Unraveling the connections between the brain and gut

Newswise — CAMBRIDGE, MA -- The brain and the digestive system maintain continuous communication, transmitting signals that regulate eating and other actions. This vast network of communication also impacts our psychological condition and has been linked to numerous neurological disorders.

MIT engineers have recently developed an innovative technology capable of investigating those interconnections. By employing fibers containing diverse sensors and incorporating light sources for optogenetic stimulation, the team has successfully demonstrated their ability to manipulate neural circuits linking the gastrointestinal system and the brain in mice.

In a recent study, the scientists exhibited their ability to elicit sensations of satiety or incentive-driven behavior in mice by manipulating intestinal cells. In their forthcoming research, they aim to investigate the connections observed between digestive well-being and neurological disorders like autism and Parkinson's disease.

Polina Anikeeva, the Matoula S. Salapatas Professor in Materials Science and Engineering, a professor of brain and cognitive sciences, associate director of MIT's Research Laboratory of Electronics, and a member of MIT's McGovern Institute for Brain Research, expresses enthusiasm about the breakthrough, stating, "The remarkable aspect is that we now possess technology capable of influencing gut function and behaviors such as feeding. What's even more significant is our ability to explore the intricate communication between the gut and the brain using optogenetics with millisecond precision, even in active animals."

Anikeeva serves as the senior author of the recently published study, featured in Nature Biotechnology. The primary contributors to the paper are Atharva Sahasrabudhe, a graduate student from MIT, Laura Rupprecht, a postdoctoral researcher from Duke University, Sirma Orguc, a postdoctoral researcher from MIT, and Tural Khudiyev, a former postdoctoral researcher from MIT.

The brain-body connection

In the previous year, the McGovern Institute introduced the K. Lisa Yang Brain-Body Center, dedicated to investigating the dynamic relationship between the brain and other bodily organs. The center's research endeavors revolve around understanding how these intricate interactions influence behavior and overall well-being, aiming to pave the way for future treatments for a range of diseases.

Anikeeva emphasizes the ongoing and reciprocal communication between the body and the brain, stating, "There is constant, two-way interaction between the body and the brain. For a considerable period, we believed that the brain acted as a commanding force, sending instructions to the organs and overseeing everything. However, we now understand that there is significant feedback from the body to the brain, which potentially regulates functions previously attributed solely to central neural control."

As the director of the newly established center, Anikeeva was particularly intrigued by investigating the signals exchanged between the brain and the enteric nervous system, which is the nervous system of the gut. She focused on understanding how sensory cells within the gut impact feelings of hunger and satiety through a combination of neuronal communication and hormone release.

Deciphering the complex interplay of hormonal and neural effects has posed challenges due to the lack of an efficient method for swiftly measuring the rapid neuronal signals that transpire within milliseconds.

Sahasrabudhe, who spearheaded the creation of the gut and brain probes, explains the motivation behind their development, stating, "In order to conduct gut optogenetics, observe its impact on brain function and behavior with millisecond precision, we realized that the required device was non-existent. Consequently, we made the decision to create it ourselves."

The researchers devised an electronic interface comprising flexible fibers capable of performing diverse functions, which can be inserted into targeted organs. Sahasrabudhe employed a method called thermal drawing to fabricate these fibers. This technique enabled him to create polymer filaments, with a thickness comparable to that of a human hair, that could be embedded with electrodes and temperature sensors.

The polymer filaments not only incorporate electrodes and temperature sensors but also feature microscale light-emitting devices. These light-emitting devices serve the purpose of optogenetically stimulating cells. Additionally, the filaments contain microfluidic channels designed for drug delivery purposes.

The mechanical characteristics of the fibers can be customized to suit various body regions. Specifically, the researchers developed stiffer fibers suitable for navigating deep into the brain. In contrast, for digestive organs like the intestine, they designed more flexible and resilient fibers that would not harm the organ lining while enduring the challenging conditions within the digestive tract.

Sahasrabudhe emphasizes the need for technological advancements to facilitate the exploration of brain-body interactions. Specifically, the development of interfaces capable of simultaneously connecting with targeted organs and the brain, while ensuring accurate recording of physiological signals with a high signal-to-noise ratio, is essential. Furthermore, the ability to selectively stimulate various cell types within both organs in mice is crucial for behavioral testing and conducting causal analyses of the underlying circuits.

