Microglial functional alteration and increased diversity in the challenged brain: Insights into novel targets for intervention
Open accessAbstract
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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Microglia are essential for brain development and play a crucial role in preserving CNS health and maintaining homeostatic balance when challenged by infectious or inflammatory cues.
“These cells are essential for brain development and play a crucial role in preserving the health of the CNS, maintaining its homeostatic balance when challenged by infectious or inflammatory cues [21, 22].”
From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [21]
The Introduction (page unavailable) describes microglia as crucial during development, and the Abstract says they actively maintain CNS health. But the Abstract and “Microglial response to environmental risk factors” (pages unavailable) say infection can compromise microglial functions; they do not establish that microglia maintain homeostatic balance when challenged by infectious or inflammatory cues. (LLM, conf=0.86)
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Minocycline as Adjunctive Therapy for Schizophrenia: An Open-Label Study
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Fractalkine Signaling and Microglia Functions in the Developing Brain
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Opposing Effects of Membrane-Anchored CX3CL1 on Amyloid and Tau Pathologies via the p38 MAPK Pathway
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Environment matters: microglia function and dysfunction in a changing world
Hanamsagar, R., & Bilbo, S. D. (2017) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2017.10.007 · Cited by 122 · see citing works
Do Microglial Sex Differences Contribute to Sex Differences in Neurodegenerative Diseases?
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New tricks for an ancient system: Physiological and pathological roles of complement in the CNS
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The role of microglia at synapses in the healthy CNS: novel insights from recent imaging studies
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Self-citationStructural plasticity: mechanisms and contribution to developmental psychiatric disorders
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From Maternal Diet to Neurodevelopmental Disorders: A Story of Neuroinflammation
Bordeleau, M., de Cossío, L. F., Chakravarty, M. M., & Tremblay, M. (2021) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2020.612705 · Cited by 108 · see citing works
Self-citationVascular contributions to 16p11.2 deletion autism syndrome modeled in mice
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Self-citationAlterations of Myelin Content in Parkinson’s Disease: A Cross-Sectional Neuroimaging Study
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Savage, J. C., St‐Pierre, M., Carrier, M., Hajj, H. E., Novak, S. W., Sánchez, M. G., Cicchetti, F., & Tremblay, M. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01782-9 · Cited by 99 · see citing works
Self-citationFrom the Cajal alumni Achúcarro and Río-Hortega to the rediscovery of never-resting microglia
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Self-citationScheff, S. W., Sparks, D. L., & PRICE, D. A. (1996) · Dementia and Geriatric Cognitive Disorders · doi:10.1159/000106884 · Cited by 95 · see citing works
The Role of Microglia in Sporadic Alzheimer’s Disease
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Microglia and sexual differentiation of the developing brain: A focus on extrinsic factors
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Microglia and Synapse: Interactions in Health and Neurodegeneration
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Self-citationBurns, J. C., Cotleur, B., Walther, D. M., Bajrami, B., Rubino, S. J., Wei, R., Franchimont, N., Cotman, S. L., Ransohoff, R. M., & Mingueneau, M. (2020) · eLife · doi:10.7554/elife.57495 · Cited by 79 · see citing works
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Picard, K., St‐Pierre, M., Vecchiarelli, H. A., Bordeleau, M., & Tremblay, M. (2021) · Neurochemistry International · doi:10.1016/j.neuint.2021.104987 · Cited by 77 · see citing works
Self-citationBordeleau, M., Carrier, M., Luheshi, G. N., & Tremblay, M.-È. (2019) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2019.06.001 · Cited by 75 · see citing works
Self-citationMinocycline attenuates subjective rewarding effects of dextroamphetamine in humans
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Joost, E., Jordão, M. J. C., Mages, B., Prinz, M., Bechmann, I., & Krueger, M. (2019) · Brain Structure and Function · doi:10.1007/s00429-019-01834-8 · Cited by 65 · see citing works
Acharjee, S., Verbeek, M., Gómez, C., Bisht, K., Lee, B., Benoit, L., Sharkey, K. A., Benediktsson, A. M., Tremblay, M., & Pittman, Q. J. (2018) · Journal of Neuroscience · doi:10.1523/jneurosci.0398-18.2018 · Cited by 63 · see citing works
Self-citationRole of Glia in the Regulation of Sleep in Health and Disease
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Self-citationShedding Light on the Dark Side of the Microglia
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Self-citationSingle Cell RNA-Seq Analysis Reveals Compartment-Specific Heterogeneity and Plasticity of Microglia
Zheng, J., Ru, W., Adolacion, J. R. T., Spurgat, M. S., Liu, X., Yuan, S., Liang, R. X., Dong, J., Potter, A. S., Potter, S. S., et al. (2020) · iScience · doi:10.1016/j.isci.2021.102186 · Cited by 63 · see citing works
Moreau, C. A., Urchs, S. G. W., Kumar, K., Orban, P., Schramm, C., Dumas, G., Labbe, A., Huguet, G., Douard, E. A., Quirion, P.-O., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-18997-2 · Cited by 60 · see citing works
Medin aggregation causes cerebrovascular dysfunction in aging wild-type mice
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Dark microglia: Why are they dark?
