A single memory is stored across many connected brain regions

Date:
April 11, 2022
Source:
Picower Institute at MIT
Summary:
Innovative brain-wide mapping study shows that 'engrams,' the
ensemble of neurons encoding a memory, is widely distributed
including among regions not previously recognized.



FULL STORY ==========================================================================
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 and Picower Professor Susumu Tonegawa. "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.


========================================================================== Story Source: Materials provided by Picower_Institute_at_MIT. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Dheeraj S. Roy, Young-Gyun Park, Minyoung E. Kim, Ying Zhang,
Sachie K.

Ogawa, Nicholas DiNapoli, Xinyi Gu, Jae H. Cho, Heejin Choi, Lee
Kamentsky, Jared Martin, Olivia Mosto, Tomomi Aida, Kwanghun Chung,
Susumu Tonegawa. Brain-wide mapping reveals that engrams for a
single memory are distributed across multiple brain regions. Nature
Communications, 2022; 13 (1) DOI: 10.1038/s41467-022-29384-4 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220411101249.htm

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