Miniature Microscope Captures Neural Activity in Freely Moving Animals

A team of scientists from the University of Colorado Anschutz Medical Campus has developed a miniature microscope capable of capturing neural activity in real time with exceptional speed, allowing imaging in freely moving animals. The tool offers a new way to observe how brain cells process information during natural behavior, providing a window into how electrical signals coordinate complex tasks. 

The microscope was created to visualize genetically encoded voltage indicators—fluorescent dyes that change brightness when neurons fire—through a small cranial window in awake animals. “Unlike most miniature microscopes that track slower calcium signals, ours captures electrical spikes at hundreds of frames per second,” said Emily Gibson lead author of the study published in Biomedical Optics Express. “This makes it possible to capture the moment a neuron fires as well as the quieter signals that build up inside neurons before firing.”

In the study, the researchers describe their compact, high-speed device optimized to detect faint fluctuations in light. Experiments in mice confirmed that the microscope records voltage changes consistent with those seen using standard widefield microscopes, reliably measuring individual neuron activity. Gibson explained that capturing these subtle electrical patterns across multiple brain regions could deepen understanding of how timing and signal strength support cognitive functions such as spatial navigation.

To monitor these rapid voltage changes, the team focused on designing an optical system small enough to remain lightweight without sacrificing performance. “We took a big step toward tackling these constraints by designing a compact, efficient optical system with high numerical aperture and pairing it with a high-speed sensor to reliably detect action potential spiking,” said co-author Juliet Gopinath. “Our microscope enables recording of both the rapid electrical spikes and the smaller sub-threshold voltage changes that occur inside neurons in freely moving animals.”. 

The instrument, named MiniVolt, features a numerical aperture of 0.6, a 250-micron field of view, and a working distance of about 1.3–1.6 mm, all within a total weight of 16.4 grams. Using the improved voltage indicator Voltron2, the MiniVolt captured in vivo spikes with a peak-to-noise ratio greater than 3 at 530 frames per second—comparable in quality to a benchtop microscope.

Future development will aim to decrease the MiniVolt’s weight for use in freely moving mice and to expand its field of view, currently constrained by the light source rather than its optical design.