Kim St-Pierre, B.Sc. Student in Biomedical Sciences, Université Laval (2016-17)
Micaël Carrier, B.Sc. Student in Biomedical Sciences, Université Laval (2016-17)
Audrey Gagné, B.Sc. Student in Biomedical Sciences, Université Laval (2017)
Jérôme Detuncq, B.Sc. Student in Biochemistry, Université Laval (2017)
Lisa Sheefhals, M.Sc. Exchange Student, Master Neuroscience & Cognition, Utrecht University, Utrecht, the Netherlands (2017) Co-supervised by Elly Hol
Fanny Decoeur, M.Sc. Exchange Student, Neurosciences Master 1, Université de Bordeaux, France (2017) Co-supervised by Dr. Agnès Nadjar
2018 – Prix Diamant recherche – relève category from the CHU de Québec-Université Laval to Marie-Ève Tremblay
2018 – GREAT travel award to Maude Bordeleau, Integrated Program in Neuroscience (McGill University)
2018 – Undergraduate student research award to Julien Blouin, Natural Sciences and Engineering Research Council of Canada (NSERC)
2018 – Travel Award from the Stress Neurobiology Workshop 2018 Meeting to Micaël Carrier
2018 – Master training award to Marie-Kim St-Pierre, Fonds de recherche du Québec – Santé (FRQS)
2018 – Master training award to Marie-Kim St-Pierre, Fonds de recherche du Québec – Nature et technologies (FRQNT)
2018 – Master training award to Micaël Carrier, FRQS
2018 – Master training award to Micaël Carrier, FRQNT
2018 – Master training award to Marie-Kim St-Pierre, Canadian Institutes of Health Research (CIHR)
2018 – Tenacity scholarship awarded at the end of PhD to Kanchan Bisht, Faculty of Medicine, Université Laval
2018 – Travel Award from the Canadian Association for Neuroscience Annual Meeting to Micaël Carrier
2017 – Admission excellence scholarship to Micaël Carrier, Faculty of Medicine, Université Laval
2017 – Excellence scholarship from the 5th research day on molecular medicine to Marie-Kim St-Pierre
2017 – Excellence scholarship from the Fondation du CHU de Québec to Katherine Picard
2017 – Excellence scholarship from the Fondation du CHU de Québec to Marie-Kim St-Pierre
2017 – Admission excellence scholarship to Marie-Kim St-Pierre, Faculty of Medicine, Université Laval
2017 – Doctoral training award to Maude Bordeleau, FRQS
2017 – Postdoctoral training award to Julie Savage, FRQS
2017 – Postdoctoral training award to Chin Wai (Thomas) Hui, FRQS
2017 – Excellence scholarship to Audrey Gagné, Fédération des caisses Desjardins du Québec
2017 – First-author publication award to Kanchan Bisht, Faculty of Medicine, Université Laval
2017 – Travel award from the Association des chercheuses et chercheurs étudiant à la Faculté de Médecine (ACCEM) of Université Laval to Kanchan Bisht
2017 – Undergraduate student research award to Jérôme Detuncq, NSERC
2017 – Undergraduate student research award to Marie-Kim St-Pierre, NSERC, with supplement from FRQNT
2016 – Claude-Fortier award to Micaël Carrier for academic excellence and his implication with the Biomedical Sciences program
2016 – Best poster award to Mathilde Henry, Journée Phare, Bromont, Québec
2016 – Travel award Marie Giguère to Maude Bordeleau
2016 – Travel award from the ACCEM of Université Laval to Mathilde Henry
2016 – Excellence scholarship (Bourse Didier-Mouginot) from the Fondation du CHU de Québec to Cynthia Lecours
2016 – Excellence scholarship from the Fondation du CHU de Québec to Kanchan Bisht
2016 – Excellence scholarship from the Molecular Medicine Department to Cynthia Lecours
2016 – Excellence scholarship from the Molecular Medicine Department to Kanchan Bisht
2016 – Master training award to Cynthia Lecours, FRQS
2016 – Undergraduate student research award to Cynthia Lecours, NSERC
2015 – Best poster award to Julie Savage, Neuroscience Day of Université Laval
2015 – Travel award to Hassan El Hajj to attend the Americas School of Neuroimmunology in Calgary
2015 – Scholarship from the Lebanese Ministry of Education and Higher Education to Hassan El Hajj
2015 – Scholarship from the Indo-Canadian Shastri Foundation to Kanchan Bisht
2015 – Travel Award from the National Institute of Neurological Disorders and Stroke to Kanchan Bisht
2015 – Undergraduate student research award to Isabelle Girard, NSERC
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