MIT
Neuroscientists Build Case for New Theory of Memory Formation
Existence of “silent engrams” suggests that existing models of memory formation should be revised.
ByAnne Trafton | MIT News Office
Existence of “silent engrams” suggests that existing models of memory formation should be revised.
ByAnne Trafton | MIT News Office
October 23, 2017 -- Learning and memory are generally thought to
be composed of three major steps: encoding events into the brain network,
storing the encoded information, and later retrieving it for recall.
Two years ago, MIT neuroscientists
discovered that under certain types of retrograde amnesia, memories of a
particular event could be stored in the brain even though they could not be
retrieved through natural recall cues. This phenomenon suggests that existing
models of memory formation need to be revised, as the researchers propose in a
new paper in which they further detail how these “silent engrams” are formed
and re-activated.
The researchers believe their
findings offer evidence that memory storage does not rely on the strengthening
of connections, or “synapses,” between memory cells, as has long been thought.
Instead, a pattern of connections that form between these cells during the
first few minutes after an event occurs are sufficient to store a memory.
“One of our main conclusions in
this study is that a specific memory is stored in a specific pattern of
connectivity between engram cell ensembles that lie along an anatomical
pathway. This conclusion is provocative because the dogma has been that a
memory is instead stored by synaptic strength,” says Susumu Tonegawa, the
Picower Professor of Biology and Neuroscience, the director of the RIKEN-MIT Center
The researchers also showed that
even though memories held by silent engrams cannot be naturally recalled, the
memories persist for at least a week and can be “awakened” days later by
treating cells with a protein that stimulates synapse formation.
Dheeraj Roy, a recent MIT PhD
recipient, is the lead author of the paper, which appears in the Proceedings
of the National Academy of Sciences the week of Oct. 23. Other authors are
MIT postdoc Shruti Muralidhar and technical associate Lillian Smith.
Silent memories
Neuroscientists have long believed
that memories of events are stored when synaptic connections, which allow
neurons to communicate with each other, are strengthened. Previous studies have
found that if synthesis of certain cellular proteins is blocked in mice
immediately after an event occurs, the mice will have no long-term memory of
the event.
However, in a 2015 paper, Tonegawa and his
colleagues showed for the first time that memories could be stored
even when synthesis of the cellular proteins is blocked. They found that while
the mice could not recall those memories in response to natural cues, such as
being placed in the cage where a fearful event took place, the memories were
still there and could be artificially retrieved using a technique known as
optogenetics.
The researchers have dubbed these
memory cells “silent engrams,” and they have since found that these engrams can
also be formed in other situations. In a study of mice with symptoms that mimic
early Alzheimer’s disease, the researchers
found that while the mice had trouble recalling memories, those
memories still existed and could be optogenetically retrieved.
In a more recent study of a process
called systems consolidation of memory, the researchers
found engrams in the hippocampus and the prefrontal cortex that
encoded the same memory. However, the prefrontal cortex engrams were silent for
about two weeks after the memory was initially encoded, while the hippocampal
engrams were active right away. Over time, the memory in the prefrontal cortex
became active, while the hippocampal engram slowly became silent.
In their new PNAS study,
the researchers investigated further how these silent engrams are formed, how
long they last, and how they can be re-activated.
Similar to their original 2015
study, they trained mice to fear being placed in a certain cage, by delivering
a mild foot shock. After this training, the mice freeze when placed back in
that cage. As the mice were trained, their memory cells were labeled with a
light-sensitive protein that allows the cells to be re-activated with light.
The researchers also inhibited the synthesis of cellular proteins immediately
after the training occurred.
They found that after the training,
the mice did not react when placed back in the cage where the training took
place. However, the mice did freeze when the memory cells were activated with
laser light while the animals were in a cage that should not have had any
fearful associations. These silent memories could be activated by laser light
for up to eight days after the original training.
Making connections
The findings offer support for
Tonegawa’s new hypothesis that the strengthening of synaptic connections, while
necessary for a memory to be initially encoded, is not necessary for its
subsequent long-term storage. Instead, he proposes that memories are stored in
the specific pattern of connections formed between engram cell ensembles. These
connections, which form very rapidly during encoding, are distinct from the
synaptic strengthening that occurs later (within a few hours of the event) with
the help of protein synthesis.
“What we are saying is that even
without new cellular protein synthesis, once a new connection is made, or a
pre-existing connection is strengthened during encoding, that new pattern of
connections is maintained,” Tonegawa says. “Even if you cannot induce natural
memory recall, the memory information is still there.”
This raised a question about the
purpose of the post-encoding protein synthesis. Considering that silent engrams
are not retrieved by natural cues, the researchers believe the primary purpose
of the protein synthesis is to enable natural recall cues to do their job
efficiently.
The researchers also tried to
reactivate the silent engrams by treating the mice with a protein called PAK1,
which promotes the formation of synapses. They found that this treatment, given
two days after the original event took place, was enough to grow new synapses
between engram cells. A few days after the treatment, mice whose ability to
recall the memory had been blocked initially would freeze after being placed in
the cage where the training took place. Furthermore, their reaction was just as
strong as that of mice whose memories had been formed with no interference.
Sheena Josselyn, an associate
professor of psychology and physiology at the University of Toronto
“They showed that a memory formed
during protein-synthesis inhibition may be artificially (but not naturally)
recalled. That is, the memory is still retained in the brain without protein
synthesis, but this memory cannot be accessed under normal conditions,
suggesting that spines may not be the key keepers of information,” says
Josselyn, who was not involved in the research. “The findings are
controversial, but many paradigm-shifting papers are.”
Along with the researchers’
previous findings on silent engrams in early Alzheimer’s disease, this study
suggests that re-activating certain synapses could help restore some memory
recall function in patients with early stage Alzheimer’s disease, Roy
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