A new type of micro-endoscope lets scientists watch nerve cells and blood vessels deep inside the brain of a living animal over days, weeks, or even months. A team led by Mark Schnitzer, associate professor of biology and applied physics at Stanford University, developed the endoscope—an optical instrument used to peer into the body—along with a system to insert it into the same spot time after time. This feature allowed scientists to track changes in minute features, such as the connections between cells in the brain.
“I think it will be a potent tool for tracking properties of cells over long periods of time in response to changes in the environment, over the course of learning, during aging or the progression of disease,” says Schnitzer. Some developmental and neurodegenerative diseases, for example, damage connections between neurons deep in the brain.
Of particular interest to neuroscientists is the hippocampus, an area deep in the brain that is crucial to memory. Previously, scientists had been able to look at regions such as this one in detail only with highly invasive methods and at a single point in time. “But a lot of brain disorders occur slowly,” says Schnitzer. “We don’t just want a snapshot, we want a time-lapse [movie] on a time scale that is relevant to the progression of the disease.”
Schnitzer’s team has been developing the micro-endoscope for several years. Dubbed the optical needle, it is 500 to 1,000 microns in diameter at its tip—about half the width of a grain of rice. While the device resembles a scaled-down version of the endoscopes now commonly used for surgery, the tiny lens is slightly different. The small size of the device means that a curved lens, typical in most microscopes, is impractical. Instead, its lens is made from a material that has internal variations in its refractive profile to guide rays of light.
In the new study, published online this month in Nature Medicine, researchers demonstrate that they can use the micro-endoscope to observe the same spot in the brain over time. They first implant a glass guide tube into an animal’s brain, placing it just above the area of interest, with a tiny microscope slide covering its tip. They can then insert the micro-endoscope into the tube, taking pictures of the cells using a standard two-photon microscope. After imaging, “you can pull the microneedle out, return the animal to its cage, then reinsert it [days or weeks] later and look again,” says Schnitzer.
Elly Nedivi, associate professor of neurobiology at MIT, says that being able to return to the same spot again and again may be one of the most important applications of the micro-endoscope. “You could use it to see if drugs are having an effect, such as whether a tumor is responding to treatment,” she says.
In their initial experiments, the Stanford researchers examined neural structures in the hippocampus, one of the only places in the brain where new neurons are born in adulthood. Schnitzer hypothesized that, because of this close proximity to new cells, these structures would change with the formation of new memories. “But that’s not what we found,” he says. “After looking at more than 4,000 dendrites, we saw very few instances of change.”
In a second set of experiments designed to see how the brain changes in response to disease, Schnitzer’s team injected cancer cells into one side of a mouse’s brain. These cells then grew into tumors, allowing scientists to observe the changes in blood vessels that accompany cancer. Researchers found that the vessels on the cancerous side of the brain were unstable, and blood flow slowed down. The healthy side of the brain remained stable.
Emily Singer is the biomedicine editor of Technology Review.
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