Retrograde amnesia is the inability to recall
established memories. In humans, amnesia is
associated with traumatic brain injury, Alzheimer’s
disease, and other neurological conditions. Whether
memories lost to amnesia are completely erased or
merely unable to be recalled remains an open
question. Now, in a finding that casts new light on
the nature of memory, published in Science,
researchers from the RIKEN-MIT Center for Neural
Circuit Genetics demonstrated in mice that traces of
old memories do remain in the amnestic brain, and
that the cellular pathways underlying them can be
reactivated, allowing lost memories to be found.
The research team, led by Susumu Tonegawa, Director
of the RIKEN Brain Science Institute in Saitama,
Japan, was interested in how stable memories are
formed in the brain and whether memories whose
storage was disrupted by chemically inducing
retrograde amnesia, could still be recalled. "Brain
researchers have been divided for decades on whether
amnesia is caused by an impairment in the storage of
a memory, or in its recall," said Tonegawa.
To make mice amnestic, they were first trained to
associate a mild foot shock with a specific
environment, chamber A, eliciting a typical
"freezing" behavior. Eventually, trained mice would
freeze in chamber A even without the shock. Neurons
activated during memory formation were genetically
labeled to allow their visualization and
reactivation. Then, some mice were given a chemical,
anisomycin, which inhibits new protein synthesis and
prevents increases in synaptic strength important
for memory encoding, thus inducing retrograde
amnesia. Other mice received saline as a control. As
expected, amnestic mice returned to chamber A did
not freeze, indicating that they could not recall
the memory for the specific association of the
chamber and the mild foot shock.
Next, to investigate whether the stored memory from
the foot shock training in chamber A was absent from
the amnestic mice or remained present but was not
retrievable, the researchers used optogenetic
technology to selectively activate neurons that were
genetically labeled during their training in chamber
A with a blue light-sensitive protein,
channelrhodopsin, but this time while the mice were
in a novel, neutral environment, chamber B.
Surprisingly, during activation of the cells
involved in the foot shock memory, collectively
called a "memory engram", with blue light pulses,
the amnestic mice froze just as much as the control
mice, indicating that they remembered that they had
acquired the memory, even though they could not
recall it when placed in chamber A.
To explain how the "lost" memory was recalled during
light stimulation of the memory engram, despite the
induction of retrograde amnesia, the authors suggest
that different processes may control memory encoding
and recall.
For example, during the training period, brain
connections between unique memory engrams in
neighboring brain structures may be strengthened and
once this has occurred, may not require an increase
in synaptic strength in order to store, but not
recall, the contextual fear memory and would be
preserved in the amnestic state.
Indeed, they observed that connectivity was enhanced
between memory engram cells in the fear
memory-holding amygdala and context memory-holding
hippocampus of amnestic mice, even though synaptic
changes remained stable.
"Our conclusion," says Tonegawa, "is that in
retrograde amnesia, past memories may not be erased,
but could simply be lost and inaccessible for
recall. These findings provide striking insight into
the fleeting nature of memories, and will stimulate
future research on the biology of memory and its
clinical restoration."
For more information
Tomás J. Ryan, Dheeraj S. Roy, Michele Pignatelli,
Autumn Arons and Susumu Tonegawa, "Engram Cells
Retain Memory Under Retrograde Amnesia", Science,
doi: 10.1126/science.aaa5542
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