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SUNDAY SCIENCE: MEMORIES ARE MADE BY BREAKING DNA — AND FIXING IT
 
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Max Kozlov
March 27, 2024
Nature [[link removed]]

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_ Nerve cells form long-term memories with the help of an
inflammatory response, study in mice finds. _

Neurons (shown here in a coloured scanning electron micrograph) mend
broken DNA during memory formation. , Ted Kinsman/Science Photo
Library

 

When a long-term memory forms, some brain cells experience a rush of
electrical activity so strong that it snaps their DNA. Then, an
inflammatory response kicks in, repairing this damage and helping to
cement the memory, a study in mice shows.

The findings, published on 27 March in _Nature_1
[[link removed]], are
“extremely exciting”, says Li-Huei Tsai, a neurobiologist at the
Massachusetts Institute of Technology in Cambridge who was not
involved in the work. They contribute to the picture that forming
memories is a “risky business”, she says. Normally, breaks in both
strands of the double helix DNA molecule are associated with diseases
including cancer. But in this case, the DNA damage-and-repair cycle
offers one explanation for how memories might form and last.

It also suggests a tantalizing possibility: this cycle might be faulty
in people with neurodegenerative diseases such as Alzheimer’s,
causing a build-up of errors in a neuron’s DNA, says study co-author
Jelena Radulovic, a neuroscientist at the Albert Einstein College of
Medicine in New York City.

Inflammatory response

This isn’t the first time that DNA damage has been associated with
memory. In 2021, Tsai and her colleagues showed that double-stranded
DNA breaks are widespread in the brain, and linked them with learning2
[[link removed]].

To better understand the part these DNA breaks play in memory
formation, Radulovic and her colleagues trained mice to associate a
small electrical shock with a new environment, so that when the
animals were once again put into that environment, they would
‘remember’ the experience and show signs of fear, such as freezing
in place. Then the researchers examined gene activity in neurons in a
brain area key to memory — the hippocampus. They found that some
genes responsible for inflammation were active in a set of neurons
four days after training. Three weeks after training, the same genes
were much less active.

The team pinpointed the cause of the inflammation: a protein called
TLR9, which triggers an immune response to DNA fragments floating
around the insides of cells. This inflammatory response is similar to
one that immune cells use when they defend against genetic material
from invading pathogens, Radulovic says. However, in this case, the
nerve cells were responding not to invaders, but to their own DNA, the
researchers found.

TLR9 was most active in a subset of hippocampal neurons in which DNA
breaks resisted repair. In these cells, DNA repair machinery
accumulated in an organelle called the centrosome, which is often
associated with cell division and differentiation. However, mature
neurons don’t divide, Radulovic says, so it is surprising to see
centrosomes participating in DNA repair. She wonders whether memories
form through a mechanism that is similar to how immune cells become
attuned to foreign substances that they encounter. In other words,
during damage-and-repair cycles, neurons might encode information
about the memory-formation event that triggered the DNA breaks, she
says.

When the researchers deleted the gene encoding the TLR9 protein from
mice, the animals had trouble recalling long-term memories about their
training: they froze much less often when placed into the environment
where they had previously been shocked than did mice that had the gene
intact. These findings suggest that “we are using our own DNA as a
signalling system” to “retain information over a long time”,
Radulovic says.

Fitting in

How the team’s findings fit with other discoveries about memory
formation is still unclear. For instance, researchers have shown that
a subset of hippocampal neurons known as an engram are key to memory
formation3
[[link removed]]. These
cells can be thought of as a physical trace of a single memory, and
they express certain genes after a learning event. But the group of
neurons in which Radulovic and her colleagues observed the
memory-related inflammation are mostly different from the engram
neurons, the authors say.

Tomás Ryan, an engram neuroscientist at Trinity College Dublin, says
the study provides “the best evidence so far that DNA repair is
important for memory”. But he questions whether the neurons encode
something distinct from the engram — instead, he says, the DNA
damage and repair could be a consequence of engram creation.
“Forming an engram is a high-impact event; you have to do a lot of
housekeeping after,” he says.

Tsai hopes that future research will address how the double-stranded
DNA breaks happen and whether they occur in other brain regions, too.

Clara Ortega de San Luis, a neuroscientist who works with Ryan at
Trinity College Dublin, says that these results bring much-needed
attention to mechanisms of memory formation and persistence inside
cells. “We know a lot about connectivity” between neurons “and
neural plasticity, but not nearly as much about what happens inside
neurons”, she says.

_doi: [link removed]

References

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Jovasevic, V. _et al._ _Nature_ 628, 145–153 (2024).

Article [[link removed]] Google Scholar
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*
Stott, R. T., Kritsky, O. & Tsai, L.-H. _PLoS ONE_ 16, e0249691
(2021).

Article [[link removed]] PubMed
[[link removed]] Google
Scholar
[[link removed].] 

*
Josselyn, S. A. & Tonegawa, S. _Science_ 367, eaaw4325 (2020).

Article [[link removed]] Google Scholar
[[link removed].]

_MAX KOZLOV is a science journalist at Nature who writes about
biomedical science. His work has also appeared in The Atlantic, Quanta
Magazine, Science, and The St. Louis Post-Dispatch._

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