Additionally, the fibers have been designed with wireless control capabilities, enabling external manipulation through an attached control circuit. This wireless control circuit was created by Orguc, a Schmidt Science Fellow, and Harrison Allen '20, MEng '22, who received guidance from both the Anikeeva lab and the lab of Anantha Chandrakasan, the dean of MIT's School of Engineering and the Vannevar Bush Professor of Electrical Engineering and Computer Science. During experiments, this control circuit can be temporarily affixed to the animal, allowing for remote control of the fibers.

Driving behavior

Utilizing this interface, the researchers conducted a series of experiments demonstrating their ability to impact behavior by manipulating both the gut and the brain. Through their interventions, they successfully showcased the profound influence exerted on behavior when these two systems were manipulated simultaneously.

Initially, the researchers utilized fibers to administer optogenetic stimulation to a specific region in the brain known as the ventral tegmental area (VTA), responsible for dopamine release. They conducted an experiment using mice by placing them in a three-chambered cage. Whenever the mice entered a particular chamber, the scientists activated the dopamine neurons. Consequently, the mice experienced a surge of dopamine, increasing their inclination to revisit that specific chamber in pursuit of the rewarding dopamine stimulus.

Subsequently, the researchers proceeded to investigate whether they could elicit the same reward-seeking behavior by influencing the gut. To accomplish this, they employed gut fibers to release sucrose, which in turn activated dopamine release in the brain and motivated the animals to seek the chamber in which the sucrose was administered.

In a collaborative effort with colleagues from Duke University, the researchers made a significant discovery. They found that they could replicate the reward-seeking behavior without using sucrose. Instead, they opted to directly stimulate nerve endings in the gut through optogenetics. These nerve endings transmit signals to the vagus nerve, a crucial regulator of digestion and other bodily functions. By stimulating these specific nerve endings, the researchers were able to induce the same reward-seeking behavior observed in the previous experiment.

Anikeeva states that once again, we are witnessing the occurrence of place preference behavior, which has been previously observed through brain stimulation. However, this time, we are not directly interacting with the brain. Instead, we are stimulating the gut and observing how central functions can be controlled from the periphery.

Sahasrabudhe collaborated closely with Rupprecht, a postdoctoral researcher in Professor Diego Bohorquez's team at Duke University, to examine the efficacy of the fibers in regulating feeding behaviors. Their investigations revealed that the implanted devices were capable of optogenetically stimulating cholecystokinin-producing cells, which are responsible for promoting feelings of satiety. By activating the release of this hormone, the animals' appetites were suppressed, even after undergoing a fasting period of several hours. Furthermore, the researchers replicated a similar outcome by stimulating cells that produce a peptide called PYY, which typically reduces appetite following the consumption of high-calorie foods.

With the successful development of this interface, the researchers have set their sights on investigating neurological disorders that are thought to involve a connection between the gut and the brain. One such condition is autism, where studies have indicated a higher prevalence of gastrointestinal (GI) dysfunction among affected children compared to their peers. Additionally, there is a shared genetic risk between anxiety and irritable bowel syndrome (IBS). Consequently, the researchers intend to utilize this interface to delve into these neurological disorders and gain a deeper understanding of their underlying mechanisms and potential gut-brain interactions.

Anikeeva highlights that with the advancement of this interface, researchers can now pose the question: Are the observed connections between the gut and the brain merely coincidental, or is there indeed a genuine link? This newfound ability to stimulate peripheral circuits without directly interacting with the brain provides an opportunity to explore the potential of leveraging gut-brain circuits for managing certain conditions. By manipulating these peripheral circuits in a less invasive manner, there may be prospects for effectively addressing and managing these conditions.

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The research was funded, in part, by the Hock E. Tan and K. Lisa Yang Center for Autism Research and the K. Lisa Yang Brain-Body Center at the McGovern Institute, the National Institute of Neurological Disorders and Stroke, the National Science Foundation (NSF) Center for Materials Science and Engineering, the NSF Center for Neurotechnology, the National Center for Complementary and Integrative Health, a National Institutes of Health Director’s Pioneer Award, the National Institute of Mental Health, and the National Institute of Diabetes and Digestive and Kidney Diseases.