The unique mini microscope offers insights into complex brain functions

Researchers at the Twin Cities College of Science and Technology and the University of Minnesota Medical School have developed a unique head-mounted miniature microscope that allows them to map complex brain functions of freely moving mice in real time over a period of more than 300 days.

Known as the Mini-MScope, the device provides an important new tool for studying how neural activity from multiple regions of the outer part of the brain called the cortex contribute to behavior, cognition, and perception. The groundbreaking study offers new insights into basic research that could improve human brain diseases such as concussions, autism, Alzheimer's and Parkinson's, as well as better understand the brain's role in addiction.

The researchers developed the miniaturized, head-mounted microscope for examining the mouse brain with LEDs for lighting, miniature lenses for focusing, and a complementary metal-oxide semiconductor (CMOS) for capturing images. It contains interlocking magnets that allow it to be easily attached to structurally realistic 3D-printed transparent polymer skulls (see shells) that researchers developed in previous studies. Photo credit: Rynes and Surinach et al., Kodandaramaiah Lab, University of Minnesota

The Research was published in the journal Nature Methods. The authors of the study will also present their research results at the virtual 2021 OSA Biophotonics Congress: Optics in the life sciences.

In the past, scientists have studied how neural activity in certain regions of the cerebral cortex contributes to behavior. However, it was difficult to study the activity of several cortical regions at the same time. For mice, even the simple task of moving a single whisker in response to a stimulus is to process information in multiple cortical areas. Mice are often used to study the brain because they share many of the same brain structures and connectivity as humans.

"With this device, we can image most of the mouse's brain in free and unrestrained behavior, whereas previous mesoscale imaging was usually done on immobile mice with devices such as MRIs or two-photon microscopes," said Suhasa Kodandaramaiah, chief executive Study author and University of Minnesota Benjamin Mayhugh Assistant Professor of Mechanical Engineering at the College of Science and Engineering. “With this new device, we can understand how different areas of the brain interact in complex behaviors where multiple areas of the brain work together at the same time. This opens up research to understand how connectivity changes in disease states, traumatic brain injuries, or addiction. "

The new Mini-MScope is a fluorescence microscope that can image an area of ​​around 10 x 12 millimeters and weighs around 3 grams. This enables a holistic image of a large part of the mouse's brain surface. The device is used for calcium imaging, a technique commonly used to monitor electrical activity in the brain. Attached to the head of the mouse, the device captures images almost at the cellular level, making it possible to study connections between regions throughout the cortex.

The researchers developed the miniaturized microscope with LEDs for lighting, miniature lenses for focusing and a complementary metal oxide semiconductor (CMOS) for recording images. It contains interlocking magnets that allow it to be easily attached to structurally realistic 3D-printed transparent polymer skulls (see shells) that researchers developed in previous studies. When implanted in mice, the see-shells create a window through which long-term microscopy can be performed. The new microscope can record the brain activity of mice for almost a year.

The researchers demonstrated the Mini-MScope by using it to map the mouse's brain activity in response to a visual stimulus for the eye, a vibration stimulus for the hind leg, and a somatosensory stimulus for the whisker. They also created functional connectivity maps of the brain when a mouse wearing the head-mounted microscope interacted with another mouse. They saw that intracortical connectivity increased when the mouse behaved socially with the other mouse.

"Our team is creating a set of tools that will allow us to access and communicate with large parts of the cortex with high spatial and temporal resolution," said Mathew Rynes, Ph.D. Candidate who co-directed the study. "This study shows that the Mini-MScope can be used to study functional connectivity in freely behaved mice, making it an important contribution to this toolkit," added Rynes.

The team had to overcome several technical challenges to create the device.

"In order to map the brain in freely behaving mice, the device had to be light enough to be carried and carried by the mice," said Daniel Surinach, a recently completed master's degree in mechanical engineering from the University of Minnesota who also conducted the study co-led. “In this small area, we also had to tweak the resolution of the optics, electrical hardware and imaging hardware, focus and lighting designs to provide the brain with light for imaging, and other elements to get clear images of natural and vigorous behaviors of the mouse brain. In the end, we designed and tested 175+ unique prototypes to get the final device working! "

Researchers are now using the Mini-MScope to study how cortical connectivity changes in a variety of behavioral paradigms, such as exploring a new space. They also work with staff using the Mini-MScope to study how cortical activity changes as mice learn difficult motor tasks.

"With this device, we can examine the brain in ways we could never have done before," said Kodandaramaiah, who also holds appointments with the University of Minnesota Department of Biomedical Engineering and Medical School. “For example, we can imagine the brain activity of the mouse as it drains and drains during natural movement in its space, when falling asleep and when waking up. This provides a lot of valuable information to help us better understand the brain, to help people with illness or injuries improve their lives. "

The researchers said the next steps are to improve the resolution of the imaging and examine the brain down to the finest detail, down to examining individual neurons.

Source: University of Minnesota

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