More than a century ago, memory pioneer Richard Semon predicted a “unified engram complex”, that is, a complex of connected brain regions that would all be involved in the recall of a single memory.
Now, a new study by researchers at the Picower Institute for Learning and Memory at MIT, US, suggests Semon may have been on to something. Evidence is mounting that a single memory dances across many different brain regions at once, linked to clusters of memory recall-cells called engrams.
In the new study, published in Nature Communications, the team of researchers identified and ranked dozens of areas that hadn’t previously been thought associated with memory. By conducting experiments on mice in the lab, they ultimately built a huge map of all the brain regions that seem involved with the art of remembering.
So, how did they do it?
Mapping memory in mice
To test which brain regions might be roped into memory recall, the team performed a set of experiments on mice. Firstly, they analysed 247 brain regions in mice that were taken from their home cage to another cage where they were exposed to 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 (i.e. storing the information as a memory). In another group, cells activated by remembering the electrical zap were fluorescently labelled.
Once the mouse brains were preserved, the researchers could use a computer to count the fluorescing cells in each sample. This allowed them to create a brain map of regions with a clear link to memory encoding and memory recall.
By comparing these mapped regions to the brains of control mice that weren’t exposed to zaps, they were able to discount certain regions, and produce a ranked order of 117 regions with a clear likelihood of involvement in memory.
To really be an engram cell, the authors theorised, a neuron should be activated in both the encoding (recording) and recall (remembering) of a memory.
Many brain regions found likely to be involved in encoding a memory (top) were also found to be involved in recall upon reactivation (bottom). Credit: Tonegawa Lab/MIT Picower Institute
What they found was a massive engram complex.
“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 write. “Importantly when we compared the brain regions identified by the engram index analysis with these reactivated regions, we observed that around 60% of the regions were consistent between analyses.”
Manipulating memories
Having ranked all the regions likely to be engaged in the engram complex, the team decided to test its predictions.
The researchers engineered some of the mice so that cells activated by memory encoding would also become controllable with flashes of light (a technique known as “optogenetics”). They then applied flashes of light to select brain regions from their engram index list to see if, when hit with the light stimulus, the mice would freeze in place, which is a classic fear behaviour.
“Strikingly, all these brain regions induced robust memory recall when they were optogenetically stimulated,” the researchers write. Stimulating areas that their analysis suggested were insignificant to memory, on the other hand, did not produce freezing behaviour – suggesting they weren’t recalling the zap.
Then, they tested how each region in the complex connects to one another, and found that stimulating just one part of the complex would produce a less robust memory recall than stimulating all – inferred because stimulating just one region produced a less dramatic freeze response.
It suggests that this massive memory complex can make memories stronger.
What’s all the fuss?
You might wonder, why put these poor little mice through such experiments? But the neuroscience of memory is important; the more we understand it, the more we can understand when it goes wrong.
Co-lead author Dheeraj Roy says that by storing a single memory across such a massive complex, the brain may 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 says.
“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.”
This second point could suggest the way to an actual clinical application of this engram complex.
“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?” Roy says.