22 THE SCIENTIST | the-scientist.com
CHAO WANGNOTEBOOKBut neurogenesis might not be the
only way memories are removed from the
brain, notes Ya n Gu, a neuroscientist at
Zhejiang University School of Medicine
in Hangzhou, China. Research that he
and others have carried out since Josselyn
and Frankland’s study shows that immune
cells called microglia also aid in forgetting,
eating away at the connections among
nerve cells where memories may reside.
Gu and colleagues made this find-
ing in 2019 in a series of experiments in
which they manipulated the numbers of
microglia and new neurons in the brains
of mice. From past studies, the team knew
that microglia remove extra synapses early
in life. Given synapses’ suspected role in
memory storage, the team wondered
whether there was a connection between
microglia and memory. To test the idea,
the team repeated the experiment Josse-
lyn and Frankland had run, putting adult
mice in an unfamiliar cage, then shocking
their feet with electricity. The team then
returned the mice to their home cages
and used a drug to wipe out microglia in
some of the animals’ brains, particularlyin the dentate gyrus, the specific region of
the hippocampus where new neurons are
made. When put back into the cage where
they’d been shocked, the drug-treated
mice froze while the untreated mice didn’t,
suggesting that mice with reduced microg-
lia had held onto their memory of the foot
shocks better than mice with normal levels
of the immune cells.
“After we found depleting microglia
prevented forgetting, we then started to
investigate why and how microglia reg-
ulate forgetting in the brain,” Gu writes
in an email to The Scientist. One of the
first tests the team did was to determine
how mice behaved if they had normal
levels of microglia but the immune cells
weren’t able to consume synapses as they
normally do. Mice given a drug to block
microglia’s eating behaviors remembered
the foot shock better than mice not given
the drug, the team found, confirming that
their propensity for forgetting had to do
with the immune cells’ ability to manipu-
late connections among nerve cells. The
team then gave another set of mice a drug
to boost hippocampal neurogenesis, fol-lowed by the drug that blocked microglia
from manipulating synapses. Again, the
mice froze in the shock box more than
untreated mice did, showing that even
boosting neurogenesis—which Josselyn
and Frankland had found promotes for-
getting—couldn’t counteract the mem-
ory-protecting effects of knocking out
the microglia.
“This connection between microglia
and forgetting is fascinating,” says Jorge
Valero, a neuroscientist at the Achu-
carro Basque Center for Neuroscience
in Leioa, Spain, who wasn’t involved
in Gu’s work but also studies microg-
lia’s role in this phenomenon. Valero
and his colleagues recently reported
in the Journal of Neuroscience that the
immune cells gobble down newly made
neurons tagged for cell death (40:1453–
82, 2020). When they ingest those new
neurons, the microglia begin to secrete
chemicals that reduce neurogenesis.
Curious whether microglia’s memory-
destroying activity is dependent on neuro-
genesis, or whether it can still occur even
when neurogenesis is absent, Gu’s team
tried their experiments again, this time
wiping out microglia in a region of the
hippocampus where there’s no neuro-
genesis. Again, the mice without microg-
lia froze longer when put back into the
box where they’d been shocked than
mice who still had normal numbers of
microglia, indicating that microglia aid
in the forgetting of memories that are
not tied to newly made neurons at all,
the team reported in Science in February
(367:688–94, 2020).
“It looks like a very careful study,” says
the Stony Brook University School of Med-
icine’s Stella Tsirka, who was not involved
in the research. She’s studied microglia for
several decades and has long suspected
that the cells have a function not only in
immune responses during disease but in
the normal, healthy brain. Gu’s work pro-
vides solid evidence for microglia’s role in
forgetting in the hippocampus, she says,
though it’s not yet clear if the immune cells
also munch on memories in other regions
of the brain.
—Ashley YeagerMEMORY POLICE: Brain cells called microglia
(red) snip connections between nerve cells
(blue) in the mouse hippocampus, in a process
that may influence forgetting.