When Emily Gibson and her team at the University of Colorado started building a microscope small enough to sit on a mouse's head, they ran into what seemed like an impossible problem. The tolerances required for the optics were so precise that their 3D printers could barely meet them. But they kept trying anyway — and eventually succeeded in creating a device that weighs just 5 grams, about as much as a small paperclip.
The new microscope, called Opto2P-FCM, was developed by researchers at CU Anschutz and CU Boulder. Unlike earlier brain microscopes, this one can actually watch and control brain cells while an animal moves around freely. That might not sound revolutionary, but for neuroscientists, it is a very big deal.
For decades, the best way to see inside a living brain was a technique called two-photon microscopy, which produces incredibly sharp images of brain tissue. The catch? The subject had to stay completely still. That made it nearly impossible to study how the brain actually works during everyday activities like walking, exploring, or interacting with others.
Smaller microscopes helped solve that problem, but they often suffered from blurry images or could not precisely control individual brain cells. The Opto2P-FCM gets around both limitations using a clever design with two separate optical pathways. One pathway produces the sharp images, while the other delivers patterned light to activate specific neurons without getting in the way. By separating these two jobs, the device can do both better than anything before it.
"This microscope is a game changer," said Juliet Gopinath, a professor of electrical and computer engineering and physics at CU Boulder who worked on the project. She said the ability to both read brain signals and control individual cells could lead to breakthroughs in understanding diseases caused by disrupted brain circuits, including Alzheimer’s disease.
The project required engineers, physicists, and neuroscientists to work closely together. Co-first author Gregory Futia, a senior research associate at CU Anschutz, said aligning all the tiny optics inside took careful mechanical design and many rounds of testing. Every single component had to be accounted for down to the smallest tolerance.
The device was described in the journal Optica. The researchers say it opens the door to experiments that were previously very difficult or even impossible to perform. Scientists can now watch exactly how groups of neurons work together to produce behavior — while the subject is wide awake and moving naturally. For researchers studying brain disorders, that kind of access could be transformative.