Scientists study many diseases of the deep brain using mouse models, mice that have been bred or genetically engineered to have diseases similar to human afflictions.

"Researchers will now be able to study mouse models in these deep areas in a way that wasn't available before," said senior author Mark Schnitzer, associate professor of biology and of applied physics.

Because light microscopy can only penetrate the outermost layer of tissues, any region of the brain deeper than 700 microns or so (about 1/32 of an inch) cannot be reached by traditional microscopy techniques. Recent advances in micro-optics had allowed scientists to briefly peer deeper into living tissues, but it was nearly impossible to return to the same location of the brain and it was very likely that the tissue of interest would become damaged or infected.

With the new method, "Imaging is possible over a very long time without damaging the region of interest," said Juergen Jung, operations manager of the Schnitzer lab. Tiny glass tubes, about half the width of a grain of rice, are carefully placed in the deep brain of an anaesthetized mouse. Once the tubes are in place, the brain is not exposed to the outside environment, thus preventing infection. When researchers want to examine the cells and their interactions at this site, they insert a tiny optical instrument called a microendoscope inside the glass guide tube. The guide tubes have glass windows at the ends through which scientists can examine the interior of the brain.

Stanford researchers have developed a new technique that allows them to monitor the tiny branches of neurons in a live brain for months at a time. Neuroscientists will now be able to monitor the microscopic changes that occur over the course of progressive brain disease.

(Photo Credit: Jack Hubbard, Stanford University News Service)

"It's a bit like looking through a porthole in a submarine," said Schnitzer.

The guide tubes allow researchers to return to exactly the same location of the deep brain repeatedly over weeks or months. While techniques like MRI scans could examine the deep brain, "they couldn't look at individual cells on a microscopic scale," said Schnitzer. Now, the delicate branches of neurons can be monitored during prolonged experiments.

To test the use of the technique for investigating brain disease, the researchers looked at a mouse model of glioma, a deadly form of brain cancer. They saw hallmarks of glioma growth in the deep brain that were previously known in tumors described as surficial (on or near the surface).

The severity of glioma tumors depends on their location. "The most aggressive brain tumors arise deep and not superficially," said Lawrence Recht, professor of neurology and neurological sciences. Why the position of glioma tumors affects their growth rate isn't understood, but this method would be a way to explore that question, Recht said.

In addition to continuing their studies of brain disease and the neuroscience of memory, the researchers hope to teach other researchers how to perform the technique.

Mark Schnitzer, associate professor of biology and applied physics, right, and Juergen Jung, operations director of the Schnitzer lab, in front of the microscope setup used to image the deep brain.

(Photo Credit: L.A. Cicero, Stanford University News Service)

This is a diagram of the experimental setup. (left) Tiny optical instruments called microendoscopes are inserted into glass imaging guide tubes, which maintain a precise position in the brain. This allows researchers to view the exact same neuron with a microscope (right) again and again, a new technique for brain researchers. Scientists can also compare diseased tissue, such as a tumor, to healthy tissue in the same animal.

(Photo Credit: Modified image courtesy Mark Schnitzer and Nature Medicine.)