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Page 250 Benusa et al. Neuroimmunol Neuroinflammation 2020;7:248-63 I http://dx.doi.org/10.20517/2347-8659.2020.03
[36]
C-X3-C motif chemokine receptor 1 (Cx3Cr1) and “eat me” signals such as calreticulin/low-density
[37]
lipoprotein receptor related protein . These signals, which are not present in the healthy CNS, cue
microglia to assume a phagocytic phenotype and to “find” and “eat” the compromised cells. Therefore,
environmental cues have the capacity to drive the transformation of microglia from a surveying to a
phagocytic phenotype. It remains unclear if all microglia in the neighborhood of the “find me” and “eat
me” signals respond in the same manner, or if intrinsic heterogeneity results in the response from select
subclasses of the microglial population.

Heterogeneity between brain regions
[38]
Some of the earliest evidence of heterogeneity within the microglial population was presented by Lawson et al. ,
who reported brain-region specific densities of cells with higher densities in the hippocampus and
thalamus, and a lower density in the cerebellum. Although no functional differences were established,
such density differences are consistent with local environmental cues regulating the microglial population.
[39]
In line with this idea, De Biase et al. reported that regional differences are tightly and specifically
regulated since closely apposed nuclei within the basal ganglia present with dramatically different
microglial densities while other cell types in the same basal ganglia nuclei present with uniform densities,
[40]
indicating that differential cell densities are not dictated by the spatial constraints of the tissue. Precisely
how these region-specific differences are regulated remains to be fully explained although region-specific
[41]
self-renewal rates have been presented and it is possible that region-specific cues regulate proliferation
and, ultimately, cell density . Moreover, factors that regulate microglia numbers in the embryonic brain
[42]
vs. the adult brain may also differ [43,44] , which would be consistent with local cues defining both distribution
[45]
and heterogeneity within the microglial population. This concept was supported by Grabert et al. , who
demonstrated that microglia have regionally distinct transcription profiles.

Heterogeneity between sexes
Variations in cell density and transcription profiles are not limited to regional differences as similar
distinctions have also been reported between microglia from male and female mice. Male mice present with
more microglia in the cortex, hippocampus, dentate gyrus, and amygdala in early postnatal brains. As the
[46]
mice mature, these densities flip with female mice presenting with a greater cell density in these regions .
Although there is no direct evidence that sex-dependent differences in cell density are responsible for
functional differences, studies have shown that male and female microglia are functionally distinct and
[40]
[49]
respond differently to noxious stimuli [47,48] . For example, Nelson et al. and Yanguas-Casás et al. showed
that female microglia have a greater phagocytic capacity but male microglia have greater migratory activity
[50]
under both basal and interferon γ-induced inflammatory conditions. Guneykaya et al. then reported
that male microglia display a higher antigen-presenting capacity as compared to female cells. Interestingly,
microglia may also play a role in sex determination since the inhibition of microglial activity in male
rodent neonates, at an age critical for sex determination, resulted in the reduction of masculine dendritic
spine density and altered copulatory behavior in adults . A potential caveat to this work, however, was
[51]
that microglial activity was inhibited by minocycline, which is a broad spectrum antibiotic that is known to
target both T cells and astrocytes [52,53] .

Intrinsically defined heterogeneity?
The mechanisms responsible for these sex differences are not known and transcriptomic studies comparing
male and female microglia reveal expression differences in both the healthy and perturbed states [48,50,54,55] .
Whether microglia are intrinsically distinct between males and females, or if the local sex-specific
environment differentially regulate male and female cells remains to be determined. Microglia from male vs.
female mice express different sex hormone receptors [56-58] however, and present with sex-specific outcomes
when exposed to these hormones [49,51,59-61] . Independent of sex, microglia have also been shown to express
[62]
[62]
different levels of markers in the adult, unchallenged brain . Bertolotto et al. showed that microglia