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In vivo imaging of the kinetics of microglial self-renewal and maturation in the adult visual cortex

View ORCID ProfileMendes Mendes S, Jason Atlas, Zachary Brehm, Antonio Ladron-de-Guevara, Matthew N. McCall, View ORCID ProfileAnia K. Majewska
doi: https://doi.org/10.1101/2020.03.05.977553
Mendes Mendes S
1Department of Neuroscience, University of Rochester Medical Center, Rochester NY, United States
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Jason Atlas
1Department of Neuroscience, University of Rochester Medical Center, Rochester NY, United States
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Zachary Brehm
2Department of Biostatistics, University of Rochester Medical Center, Rochester NY, United States
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Antonio Ladron-de-Guevara
1Department of Neuroscience, University of Rochester Medical Center, Rochester NY, United States
3Department of Biomedical Engineering, University of Rochester, Rochester NY, United States
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Matthew N. McCall
2Department of Biostatistics, University of Rochester Medical Center, Rochester NY, United States
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Ania K. Majewska
1Department of Neuroscience, University of Rochester Medical Center, Rochester NY, United States
4Center for Visual Science, University of Rochester, Rochester NY, United States
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  • For correspondence: ania_majewska@urmc.rochester.edu
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Abstract

Microglia are the resident immune cells in the brain with the capacity to autonomously self-renew. Under basal conditions, microglial self-renewal appears to be slow and stochastic, although microglia have the ability to proliferate very rapidly following depletion or in response to injury. Because microglial self-renewal has largely been studied using static tools, the mechanisms and kinetics by which microglia renew and acquire mature characteristics in the adult brain are not well understood. Using chronic in vivo two-photon imaging in awake mice and PLX5622 (Colony stimulating factor 1 receptor (CSF1R) inhibitor) to deplete microglia, we set out to understand the dynamic self-organization and maturation of microglia following depletion in the visual cortex. We confirm that under basal conditions, cortical microglia show limited turnover and migration. Following depletion, however, microglial repopulation is remarkably rapid and is sustained by the dynamic division of the remaining microglia in a manner that is largely independent of signaling through the P2Y12 receptor. Mathematical modeling of microglial division demonstrates that the observed division rates can account for the rapid repopulation observed in vivo. Additionally, newly-born microglia resemble mature microglia, in terms of their morphology, dynamics and ability to respond to injury, within days of repopulation. Our work suggests that microglia rapidly self-renew locally, without the involvement of a special progenitor cell, and that newly born microglia do not recapitulate a slow developmental maturation but instead quickly take on mature roles in the nervous system.

Graphical Abstract (a) Microglial dynamics during control condition. Cartoon depiction of the heterogenous microglia in the visual cortex equally spaced. (b) During the early stages of repopulation, microglia are irregularly spaced and sparse. (c) During the later stages of repopulation, the number of microglia and the spatial distribution return to baseline. (d-f) We then created and ran a mathematical model that sampled the number of microglia, (d) the persistent doublets, (e) the rapid divisions of microglia and (f) the secondary divisions of microglia during the peak of repopulation day 2-day 3. The mathematical model suggested that residual microglia can account for the rapid repopulation we observed in vivo.

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Posted March 06, 2020.
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In vivo imaging of the kinetics of microglial self-renewal and maturation in the adult visual cortex
Mendes Mendes S, Jason Atlas, Zachary Brehm, Antonio Ladron-de-Guevara, Matthew N. McCall, Ania K. Majewska
bioRxiv 2020.03.05.977553; doi: https://doi.org/10.1101/2020.03.05.977553
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In vivo imaging of the kinetics of microglial self-renewal and maturation in the adult visual cortex
Mendes Mendes S, Jason Atlas, Zachary Brehm, Antonio Ladron-de-Guevara, Matthew N. McCall, Ania K. Majewska
bioRxiv 2020.03.05.977553; doi: https://doi.org/10.1101/2020.03.05.977553

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