Implanted wireless device allows mice to form an instant link


The fully implantable wireless device enables ontogenetic research in unattached animals with dynamically programmable operation. Credit: Northwestern University

First study based on the optogenetics of unlimited social interactions within groups of animals.

Northwestern University researchers make social connections with beams of light.

For the first time ever, Northwestern engineers and neurobiologists wirelessly programmed – then deprogrammed – mice to interact socially in real time. The advance is due to an ultraminiature, cordless, battery-free and fully implantable device that uses light to activate neurons.

This study is the first paper on optogenetics (a method of controlling neurons with light) exploring social interactions within groups of animals, which was previously impossible with current technologies.

The research will be published on May 10 in the journal Neuroscience of nature.

The slim, flexible and wireless nature of the implant allows mice to appear normal and behave normally in realistic environments, allowing researchers to observe them under natural conditions. Previous research using optogenetics required fiber optic wires, which restricted mouse movements and caused them to become entangled during social interactions or in complex environments.

The video shows the social preferences of mice when they are synced and then unsynchronized. Credit: Northwestern University

“With previous technologies, we were unable to observe multiple animals interacting socially in complex environments because they were attached,” said Northwestern neurobiologist Yevgenia Kozorovitskiy, who designed the experiment. “The fibers would break or the animals would get tangled. In order to ask more complex questions about animal behavior in realistic environments, we needed this innovative wireless technology. It’s great to get away from the ties.

“This article represents the first time that we are able to realize wireless and battery-less implants for optogenetics with full and independent digital control of several devices simultaneously in a given environment,” said the bioelectronics pioneer of the Northwest, John A. Rogers, who led the development of the technology. “Brain activity in an isolated animal is interesting, but going beyond research on individuals to study complex and socially interacting groups is one of the most important and exciting frontiers in neuroscience. We now have the technology to study how bonds form and break between individuals in these groups and to examine how social hierarchies arise from these interactions.

Kozorovitskiy is Soretta and Henry Shapiro Research Professor in Molecular Biology and Associate Professor of Neurobiology at Northwestern’s Weinberg College of Arts and Sciences. She is also a member of the Institute for Chemistry of Life Processes. Rogers is the Louis Simpson and Kimberly Querrey Professor of Materials Science and Engineering, Biomedical Engineering, and Neurological Surgery at the McCormick School of Engineering and Northwestern University Feinberg School of Medicine and Director of the Querrey Simpson Institute for Bioelectronics.

Kozorovitskiy and Rogers led the work with Yonggang Huang, Professor Jan and Marcia Achenbach in Mechanical Engineering at McCormick, and Zhaoqian Xie, Professor of Mechanical Engineering at Dalian University of Technology in China. The co-first authors of the article are Yiyuan Yang, Mingzheng Wu, and Abraham Vázquez-Guardado – all at Northwestern.

The Promise and Problems of Optogenetics

Because the human brain is a system of nearly 100 billion intertwined neurons, it is extremely difficult to probe single neurons, or even groups of neurons. Introduced in animal models around 2005, optogenetics makes it possible to control specific and genetically targeted neurons in order to probe them in unprecedented detail to study their connectivity or their release of neurotransmitters. Researchers first modify neurons in living mice to express a modified gene from light-sensitive algae. Then they can use the external light to specifically control and monitor brain activity. Due to the genetic engineering involved, the method is not yet approved in humans.

“It sounds like science fiction, but it’s an incredibly useful technique,” ​​Kozorovitskiy said. “Optogenetics could soon be used to correct blindness or reverse paralysis.”

However, previous optogenetic studies were limited by the technology available to deliver light. Although researchers could easily probe an animal in isolation, it was difficult to simultaneously monitor neuronal activity in flexible models within groups of socially interacting animals. Fiber optic wires typically emerged from an animal’s head, connecting to an external light source. Then software could be used to turn the light off and on, while also monitoring the animal’s behavior.

“As it moved, the fibers were pulling in different ways,” Rogers said. “As expected, these effects changed the animal’s movement patterns. So you have to ask yourself: what behavior are you really studying? Are you studying natural behaviors or behaviors associated with physical stress? “

Real-time wireless control

A globally recognized leader in portable wireless technology, Rogers and his team have developed a small, wireless device that sits gently on the outer surface of the skull but under the skin and fur of a small animal. The half-millimeter thick device connects to a thin, flexible filamentary probe with LEDs on the tip, which descend into the brain through a tiny cranial defect.

The miniature device uses near-field communication protocols, the same technology used in smartphones for electronic payments. Researchers operate the light wirelessly in real time with a user interface on a computer. An antenna surrounding the animal enclosure supplies power to the wireless device, eliminating the need for a bulky and heavy battery.

Activate social connections

To establish the proof of principle for Rogers’ technology, Kozorovitskiy and his colleagues designed an experiment to explore an optogenetic approach to remotely control social interactions between pairs or groups of mice.

When the mice were physically close to each other in an enclosed environment, Kozorovitskiy’s team wirelessly activated a set of neurons synchronously in a region of the brain linked to higher-order executive function, which caused them lead to an increase in the frequency and duration of social interactions. The desynchronization of the stimulation quickly reduced social interactions in the same pair of mice. In a group setting, researchers could bias an arbitrarily chosen pair to interact more than others.

“We didn’t really think it would work,” Kozorovitskiy said. “To our knowledge, this is the first direct evaluation of a long-standing major hypothesis on neural synchrony in social behavior.”

Reference: “Real-time control of wireless multilateral optogenetics for broad neuroscientific applications” May 10, 2021, Neuroscience of nature.
DOI: 10.1038 / s41593-021-00849-x

The study was supported by the National Science Foundation, the National Institutes of Health, and several foundations.

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