The brain-gut connection is known to influence hunger and mood, and it has also been associated with neurological and other disorders. To explore the signaling that occurs between these two organs, scientists at MIT integrated light sources, thermal sensors, microelectronics, and microfluidics in a device that enables stable bioelectronic interfaces with the brain and gastrointestinal tract in mice. “To be able to perform gut optogenetics and then measure the effects on brain function and behavior, which requires millisecond precision, we needed a device that didn’t exist. So, we decided to make it,” researcher Atharva Sahasrabudhe said. The multifunctional, microelectronic device provides wireless modulation and optogenetic stimulation of the brain and gut neural circuits. These flexible fibers, which are embedded with sensors and light sources, can be used to manipulate and monitor the connections between the brain and the digestive tract. Courtesy of A. Sahasrabudhe et al., doi: 10.1038/s41587-023-01833-5. “To study the interaction between the brain and the body, it is necessary to develop technologies that can interface with organs of interest as well as the brain at the same time, while recording physiological signals with high signal-to-noise ratio,” Sahasrabudhe said. “We also need to be able to selectively stimulate different cell types in both organs in mice so that we can test their behaviors and perform causal analyses of these circuits.” Using thermal drawing, the scientists developed polymer fibers embedded with solid-state microelectronic components. The microscale fibers contain surface-localized, microscale LEDs (µLEDs) for optogenetics, microscale thermal sensors for precision thermometry, microelectrodes for electrophysiology, and microfluidic channels for drug and gene delivery. The researchers engineered the mechanical properties of the fibers to ensure that the fibers’ architectures were compatible with implantation in the deep-brain and the gastrointestinal tract. They produced stiff, yet flexible, multifunctional fibers to interface with the brain. They designed soft, compliant fibers to withstand the environment of the digestive tract without damaging the digestive organs. To give wireless control of the fibers, the researchers developed a modular wireless control circuit, NeuroStack, to interface with the fibers. The NeuroStack module permits the fibers to deliver programmable light across multiple independent channels in real time, and it allows wireless data transfer for recording the local tissue temperature in the mice. NeuroStack is mounted externally on the animal and uses a Bluetooth protocol without specialized antennas. The team validated the technology through a series of experiments that showed how modulating the brains and guts of the mice influenced their behavior. The researchers used the fibers to deliver optogenetic stimulation to a part of the brain that releases dopamine, a neurotransmitter associated with pleasure and reward. The mice were placed in a cage with three chambers, and when they entered one chamber, the researchers activated the mice’s dopamine neurons. The dopamine burst made the mice more likely to return to the same chamber in search of the dopamine reward. Duke University postdoc Laura Rupprecht, MIT graduate student Atharva Sahasrabudhe, and MIT postdoc Sirma Orguc in the lab. Courtesy of A. Sahasrabudhe et al., doi: 10.1038/s41587-023-01833-5. The researchers then used the fibers interfaced with the gut to release sucrose, a carbohydrate that activates a dopamine release in the brain. The mice responded by seeking out the chamber they were in when the sucrose was delivered, demonstrating that the technology could induce reward-seeking behavior by influencing the gut. Working with colleagues from Duke University, the researchers found that they could generate the same reward-seeking behavior in the mice by skipping the sucrose and optogenetically stimulating nerve endings in the gut that provide input to the vagus nerve, which controls digestion and other bodily functions. “We got this place preference behavior that people have previously seen with stimulation in the brain, but now we are not touching the brain,” professor Polina Anikeeva said. “We are just stimulating the gut, and we are observing control of central function from the periphery. “The exciting thing here is that we now have technology that can drive gut function and behaviors such as feeding,” Anikeeva said. “More importantly, we have the ability to start accessing the crosstalk between the gut and the brain with the millisecond precision of optogenetics, and we can do it in behaving animals.” In tests to determine the fibers’ ability to control feeding behaviors, the researchers found that the fiber-based devices could optogenetically stimulate cells that produce a hormone that promotes satiety. When the hormone was activated, the animals’ appetites were suppressed, even though they had been fasting for several hours. The researchers demonstrated a similar effect when they stimulated cells that produce a peptide that curbs appetite after very rich foods are consumed. The researchers will use the multifunctional, microelectronic fiber technology to study conditions such as irritable bowel syndrome, autism spectrum disorder, and Parkinson’s disease, which are believed to have a gut-brain connection. “There’s continuous, bidirectional crosstalk between the body and the brain,” Anikeeva said. “For a long time, we thought the brain is a tyrant that sends output into the organs and controls everything. But now we know there’s a lot of feedback back into the brain, and this feedback potentially controls some of the functions that we have previously attributed exclusively to the central neural control. “We can now begin asking, are those coincidences, or is there a connection between the gut and the brain? And maybe there is an opportunity for us to tap into those gut-brain circuits to begin managing some of those conditions by manipulating the peripheral circuits in a way that does not directly ‘touch’ the brain and is less invasive,” she said. The research was published in Nature Biotechnology (www.doi.org/10.1038/s41587-023-01833-5).
