A team at the University of Minnesota developed a new technique that lets them view gene expression in the brains of live mice in real time. The approach relies on two-photon excitation microscopy, specialized imaging processing techniques, and genetically modified mice that express mRNA that naturally includes a fluorescent protein. Using the method, the researchers were able to gain insights into how long-term memories are formed in the brain, and hope that this knowledge could lead to breakthroughs in understanding and treating Alzheimer’s disease. The method will likely also be useful in deciphering the mechanisms underlying other diseases.
Observing gene expression in real time sounds like science fiction, but these researchers have achieved just that. The method allows them to see if a gene is being expressed as an animal performs a certain task, such as recalling a memory, allowing an unprecedented view of the biological basis for long-term memory.
Here’s an example video of a 3D view of a region of the hippocampus in a live mouse:
The new technique involves looking at messenger RNA, a key link in gene expression. “We still know very little about memories in the brain,” said Hye Yoon Park, a researcher involved in the study. “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.”
The new method uses genetically modified mice that express mRNA that is labelled with green fluorescent proteins, and the mRNA in question derives from a gene called Arc that is involved in memory formation. This means that it was possible to image the brain through two-photon excitation microscopy and identify which cells are expressing Arc in real time when the mouse was creating or recalling memories.
Previously, researchers had thought that specific neurons fire when a memory is formed and then those same neurons fire again when it is recalled. However, the new technique revealed that mostly different neurons fire each time a memory is recalled, with only a small number in the retrosplenial cortex region of the brain firing consistently, leading the researchers to conclude that this area is likely responsible for long-term memories.
“Our research is about memory generation and retrieval,” said Park. “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.”
Study in Proceedings of the National Academy of Sciences: Real-time visualization of mRNA synthesis during memory formation in live mice