Epigenetic State Determines Which Neurons Are Selected for Memory Formation in Mice

When a new memory forms the brain undergoes physical and functional changes known collectively as a “memory trace.” This memory trace represents the specific patterns of neuronal activity and structural modifications that occur when a memory is formed and later recalled.

But how does the brain “decide” which neurons will be involved in a memory trace? Scientists at EPFL explored whether epigenetics might affect the likelihood of specific neurons being selected for memory formation. Their research in mice showed that the epigenetic state of a neuron is key to its role in memory encoding. “We are shedding light on the earliest step of memory formation from a DNA-centric level,” said neuroscientist Johannes Gräff, PhD.

The findings, the researchers suggested, may one day even lead to the development of new approaches for improving learning. “They move away from the dominant neuroscientific view on learning and memory that focuses on the importance of synaptic plasticity, and newly place emphasis on what happens inside the nucleus of a neuron, on its DNA,” said research lead Gräff. “This is especially important, as many cognitive disorders such as Alzheimer’s disease and post-traumatic stress disorder are characterized by epigenetic mechanisms gone wrong.”

Gräff and colleagues described their work and findings in Science in a paper titled, “Chromatin plasticity predetermines neuronal eligibility for memory trace formation.” In their research article summary, the team stated, “Our findings show that a neuron’s eligibility to be recruited into the memory trace depends on its epigenetic state prior to learning, and thereby identify chromatin plasticity as a novel form of plasticity important for information encoding.”

One of the most intriguing features of neurons is their capacity for information encoding, the researchers wrote. “Notably, for each new piece of information memorized the brain deploys only a subset of its neurons, implying that even within the same developmentally defined cell type, not all neurons are equally fit for information encoding at any given time.”

While studies have suggested that the inherent excitability of neurons may play a role in which neurons are selected, the currently accepted view of learning has not looked to the neuronal nucleus, and to epigenetic factors, the researchers noted. As the team pointed out in their paper, “… it remains unknown whether and to what extent nuclear plasticity at the chromatin level contributes to neuronal selection for information encoding.”

Inside every cell, the genetic material encoded by DNA is the same, but the various cell types that make up the body, including skin cells, kidney cells, or nerve cells, each express a different set of genes. Epigenetics is the mechanism of how cells control gene activity without changing the DNA sequence.

Gräff and his team wondered if epigenetic factors could influence the “mnemonic” function of a neuron. A neuron can be epigenetically open when the DNA inside its nucleus is unraveled or relaxed, and closed when the DNA is compact and tight.

Studying the mouse lateral amygdala region of the brain, which is involved in some areas of memory formation, the team discovered that it is the open neurons that are more likely to be recruited into the “memory trace,” the sparse set of neurons in the brain that shows electrical activity when learning something new. Indeed, the neurons that were in a more open chromatin state were also the ones demonstrating higher electrical activity. “Focusing on the mouse lateral amygdala, a key brain region responsible for the encoding of associative forms of memory, we discovered that its excitatory neurons indeed exhibit heterogeneous chromatin plasticity, and further, that those preferentially recruited into learning-activated neurons were enriched for hyperacetylated histones, an abundant epigenetic modification in the brain,” the investigators wrote.

The EPFL scientists then used a virus to deliver epigenetic enzymes to artificially induce openness of the neurons. They found that the corresponding mice learned much better. Conversely, when the scientists used the opposite approach to close the neurons’ DNA, the animals’ ability to learn was canceled. “We found that a gain-of-function of histone acetylation-mediated epigenetic plasticity facilitated neuronal recruitment into the memory trace whereas a loss-of-function thereof prevented memory allocation,” they added.

The findings open up new avenues for helping to understand learning that encompass the neuron’s nucleus, and epigenetic mechanisms. The findings and further study may one day even lead to the development of medications for improving learning. The team commented, “These results identify the epigenetic state of a neuron as a key factor enabling information encoding.” A neuron’s epigenetic landscape might then represent “… an adaptable template so as to register and integrate environmental signals in a dynamic, yet long-lasting manner.”

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