Mice are the mainstay of modern biomedical research, but the ability to image their brain cells while they're scampering around is no easy task. Scientists at Stanford University have created a powerful mini-microscope that can fit on a mouse head and stay there without interfering with the mouse's actions.
"It's like a little high-tech hat," said Mark Schnitzer, an associate professor of biological sciences and applied physics at Stanford who led the development with Stanford engineering professor Abbas El Gamal. "The mouse can behave very naturally and freely."
Although the individual parts aren't novel by themselves, they do create a tiny little novel system when combined. The microscope is an advancement of an earlier one that Schnitzer's lab designed in 2008. Unlike that one, the latest fluorescence microscope integrates all the optical parts into 1.9 grams so that there are no ancillary components to make it bulky. The technology is described in the latest issue of the journal Nature Methods.
Before the 2008 microscope, optical studies on mice brains usually required the animals to be held in place or walk on a moving platform keeping their heads still. Although that method had some advantages, it required training the mice. By affixing tiny microscopes to mice heads, scientists hope to learn more about function in the poorly understood cerebellum, the part of the brain that controls motor coordination and balance.
The new mini-microscope looks like a boxy Lincoln-style top hat. Inside are special filters, little lenses, a camera made from semiconductor sensors, a mirror, an objective and a tiny LED for illumination.
The tiny scope has strong capabilities. Image sensors made from a metal-oxide semiconductor have the capability of doing intelligent pixel-by-pixel image analysis. A test of the new tech showed that their microscope can count cells and even detect tuberculosis bacterial labeled with a fluorescent stain.
The scientists point out that although the microscope is more powerful than their previous version, the parts could be mass-produced rather inexpensively, making the tiny hats more affordable.
For example, the optoelectronic parts cost between $25,000 and $50,000 for their last microscope, but the mass-produced versions only cost between about $1 and $10 for the new one.
Portability is another advantage, giving researchers the opportunity to shove a few microscopes in their pocket and bring sophisticated analysis capabilities with them.
"You could take the technology into areas that conventional microscopes can't visit," Schnitzer said. "That would allow one to perform microbiology diagnostics in areas that are poorly serviced by conventional microscopy."
Next, the scientists plan to use the technology to examine other parts of the mouse brain. Schnitzer and his co-authors also have equity in a startup that aims to commercialize the mini-microscope technology.
David Kleinfeld is a physics professor at the University of California at San Diego who also teaches neuroscience. He said he thinks the new microscope should reinvigorate research into part of the brain that humans are embarrassingly ignorant about.
"The system as a whole represents an order of magnitude improvement in size and price point over past designs," Kleinfeld said. "(It) may lead to a quantum jump in the ubiquity of imaging in biomedical research."