Mini Microscope Watches Mouse Brain Cell Activity

A microscope small enough to be mounted to the head of a freely moving mouse makes it possible to watch brain cell activity and whole animal behavior simultaneously in mice. The device offers researchers a new way to study of human diseases using transgenic mice. (Videos after the jump)


Since researchers created the first transgenic mice in the 1980s, the mouse has become the lab animal of choice for medical research. There are now mouse “models” for a wide range of human genetic disorders, from Parkinson’s to asthma.

But correlating the activity inside cells with the behavior of an animal as a whole is still a challenge, says Mark Schnitzer at Stanford University.
Cell spotter

“A lot of work has been done using brain slices, or anesthetized animals – even using animals that are awake but restrained,” he says. But so far it has been impossible to image cellular-level activity in a freely moving mouse.

Schnitzer’s team has now made it possible. They designed a tiny microscope weighing just 1.1 grams that can be worn by a mouse without significantly impairing its movement. The device has already been used to study the circulation of blood through the one-cell-wide capillaries in the brain of active mice.

The microscope is attached to the head of a mouse under anesthetic, while a marker dye is injected into the brain to label blood plasma, but leave blood cells unaffected. The microscope uses light delivered by a mercury arc lamp through a bundle of optical fibres.


 The entire neural network of a mouse’s brain has been seen in 3D for the
first time, using a new technique that renders tissues transparent.

Light from the lamp causes the dyed blood plasma to fluoresce, showing up individual blood cells as dark spots. The image is sent back up the fiber-optic bundle to a camera that records the image.

Roughly 100 images are taken every second, allowing the researchers to watch high-speed video of individual blood cells flowing in the brain. Once the mouse wakes up from the anesthetic, it is possible to watch the movement of cells as it behaves normally.
Limited range

Using the technique with a dye that makes the activity of brain cells visible, the researchers could see how Purkinje neurons, involved in controlling movement, become more active when a mouse is moving than when resting.

“The advance here is we are able to look at cells in [moving] animals and we can do this in mice – the mammalian species of choice from the perspective of having advanced genetic techniques,” says Schnitzer. “So we can look at mouse disease models and see what the cells are doing at the same time as we monitor what the mouse is doing.”

Carl Petersen at the Swiss Federal Institute of Technology in Lausanne, Switzerland, is also interested in studying cellular activity in active mice. “It is a good advance,” he told New Scientist, but the approach can’t look at all kinds of brain activity.

The brain scatters light extensively, meaning only cells relatively near to the microscope, labeled with dye, can be imaged. “This was not a big problem for the current study where they look at very brightly labeled structures with very high contrast,” he says. “However, there are very few structures in the brain that are organized in this way.”

But Schnitzer disagrees that the technique can only be used to study high contrast structures – he points out that the new microscope detects changes in fluorescence as small as 0.5%.