A MAC2-positive progenitor-like microglial population is resistant to CSF1R inhibition in adult mouse brain
Abstract
Microglia are the resident myeloid cells in the central nervous system (CNS). The majority of microglia rely on CSF1R signaling for survival. However, a small subset of microglia in mouse brains can survive without CSF1R signaling and reestablish the microglial homeostatic population after CSF1R signaling returns. Using single-cell transcriptomic analysis, we characterized the heterogeneous microglial populations under CSF1R inhibition, including microglia with reduced homeostatic markers and elevated markers of inflammatory chemokines and proliferation. Importantly, MAC2/Lgals3 was upregulated under CSF1R inhibition, and shared striking similarities with microglial progenitors in the yolk sac and immature microglia in early embryos. Lineage-tracing studies revealed that these MAC2+ cells were of microglial origin. MAC2+ microglia were also present in non-treated adult mouse brains and exhibited immature transcriptomic signatures indistinguishable from those that survived CSF1R inhibition, supporting the notion that MAC2+ progenitor-like cells are present among adult microglia.
Data availability
The raw count matrix of the scRNA-seq data can be accessed on GEO with accession number (GSE150169). A list of R codes used for the analyses are available on Github (https://github.com/lifan36/Zhan-Fan-et-al-2019-scRNAseq).
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scRNA-seqNCBI Gene Expression Omnibus, GSE150169.
Article and author information
Author details
Funding
National Institutes of Health (1R01AG054214-01A1)
- Li Gan
National Institutes of Health (U54NS100717)
- Li Gan
National Institutes of Health (R01AG051390)
- Li Gan
Tau Consortium grant
- Li Gan
National Institute of Aging (F30 AG062043-02)
- Lay Kodama
National Institutes of Health (T32GM007618)
- Lay Kodama
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#AN173162-02) of the University of California, San Francisco.
Copyright
© 2020, Zhan et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Further reading
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- Neuroscience
When navigating environments with changing rules, human brain circuits flexibly adapt how and where we retain information to help us achieve our immediate goals.
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- Neuroscience
When holding visual information temporarily in working memory (WM), the neural representation of the memorandum is distributed across various cortical regions, including visual and frontal cortices. However, the role of stimulus representation in visual and frontal cortices during WM has been controversial. Here, we tested the hypothesis that stimulus representation persists in the frontal cortex to facilitate flexible control demands in WM. During functional MRI, participants flexibly switched between simple WM maintenance of visual stimulus or more complex rule-based categorization of maintained stimulus on a trial-by-trial basis. Our results demonstrated enhanced stimulus representation in the frontal cortex that tracked demands for active WM control and enhanced stimulus representation in the visual cortex that tracked demands for precise WM maintenance. This differential frontal stimulus representation traded off with the newly-generated category representation with varying control demands. Simulation using multi-module recurrent neural networks replicated human neural patterns when stimulus information was preserved for network readout. Altogether, these findings help reconcile the long-standing debate in WM research, and provide empirical and computational evidence that flexible stimulus representation in the frontal cortex during WM serves as a potential neural coding scheme to accommodate the ever-changing environment.