Bisht, K., Sharma, K. P., Lacoste, B., & Tremblay, M. (2016) · Communicative & Integrative Biology · doi:10.1080/19420889.2016.1230575 · Cited by 39 · see citing works
Self-citationMicroglia in Health and Disease
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Self-citationMicroglial heterogeneity in aging and Alzheimer's disease: Is sex relevant?
Delage, C. I., Šimončičová, E., & Tremblay, M. (2021) · Journal of Pharmacological Sciences · doi:10.1016/j.jphs.2021.03.006 · Cited by 35 · see citing works
Self-citationMicroglia: Senescence Impairs Clearance of Myelin Debris
Thériault, P., & Rivest, S. (2016) · Current Biology · doi:10.1016/j.cub.2016.06.066 · Cited by 34 · see citing works
Hui, C. W., Bhardwaj, S. K., Sharma, K. P., Joseph, A. T., Bisht, K., Picard, K., Tremblay, M., & Srivastava, L. K. (2018) · Neuropharmacology · doi:10.1016/j.neuropharm.2018.12.007 · Cited by 23 · see citing works
Self-citationOta, M., Sato, N., Kimura, Y., Shigemoto, Y., Kunugi, H., & Matsuda, H. (2019) · Dementia and Geriatric Cognitive Disorders Extra · doi:10.1159/000493937 · Cited by 21 · see citing works
Microglia control cerebral blood flow and neurovascular coupling via P2Y12R-mediated actions
Császár, E., Lénárt, N., Cserép, C., Környei, Z., Fekete, R., Pósfai, B., Balázsfi, D., Hangya, B., Schwarcz, A. D., Szöllősi, D., et al. (2021) · doi:10.1101/2021.02.04.429741 · Cited by 6
Moreau, C., Urchs, S., Kuldeep, K., Orban, P., Schramm, C., Dumas, G., Labbe, A., Huguet, G., Douard, E., Quirion, P.-O., et al. (2019) · doi:10.1101/862615 · Cited by 4
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Stress induced microglial activation contributes to depression
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Present and future of microglial pharmacology
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Self-citationPicker, L. D., Morrens, M., Branchi, I., Haarman, B. C. M., Terada, T., Kang, M. S., Boche, D., Tremblay, M., Leroy, C., Bottlaender, M., et al. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.07.023 · Cited by 78 · see citing works
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- Authors
- Tremblay, M.-È.
- Affiliations
- University of British Columbia (CA)
- Corresponding author
- Tremblay, Marie-Ève
- ORCID
- Tremblay, Marie-Ève
- Venue
- Brain, Behavior, & Immunity - Health
- Publisher
- Elsevier BV
- Published
- 2021-10
- Volume
- 16
- Pages
- 100301
- ISSN
- 2666-3546 (ISSN-L)
- PMC
- PMC8474548
- OpenAlex
- W3186653410
- Cited by
- 42
- References
- 123
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 14 · 2023: 7 · 2022: 9 · 2021: 1
- FWCI
- 3.10
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Brain Behavior & Immunity - Health (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, other-oa)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UVic’s Research and Learning Repository (University of Victoria) (submittedVersion)
- Funders
- University of Victoria
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
- Keywords
- microglia, microglial heterogeneity, environmental problems, neurodevelopmental disorders, neuropsychiatric disorders, neurodegenerative diseases, chronic psychological stress, diet, viral and bacterial infections, pollution, sleep, brain functional connectivity, autism spectrum disorder, schizophrenia, major depressive disorder, Alzheimer's disease, therapeutic target
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