A tool for mapping microglial morphology, morphOMICs, reveals brain-region and sex-dependent phenotypes
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Abstract
Environmental cues influence the highly dynamic morphology of microglia. Strategies to characterize these changes usually involve user-selected morphometric features, which preclude the identification of a spectrum of context-dependent morphological phenotypes. Here we develop MorphOMICs, a topological data analysis approach, which enables semiautomatic mapping of microglial morphology into an atlas of cue-dependent phenotypes and overcomes feature-selection biases and biological variability. We extract spatially heterogeneous and sexually dimorphic morphological phenotypes for seven adult mouse brain regions. This sex-specific phenotype declines with maturation but increases over the disease trajectories in two neurodegeneration mouse models, with females showing a faster morphological shift in affected brain regions. Remarkably, microglia morphologies reflect an adaptation upon repeated exposure to ketamine anesthesia and do not recover to control morphologies. Finally, we demonstrate that both long primary processes and short terminal processes provide distinct insights to morphological phenotypes. MorphOMICs opens a new perspective to characterize microglial morphology.
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Cells portraying smaller cellular somas in addition to extensive and well-branched processes are usually linked to a surveillant state of microglia, whereas the shrinkage of processes and bigger somas are usually linked to reactive states.
“Cells portraying smaller cellular somas in addition to extensive and well-branched processes are usually linked to a surveillant state of microglia, whereas the shrinkage of processes and bigger somas are usually linked to reactive states [83–86].”
From Sex chromosomes and sex hormones differently shape microglial properties during normal physiological conditions in the adult mouse hippocampus (2025) · cites this paper as [84]
The Discussion (page unavailable) links ramified microglia with surveillance, and the Results section on 5xFAD (page unavailable) reports loss of high-level branches in disease-associated microglia. The paper does not establish the claimed smaller-versus-bigger soma sizes or a general rule that reactive microglia have shrunken processes. (LLM, conf=0.85)
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Self-citationContralateral Astrocyte Response to Acute Optic Nerve Damage Is Mitigated by PANX1 Channel Activity
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Self-citationTemporal topology provides an interpretable framework for neuronal morphogenesisPreprint
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- Authors
- Colombo, G., Cubero, R. J. A., Kanari, L., Venturino, A., Schulz, R., Scolamiero, M., Agerberg, J., Mathys, H., Tsai, L.-H., Chachólski, W., Hess, K., & Siegert, S.
- Affiliations
- Institute of Science and Technology Austria (AT)
- École Polytechnique Fédérale de Lausanne (CH)
- KTH Royal Institute of Technology (SE)
- Broad Institute (US)
- Corresponding author
- Siegert, Sandra
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2022-09-30
- Volume
- 25
- Issue
- 10
- Pages
- 1379-1393
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC9534764
- OpenAlex
- W4298137907
- Cited by
- 100
- References
- 125
- Citations by year
- 2026: 25 · 2025: 23 · 2024: 31 · 2023: 15 · 2022: 5 · 2021: 1
- FWCI
- 7.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Nature Neuroscience (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion, cc-by-nc-nd)
- SDL (submittedVersion)
- Funders
- JPB Foundation
- Institute of Science and Technology Austria (715571, 754411)
- European Commission (HORIZON2020, 754411)
- École Polytechnique Fédérale de Lausanne
- Bundesministerium für Wissenschaft, Forschung und Wirtschaft
- Board of the Swiss Federal Institutes of Technology
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke (R37NS051874)
- H2020 Marie Skłodowska-Curie Actions (754411, HORIZON2020, 715571)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biophysics › Cell Image Analysis Techniques
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- microglial morphology, morphomics, topological data analysis, sex differences, regional brain differences, microglial phenotype, neurodegeneration, ketamine anesthesia, microglial maturation, mouse brain
- MeSH terms
- Animals, Brain, Disease Models, Animal, Female, Ketamine, Male, Phenotype, Microglia, Mice
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