A new study by scientists at MIT’s Picower Institute for Learning and Memory provides the most comprehensive and rigorous evidence to date that the mammalian brain stores a single memory in a widely distributed and functionally complex complex. connected spanning many brain regions, rather than just one or even a few locations.
Memory pioneer Richard Semon predicted such a “complex of unified engrams” more than a century ago, but realizing the new study’s assertion of his hypothesis required the application of several recently developed technologies. In the study, the team identified and classified dozens of domains that were not previously known to be involved in memory and showed that memory recall becomes more behaviorally powerful when multiple storage regions memory are reactivated, rather than just one.
“When we talk about memory storage, we’re all usually talking about the hippocampus or the cortex,” said Dheeraj Roy, co-lead and co-corresponding author. He began the research while a graduate student in the RIKEN-MIT Neural Circuit Genetics Laboratory at the Picower Institute led by lead author and Picower Professor Susumu Tonegawa. “This study reflects the most comprehensive description of memory encoding cells, or memory ‘engrams’, distributed throughout the brain, not just well-known memory regions. It basically provides the first prioritized list for high probability engram regions. This list should lead to many future studies, which we look forward to, both in our labs and by other groups.
In addition to Roy, who is now a McGovern Fellow of 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.
The team was able to map the regions participating in an engram complex by performing an unbiased analysis of over 247 brain regions in mice that were taken from their home cage to another cage where they experienced a small but memorable electric zapping. In one group of mice, their neurons were engineered to fluoresce when they expressed a gene needed to encode memory. In another group, cells activated by naturally recalling memory zap (e.g. when mice returned to the scene of the zap) were fluorescently labeled instead. Cells activated by memory coding or recall could therefore be easily seen under a microscope after the brains were preserved and optically cleaned using a technology called SHIELD, developed by co-corresponding author Kwanghun Chung, associate professor in the Picower Institute, the Institute for Medical Engineering and Science and the Department of Chemical Engineering. By using a computer to count the fluorescent cells in each sample, the team produced brain-wide maps of regions with apparently significant coding or recall activity.
The maps highlighted many regions that were supposed to participate in memory, but also many regions that were not. To help factor out regions that might have been activated by activity unrelated to zap memory, the team compared what they saw in zap-encoding or zap-recall mice to what they saw in the brains of witnesses who were simply left in their cage home. This allowed them to calculate an “engram index” to rank 117 brain regions with a significant likelihood of being involved in the memory engram complex. They took the analysis further by designing new mice in which neurons involved in both memory coding and recall could be doubly labeled, revealing which cells exhibited overlap in these activities.
To truly be an engram cell, the authors noted, a neuron must be activated in both encoding and recall.
“These experiments not only revealed significant reactivation of engrams in known regions of the hippocampus and amygdala, but also showed reactivation in numerous thalamic, cortical, midbrain, and brainstem structures,” wrote writers. “Importantly, when we compared the brain regions identified by engram index analysis with these reactivated regions, we observed that approximately 60% of the regions were consistent between the analyses.”
After classifying the regions significantly likely to be involved in the engram complex, the team engaged in several manipulations to directly test their predictions and determine how the regions of the engram complex might work together.
For example, they designed mice such that cells activated by memory coding would also become controllable with flashes of light (a technique called “optogenetics”). The researchers then applied light flashes to select brain regions from their list of engram cues to see if their stimulation would artificially replicate the fear memory behavior of freezing in place, even when the mice were placed in a “neutral” cage where the zap had not occurred.
“Amazingly, all of these brain regions induced robust memory recall when stimulated by optogenesis,” the researchers observed. Moreover, the stimulating areas that their analysis suggested were insignificant for memory zapping did indeed produce no blocking behavior.
The team then demonstrated how different regions within an engram complex connect. They chose two well-known memory regions, CA1 from the hippocampus and basolateral amygdala (BLA), and optogenetically activated engram cells to induce memory recall behavior in a neutral cage. They found that stimulation of these regions produced memory recall activity in specific “downstream” areas identified as likely members of the engram complex. Meanwhile, optogenetic inhibition of natural memory zap recall in CA1 or the BLA (i.e. when mice were returned to the cage where they were zaped) resulted in reduced activity in the complex areas of downstream engrams compared to what they measured in mice with unimpeded natural recall.
Further experiments showed that optogenetic reactivations of engram complex neurons followed patterns similar to those seen in natural memory recall. So, after establishing that natural memory encoding and recall appears to occur in a large complex of engrams, the team decided to test whether reactivating multiple regions would improve memory recall compared to reactivation of one. After all, previous experiments have shown that activating a single engram area does not produce as vivid a recall as natural recall. This time, the team used a chemical means to stimulate different complex regions of engrams, and in doing so, they found that indeed the simultaneous stimulation of up to three involved regions produced more robust freezing behavior than stimulation of one or two only.
Meaning of Distributed Storage
Roy said that by storing a single memory in such a widespread complex, the brain could make memory more efficient and resilient.
“Different memory engrams may allow us to recreate memories more effectively when trying to remember a previous event (and similarly for initial encoding where different engrams may bring different information from the original experience)”, did he declare. “Second, 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 damage.”
In the long term, this second idea could suggest a clinical strategy for treating memory impairment: “If some memory impairment is due to hippocampal or cortical dysfunction, could we target understudied engram cells in other regions and could such manipulation restore some memory functions? ”
That’s just one of many new questions researchers can ask now that the study has revealed a list of places to look for at least one type of memory in mammalian brains.
Reference: Roy DS, Park YG, Kim ME, et al. Brain-wide mapping reveals that engrams of the same memory are distributed across multiple regions of the brain. Nat Common. 2022;13(1):1799. doi: 10.1038/s41467-022-29384-4
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