Researchers devise new tools for enteric neuromodulation

by James Cavuoto, editor

November 2022 issue, BioElectRx Business Report

Neural engineering researchers are developing a range of new tools and technologies for stimulating the enteric nervous system, a network of peripheral nerves that play a major role in the gut-brain connection. Polina Anikeeva from MIT gave an overview of progress in this area in a special lecture at the Neuroscience 2022 meeting in San Diego, CA earlier this month.

In her talk, Anikeeva described several forms of nanotechnology to connect molecular function in the gastrointestinal system to neural circuit dynamics and behavior. “There are a billion neurons in the enteric nervous system—the nervous system of the gut,” she said. “The question is, how does their sensory processing contribute to the function of the brain?”

One of the challenges in answering that question is the mechanical complexity of the gut. While the brain moves microscopically during movement, the gut moves macroscopically and experiences significant deformations, Anikeeva said. The innervation within the gut wall is extremely fragile, and any damage caused by an implanted device could produce a serious immune reaction. Compounding this, the GI tract presents a challenging chemical environment full of nutrients—and fecal matter for that matter. Designing a bioelectronic medicine tool that doesn’t damage that environment is extremely important.

One technological approach the MIT team has used is stretchable polymer fibers that can undergo deformation in concert with gut tissue. These thin fibers would be a key component of a luminal gut optogenetic system. Anikeeva’s colleague Atharva Sahasrabudhe at MIT added solid state microcomponents such as tiny LEDs to the fibers to act as sensors. “We can use these devices wirelessly to control both ends of our device—at the gut and the brain—independently,” Anikeeva said.

Diego Bohorquez and his colleagues at Duke University identified sensory enteroendocrine cells they called “neuropod cells” that are capable of forming synapses with vagal afferents to transduce gut luminal signals to the brainstem in milliseconds. To demonstrate that, the investigators showed that they were able to reverse a mouse’s taste preference for sucrose over sucralose simply by inhibiting the activity of the neuropad cells at the level of the duodenum.

Another approach the MIT team used to probe and modulate the enteric nervous system at the molecular level involved magnetic energy. “There’s only one form of energy that can penetrate through the skull, the skin, the fur, and go arbitrarily deep anywhere int the body and that’s a magnetic field,” Anikeeva said. But the team needed to find a way to deliver magnetic energy sufficient to activate the mechanoreceptors in the gut wall without interfering with the functioning of a behaving organism.

To solve that problem, they borrowed concepts of magnetic memory used by the disc drive industry. Some anisotropic materials are capable of producing a magnetic state called the vortex, in which all the spins of atoms are aligned in a circle, resulting in a total magnetic moment of 0. But in the presence of a very weak magnetic field, all the spins orient in a plane, yielding a type of lever to pull on the neuronal membrane to apply a mechanical torque. These magnetic nanodiscs produce a calcium influx in the sensory neurons when a magnetic field is present. The technique can also be used to activate heat receptors such as the capsaicin receptor TRPV1.

“We can use physical principles to design tools that mimic nerves and allow us to modulate and record neural activity across circuits and cells. We can use magnetic nanotransducers to approach the level of receptors and ion channels to understand molecular signaling and its relationship to behavior and physiology,” Annikeeva concluded.


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