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. Credit: L.A. Cicero, Stanford University News Service
Travel just one millimeter inside the brain and you’ll be
stepping into the dark.
Standard light microscopes don’t allow researchers to look
into the interior of the living brain, where memories are formed
and diseases such as dementia and cancer can take their
But Stanford scientists have devised a new method that not
only lets them peer deep inside the brain to examine its neurons
but also allows them to continue monitoring for months.
The technique promises to improve understanding of both the
normal biology and diseased states of this hidden tissue.
Other recent advances in micro-optics had enabled scientists
to take a peek at cells of the deep brain, but their observations
captured only a momentary snapshot of the microscopic changes that
occur over months and years with aging and illness.
The Stanford development appears online Jan. 16 in the
journal Nature Medicine. It also will appear in the February
2011 print edition.
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
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
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.
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. Credit: Modified image courtesy Mark Schnitzer and Nature Medicine.
“It’s a bit like looking through a porthole in a submarine,”
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.
SOURCE: Stanford University