neurosciencestuff:

Microglia are known to be important to brain function. The immune
cells have been found to protect the brain from injury and infection and
are critical during brain development, helping circuits wire properly.
They also seem to play a role in disease — showing up, for example,
around brain plaques in people with Alzheimer’s.

It turns out microglia aren’t monolithic. They come in different
flavors, and unlike the brain’s neurons, they’re always changing. Tim Hammond, PhD, a neuroscientist in the Stevens lab
at Boston Children’s Hospital, showed this in an ambitious
study, perhaps the most comprehensive survey of microglia ever
conducted. Published in Immunity, the findings open a new chapter in brain exploration.

“Up until now, we didn’t have a good way of classifying microglia,”
Hammond says. “We could only say how branched they look, how dense they
look under a microscope. We wanted to get an idea of what microglia were
doing and ‘thinking.’”

Eavesdropping on microglia over time

Hammond’s team collaborated with the lab of Steven McCarroll, PhD at Harvard Medical School. Starting with mice, Hammond and his colleagues sequenced RNA from more than 76,000 individual microglia to see which genes were turned on or off, using a technique known as Drop-seq,
developed in McCarroll’s lab. The cells were sampled from all over the
brain and throughout the animals’ lifespan (starting before birth), as
well after acute brain injury.

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(Image caption: Hammond and colleagues’ profiling of 76,149 cells from mouse brains identified nine microglia clusters, represented here in two-dimensional space. Credit: Timothy Hammond / Boston Children’s Hospital)

The genetic ‘signatures’ allowed Hammond to classify the microglia
into at least nine distinct groups, including some types never detected
in the past. Some types appeared almost exclusively in the embryonic or
newborn stages, others only after injury.

“The signatures also tell as something about what these cells are
doing,” he notes. “If we see microglia in disease, for example, we can
begin to parse out: Are they contributing to the disease or are they
trying to repair the brain? We think this will help uncover new and
interesting roles for microglia that weren’t known before.”

Mapping microglia

Hammond then went a step further. He overlaid the classifications on a
map of the brain, to see how the different varieties of microglia were
distributed spatially.

This yielded some interesting patterns. One group of microglia, for
example (group 4 in the schematic above), tended to cluster near the
brain’s developing white matter. This suggests they could be involved in
myelination, in which nerve fibers are given a layer of insulation to
help them carry signals over longer distances.

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(Image caption: This prenatal mouse brain shows the distribution of microglia (from left to right, the hindbrain, midbrain, forebrain and neocortex). The yellow microglia bear markers indicating that they belong to unique populations not detected in the past. Credit: Timothy Hammond)

“We don’t see those microglia at any other time point or area of the
brain,” says Hammond. “We think they could be important to how the white
matter develops, and how axons connect to different parts of the
brain.”

In sickness and in health

Another tiny but important microglial population (group 8 in the
schematic) came to light in the disease setting. The team found it first
in a mouse model mimicking multiple sclerosis, which involves a loss of
myelination, and later in brain tissue from actual patients with MS.

“These microglia are very inflammatory compared with normal
microglia,” says Hammond. “It could be a pathological subset that we
normally wouldn’t see, but because we sequenced so many microglia we
were able to detect this small population.”

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Overall, microglia were most diverse early in brain development, in
the aged brain and in disease. The researchers think these distinct
groups may shed light on what the cells are doing, and what local cues
they’re responding to.

Directing therapy?

All this information should help scientists sort out the “good” from
the “bad” when it comes to microglia, particularly in so-called
activated microglia that appear after brain injury and in diseases like
autism and Alzheimer’s. This could help direct the development of drugs
to promote the beneficial microglia subsets and block the detrimental
ones.

“Tim’s work has broad implications for the development new microglia
biomarkers and tools that can be used to track, identify and manipulate
specific subpopulations, in both health and disease,” says Beth Stevens, PhD, co-corresponding author on the paper with McCarroll and a principal investigator in Boston Children’s F.M. Kirby Neurobiology Center.

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