The Mystery of How Memories Form Just Got Less Mysterious

"I use the word 'engram' to denote this permanent change wrought by a stimulus; the sum of such engrams in an organism may be called its 'engram-store,' among which we must distinguish inherited and from acquired engrams." —Richard Wolfgang Semon (Engraphic Action of Stimuli on the Individual, 1921)

Ninety-nine years ago, a "little known but influential" memory researcher from Germany, Richard Wolfgang Semon (1859-1918), who first described the concept of a 'memory engram,' had his catchphrase posthumously immortalized in a 1921 paper, "Engraphic Action of Stimuli on the Individual." Semon was a zoologist and evolutionary biologist who had a hunch that 'memory traces' (engrams) were encoded into the nervous system and speculated that some memories could be passed on through people's genes from one generation to the next.

In a Journal of Neuroscience paper, "Heroes of the Engram" (Josselyn, Köhler, and Frankland, 2017), the authors refer to Semon as "the overlooked hero who introduced the term engram" and write: "In 1904, Richard Semon introduced the term 'engram' to describe the neural substrate responsible for (or at least important in) storing and recalling memories (i.e., a memory trace)."

Over the past century, there's been some heated debate about Semon's "mneme theory" (inspired by a Greek goddess, Mneme, the mythological muse of memory) and his hypothesis that unique memory engrams can become part of a human or animal's DNA.

My late neuroscientist father, Richard Bergland (1932-2007), frequently spoke of engrams and had a lot of theories about the role that genes might play in encoding memory traces. I have written previously: "A thought reinforces an engram (neural network), which reinforces a mindset, which reinforces your character."

Source: Goa Novi/Shutterstock

Although the concept of memory engrams has been recognized for about a century, the molecular mechanisms that drive memory formation and recall in the engram ensembles of the hippocampus (i.e., memory hub) have remained a neuroscientific mystery, until today.

This morning, MIT neuroscientists published a potentially groundbreaking paper (Marco et al., 2020) in Nature Neuroscience that shares their discovery of how the epigenomic and transcriptomic interplay within the "hippocampal engram ensemble" controls how memories are encoded and recalled in mice. Asaf Marco, a postdoc in the Tsai Laboratory at MIT, is the lead author of this paper.

"This paper is the first to really reveal this very mysterious process of how different waves of genes become activated, and what is the epigenetic mechanism underlying these different waves of gene expression," senior author Li-Huei Tsai, director of MIT's Picower Institute for Learning and Memory, said in an October 5 news release.

The MIT teams' findings reveal that for the brain to form an indelible memory of an autobiographical experience that can be retrieved at a later date a large-scale remodeling of engram neurons needs to occur. This engram remodeling appears to be driven by chromatin, a highly-organized complex of DNA and proteins called histones that control the activity of specific genes within a cell. As the authors explain:

"In this study, we used an activity-dependent tagging system in mice to determine the epigenetic state, 3D genome architecture and transcriptional landscape of engram cells over the lifespan of memory formation and recall. Collectively, our work elucidates the comprehensive transcriptional and epigenomic landscape across the lifespan of memory formation and recall in the hippocampal engram ensemble."

Neuroscientists have known for some time that during the first stage of memory formation, certain genes are turned on inside engram neurons and that the activation of a memory engram's neural network results in a recollection of the corresponding memory. However, because these genes quickly return to normal levels of activity, Marco et al. designed elaborate mouse experiments to investigate how epigenomic modifications might be altering chromatin in a way that coordinates the storage of long-term memories.

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"The formation and preservation of memory is a very delicate and coordinated event that spreads over hours and days, and might be even months—we don't know for sure," Marco noted. "During this process, there are a few waves of gene expression and protein synthesis that make the connections between the neurons stronger and faster."

Much to their surprise, Marco et al. found that immediately after a memory is formed that multiple regions of DNA in the memory engram undergo modifications that make the chromatin structure "looser," which increases accessibility to DNA. "[Our] study is the first to show that memory formation is driven by epigenomically priming enhancers to stimulate gene expression when a memory is recalled," Marco said.

Although the researchers didn't explore how long these epigenomic modifications last, Marco speculates that "they may remain for weeks or even months." Future research by the MIT team will explore how Alzheimer's disease affects the chromatin of engram cells.