How Epigenetic Mechanisms Affect Memory Expression

Memories are stored in small groups of brain cells called engrams, which carry the information of an experience and reactivate to trigger recall. While it is known that learning changes gene regulation through epigenetic mechanisms, whether these changes can directly alter a stored memory remained unclear. A team led by Professor Johannes Gräff at EPFL tackled this question by combining advanced CRISPR-based gene editing with a method to label engram cells in mice. 

The researchers focused on the gene Arc, which regulates how neurons adjust their connections. They developed CRISPR tools designed as an “epigenetic switch” that could either suppress or enhance Arc activity by adding or removing chemical tags affecting DNA accessibility. These tools were delivered to the hippocampus, a brain region essential for memory. Mice were trained to associate a specific location with a mild shock, then tested to see how modifying Arc’s epigenetic state affected their memory.

The study found that turning off Arc epigenetically in engram cells prevented the mice from forming the memory of the shock, while activating Arc strengthened their memory. Remarkably, the researchers included a “safety switch” allowing them to reverse these changes within the same animal, showing that epigenetic control could dial memory expression up or down. Even older memories, which are typically resistant to change, could be modulated. Molecular analyses confirmed that changes in gene activity and DNA packaging corresponded with behavioral outcomes. 

These results, published in Nature Genetics, represent the first direct evidence that altering the epigenetic state of memory cells is both necessary and sufficient to regulate memory expression. This discovery offers new avenues to study the storage and modification of memories. It also holds potential for exploring conditions involving dysfunctional memory processing, such as traumatic memories in PTSD, addiction-related memories, or memory impairments in neurodegenerative disorders.