Wireless miniature microscope opens up new applications

Why the Free Bird Sings

A team of investigators at Boston University has designed a miniature microscope that allows them to monitor brain activity in freely behaving animals – including the pint-size songbird. The microscope uses an open-source approach so researchers can build it themselves, adapting the design to suit their specific needs.

miniscope illo

The project was a response to a growing need in neuroscience: an ability to perform optical imaging in unconstrained animals, to see what’s happening at the cellular level as they go about their daily business.

“Most of the interesting things that animals do involve running around and exploring and interacting with other animals,” says Daniel Leman, a researcher at BU and one of the developers of the technology. “We wanted to be able to watch this but the commercially available microscopes didn’t have all the features we needed, and their closed design meant we couldn’t tweak them to offer those features.”

Specifically, Leman and colleagues wanted to study a particular region of the brain in zebra finches – an especially loud and spirited species of songbird. Their goal: to track individual neurons over weeks and months as the birds performed their songs time and time again, so they could better understand learning-related changes in that part of the brain.

The researchers knew they had several options for the study. One was to use a conventional microscope, with the birds restrained to enable accurate monitoring. Here, though, they would have needed to train the birds – since few will sing unprompted when they cannot move freely – while the use of constraints might have precluded study of motor activity in the brain.

This led them to try miniature microscopes, which would allow them to study the finches’ behavior in “the most authentic way possible.” They tested a couple of commercial instruments they had borrowed from other labs in BU’s Department of Biomedical Engineering but these didn’t offer all of the features they needed. So they did what any good engineer would do: they decided to design their own.

A tinker set for biomedical researchers

The researchers described their microscope in a Journal of Neural Engineering paper published earlier this year; Will Liberti, who originally cooked up the idea for the microscope, is the first author of the paper. Developed for single-photon fluorescence imaging in freely behaving animals, the instrument includes all of the features the researchers wanted. It is light enough (less than 1.8 grams) to use with zebra finches, it is flexible, and it can be used either wirelessly or in conjunction with active commutators. Importantly, it was designed so other research groups could make their own instruments, both inexpensively and relatively easily.

To this end, the researchers came up with a design that uses off-the-shelf components and 3D-printed parts. The off-the-shelf components used in the microscope are especially affordable thanks to advances in consumer-grade electronics in the cellular and telecommunications industries, which have driven costs down across the board. The use of a 3D-printed parts means the microscope body can be built inexpensively and to the users’ precise specifications.

And with the open-source approach, users can download the initial design from the web and then tweak it as need be. “It’s all very customizable, all very hack-able,” says Ian Davison, a researcher at BU and another of the microscope’s developers. “I like to think of it as a tinker set. We provide the materials and people can toggle it as they see fit to answer their own questions.” It doesn’t take much to assemble a microscope. After a little bit of practice, users can do so in maybe half an hour.

A huge step forward in wearable technologies

The miniature microscope has already fulfilled its promise for the BU group. Using what amounts to birdsong-triggered data acquisition, the researchers have been able to perform around-the-clock studies in the zebra finches, collecting anywhere from 400 to 1,000 song motifs per day and building a rich longitudinal sample of brain activity at cellular resolution. This data will go a long way toward advancing our understandings of how the brain codes for the learning behaviors.

The potential applications extend well beyond the study of birdsong, though. The miniature microscope really represents a huge step forward in the evolution of wearable technologies, technologies that can help to answer a host of questions that were previously essentially unanswerable.

Davison describes, for example, a burgeoning interest in olfactory processing. In rodents, many social behaviors – those that involve the animals smelling each other to intuit gender, reproductive status, etc. – are often mediated by chemicals. The challenge in studying these processes has always been how to image the relevant part of the brain while the animals are engaging in these behaviors.

The researchers didn’t just stop with designing the microscope. Supported by a grant from NIH, they are also actively working to disseminate the technology, to get it into the hands of other groups so those groups can use it to tackle their own unique sets of challenges. They have been offering training sessions at BU – three different labs in the Department of Biomedical Imaging are now using the microscopes in their work – and sharing the technology with other group across the country, including groups at Harvard, MIT and Duke University.

Now, the Neurophotonics Center is supporting the broader dissemination of the wearable technology, both across BU and beyond. Further, the Center is working with Davison, Gardner and other faculty to expand its capabilities, including improving the spatial and temporal resolution and cellular specificity. Advances in several different areas of interest are expected in the near future, such as two-color imaging, patterned illumination and wearable multi-photon microscopy. More details can be found here.

Gary Boas

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