How do mice make memories?

The first ever real-time visualization technique of mRNA in brains of living mice is a tool to uncover the secrets of memory formation and storage, and memory-related diseases including Alzheimer’s.

A new technique, developed by Hye Yoon Park (University of Minnesota Twin Cities; MN, USA) in collaboration with Seoul National University and Korea Institute of Science and Technology (both South Korea), enables the first real-time visualization of mRNA in living mouse brains. The technique will assist researchers in connecting gene expression with neuronal activity and behavior in memory-encoding neurons as well as provide insight into how memories are formed and stored in the brain.

While it is known that mRNA synthesis in memory trace neurons is pivotal to the encoding of memories, dynamic cellular monitoring of these neurons in vivo has proven difficult.

“We still know very little about memories in the brain,” explained Park. “It’s well known that mRNA synthesis is important for memory, but it was never possible to image this in a live brain. Our work is an important contribution to this field. We now have this new technology that neurobiologists can use for various different experiments and memory tests in the future.”

What can flies teach us about long-term memory?

Whilst memories are fluid at first, they can be consolidated into stable long-term memory. But what is the mechanism behind memory consolidation in animals?

In order to dynamically monitor memory trace neurons, Park’s team utilized genetically encoded RNA indicator mice that express fluorescently labeled mRNA for the Arc gene, a marker frequently used for memory trace neurons. Two-photon excitation microscopy and optimized image processing software allowed for visualization of fluorescent Arc mRNA in the conditioned mouse brains while they were still alive and actively forming and storing memories.

After several days of observation following memory creation, a small population of neurons in the retrosplenial cortex consistently expressed Arc mRNA each day while Arc expression was less consistent in other brain regions.

Additionally, dual imaging of the Arc mRNA and calcium indicator in the CA1 hippocampus region during mouse navigation in a virtual environment highlighted that only the neuronal populations expressing Arc during both memory encoding and retrieval exhibited relatively high calcium activity.

The results may indicate that the retrosplenial cortex is responsible for long-term memory storage while the hippocampus is limited to shorter timescales.

“Our research is about memory generation and retrieval,” Park commented. “If we can understand how this happens, it will be very helpful for us in understanding Alzheimer’s disease and other memory-related diseases. Maybe people with Alzheimer’s disease still store the memories somewhere – they just can’t retrieve them. So in the very long-term, perhaps this research can help us overcome these diseases.”