Visualising mRNA molecules in the brains of live mice

US and South Korean researchers have developed a technique that allows scientists and engineers to visualise mRNA molecules in the brains of living mice. Published in the journal PNAS, their work reveals new insights into how memories are formed and stored in the brain, and could provide new information about diseases such as Alzheimer’s.

There is still a lot of mystery surrounding the process of how memory is physically created and stored in the brain. It is well known that mRNA is produced during the process of forming and storing memories, but the technology for studying this process on the cellular level has been limited, and previous studies have often involved dissecting mice in order to examine their brains. The new imaging technique gives scientists a window into RNA synthesis in the brain of a mouse while it is still alive, meaning researchers can study it for longer periods of time.

“We still know very little about memories in the brain,” said lead author Hye Yoon Park, currently an associate professor at the University of Minnesota Twin Cities. “It’s well known that mRNA synthesis is important for memory, but it was never possible to image this in a live brain.

“We now have this new technology that neurobiologists can use for various different experiments and memory tests in the future.”

The process involved genetic engineering, two-photon excitation microscopy and optimised image processing software. By genetically modifying a mouse so that it produced mRNA labelled with green fluorescent proteins (proteins derived from a jellyfish), the researchers were able to see when and where the mouse’s brain generated Arc mRNA, the specific type of molecule they were looking for. The researchers subsequently performed two experiments on the mouse in which they were able to see in real time over a month what the neurons (nerve cells) were doing as the mouse was forming and storing memories.

Historically, neuroscientists have theorised that certain groups of neurons in the brain fire when a memory is formed, and that those same cells fire again when that moment or event is remembered. However, in both experiments, the researchers found that different groups of neurons fired each day they triggered the memory in the mouse.

Over the course of several days after the mouse created this memory, they were able to locate a small group of cells that overlapped or consistently generated the Arc mRNA each day, in the retrosplenial cortex (RSC) region of the brain — a group which they believe is responsible for the long-term storage of that memory.

A three-dimensional view of the hippocampus CA1 region in a live mouse brain. Video credit: Hye Yoon Park, University of Minnesota Twin Cities.

“Our research is about memory generation and retrieval,” Park said. “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.”

Image caption: By genetically modifying a mouse so that it produced mRNA labelled with green fluorescent proteins, the researchers were able to see when and where the mouse’s brain generated Arc mRNA. Image credit: Hye Yoon Park, University of Minnesota Twin Cities.

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