Innovative brain-wide mapping study shows that “engrams,” the ensembles of neurons encoding a memory, are widely distributed, including among regions not previously realized
From: The Picower
Institute for Learning and Memory at MIT
April 11, 2022 -- A new study by scientists at The
Picower Institute for Learning and Memory at MIT provides the most
comprehensive and rigorous evidence yet that the mammalian brain stores a
single memory across a widely distributed, functionally connected complex
spanning many brain regions, rather than in just one or even a few places.
Memory pioneer Richard
Semon had predicted such a “unified engram complex” more than a century ago,
but achieving the new study’s affirmation of his hypothesis required the
application of several technologies developed only recently. In the study, the
team identified and ranked dozens of areas that were not previously known to be
involved in memory and showed that memory recall becomes more behaviorally
powerful when multiple memory-storing regions are reactivated, rather than just
one.
“When talking about
memory storage we all usually talk about the hippocampus or the cortex,” said
co-lead and co-corresponding author Dheeraj Roy. He began the research while a
graduate student in the RIKEN-MIT Laboratory for Neural Circuit Genetics at The
Picower Institute led by senior author Susumu Tonegawa, Picower
Professor in the Departments of Biology and Brain and Cognitive Sciences. “This
study reflects the most comprehensive description of memory encoding cells, or
memory ‘engrams,’ distributed across the brain, not just in the well-known
memory regions. It basically provides the first rank-ordered list for
high-probability engram regions. This list should lead to many future studies,
which we are excited about, both in our labs and by other groups.”
In addition to Roy, who
is now a McGovern Fellow in the Broad Institute of MIT and Harvard and the lab
of MIT neuroscience Professor Guoping Feng, the study’s other lead authors are
Young-Gyun Park, Minyoung Kim, Ying Zhang and Sachie Ogawa.
Mapping Memory
The team was able to
map regions participating in an engram complex by conducting an unbiased analysis
of more than 247 brain regions in mice who were taken from their home cage to
another cage where they felt a small but memorable electrical zap. In one group
of mice their neurons were engineered to become fluorescent when they expressed
a gene required for memory encoding. In another group, cells activated by
naturally recalling the zap memory (e.g. when the mice returned to the scene of
the zap) were fluorescently labeled instead. Cells that were activated by
memory encoding or by recall could therefore readily be seen under a microscope
after the brains were preserved and optically cleared using a technology
called SHIELD, developed by co-corresponding author Kwanghun Chung,
Associate Professor in The Picower Institute, the Institute for Medical
Engineering & Science and the Department of Chemical Engineering. By using
a computer to count fluorescing cells in each sample, the team produced
brain-wide maps of regions with apparently significant memory encoding or
recall activity.
The maps highlighted
many regions expected to participate in memory but also many that were not. To
help factor out regions that might have been activated by activity unrelated to
the zap memory, the team compared what they saw in zap-encoding or
zap-recalling mice to what they saw in the brains of controls who were simply
left in their home cage. This allowed them to calculate an “engram index” to
rank order 117 brain regions with a significant likelihood of being involved in
the memory engram complex. They deepened the analysis by engineering new mice
in which neurons involved in both memory encoding and in recall could be doubly
labeled, thereby revealing which cells exhibited overlap of those activities.
To really be an engram
cell, the authors noted, a neuron should be activated both in encoding and
recall.
“These
experiments not only revealed significant engram reactivation in known
hippocampal and amygdala regions, but also showed reactivation in many
thalamic, cortical, midbrain and brainstem structures,” the authors wrote.
“Importantly when we compared the brain regions identified by the engram index
analysis with these reactivated regions, we observed that ~60 percent of the regions
were consistent between analyses.”
Memory manipulations
Having ranked regions
significantly likely to be involved in the engram complex, the team engaged in
several manipulations to directly test their predictions and to determine how
engram complex regions might work together.
For instance, they
engineered mice such that cells activated by memory encoding would also become
controllable with flashes of light (a technique called “optogenetics”). The
researchers then applied light flashes to select brain regions from their
engram index list to see if stimulating those would artificially reproduce the
fear memory behavior of freezing in place, even when mice were placed in a
“neutral” cage where the zap had not occurred.
“Strikingly, all these
brain regions induced robust memory recall when they were optogenetically
stimulated,” the researchers observed. Moreover, stimulating areas that their
analysis suggested were insignificant to zap memory indeed produced no freezing
behavior.
The team then
demonstrated how different regions within an engram complex connect. They chose
two well-known memory regions, CA1 of the hippocampus and the basolateral
amygdala (BLA), and optogenetically activated engram cells there to induce
memory recall behavior in a neutral cage. They found that stimulating those
regions produced memory recall activity in specific “downstream” areas
identified as being probable members of the engram complex. Meanwhile,
optogenetically inhibiting natural zap memory recall in CA1 or the BLA (i.e.
when mice were placed back in the cage where they experienced the zap) led to
reduced activity in downstream engram complex areas compared to what they
measured in mice with unhindered natural recall.
Further experiments
showed that optogenetic reactivations of engram complex neurons followed
similar patterns as those observed in natural memory recall. So having
established that natural memory encoding and recall appears to occur across a
wide engram complex, the team decided to test whether reactivating multiple
regions would improve memory recall compared to reactivating just one. After
all, prior experiments have shown that activating just one engram area does not
produce recall as vividly as natural recall. This time the team used a chemical
means to stimulate different engram complex regions and when they did, they
found that indeed stimulating up to three involved regions simultaneously
produced more robust freezing behavior than stimulating just one or two.
Meaning of distributed
storage
Roy said that by
storing a single memory across such a widespread complex the brain might be
making memory more efficient and resilient.
“Different memory
engrams may allow us to recreate memories more efficiently when we are trying
to remember a previous event (and similarly for the initial encoding where
different engrams may contribute different information from the original
experience),” he said. “Secondly, in disease states, if a few regions are
impaired, distributed memories would allow us to remember previous events and
in some ways be more robust against regional damages.”
In the long term that
second idea might suggest a clinical strategy for dealing with memory
impairment: “If some memory impairments are because of hippocampal or cortical
dysfunction, could we target understudied engram cells in other regions and
could such a manipulation restore some memory functions?”
That’s just one of many
new questions researchers can ask now that the study has revealed a listing of
where to look for at least one kind of memory in the mammalian brain.
The paper’s other
authors are Nicholas DiNapoli, Xinyi Gu, Jae Cho, Heejin Choi, Lee Kamentsky,
Jared Martin, Olivia Mosto and Tomomi Aida.
Funding sources
included the JPB Foundation, the RIKEN Center for Brain Science, the Howard
Hughes Medical Institute, a Warren Alpert Distinguished Scholar Award, the
National Institutes of Health, the Burroughs Wellcome Fund, the Searle Scholars
Program, a Packard Award in Science and Engineering, a NARSAD Young
Investigator Award, the McKnight Foundation Technology Award, the NCSOFT
Cultural Foundation, and the Institute for Basic Science.
https://picower.mit.edu/news/single-memory-stored-across-many-connected-brain-regions
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