Our experiences create traces in the brain, stored in small groups of cells known as engrams, which are clusters of neurons that hold memory information and activate when we recall something. These engrams are key for studying memory and issues like age-related forgetfulness or trauma effects. Learning also involves epigenetic changes - chemical tags added to DNA that control gene activity without altering the DNA sequence itself. Until now, it was unclear if tweaking the epigenetic state of one gene could directly affect a memory.
Researchers at EPFL used CRISPR, a gene-editing tool, combined with a method to label engram cells in mice. They targeted the Arc gene, which helps neurons form and adjust connections during learning. By focusing on the gene's control region, they tested if flipping its epigenetic switch could change memory behavior. The study is published in Nature Genetics.
An epigenetic switch
The scientists created tools to either reduce or increase Arc activity in memory cells. One tool added repressive marks to make DNA harder to read, turning the gene off, while others added activating marks to open DNA and boost the gene. These were delivered via safe viruses to the hippocampus, a brain area vital for memory storage. Mice were trained to associate a place with a mild shock, and changes to Arc's epigenetic state were observed to see if the animals remembered the fear.
The results showed that silencing Arc epigenetically prevented mice from learning the fear, so they did not freeze in the scary place. Boosting Arc made memories stronger, with more freezing even from weak training. These effects were reversible using a safety tool to undo the changes, and they worked on memories a few days old, which are usually stable. At the molecular level, the edits altered gene activity and DNA packaging, matching the behavior shifts.
This work proves that epigenetic changes in engram cells are enough to control memory. It opens paths to explore memory storage and could help with conditions like PTSD, where traumatic memories persist, addiction with drug-linked recalls, or diseases like Alzheimer's with memory loss. Future studies may adapt this for human applications.