New Study Demonstrates How Autonomic Neurons Control Digestive Functions

The autonomic nervous system orchestrates the functions of internal organ such as the heart and gut, serving as a connection between the brain and the rest of the body. It is classified in two divisions—the sympathetic and parasympathetic systems, often described as the body's accelerator and brake, respectively. For example, the sympathetic nervous system activates the "fight-or-flight" response in reaction to danger, concentrating energy on immediate survival and halting less urgent functions such as digestion.

Now, a new study from Caltech uncovers diverse neuron populations within the sympathetic nervous system and reveals how they control visceral functions in an organ-specific manner.

The research, appearing in the journal Nature on November 27, was led by graduate student Tongtong Wang and conducted in the laboratory of Yuki Oka, professor of biology and Heritage Medical Research Institute Investigator. Research in the Oka lab focuses on understanding how the brain and body cooperate to maintain a healthy internal balance. In 2022, the team discovered a body-to-brain system that transmits signals about hydration levels. But the mechanisms by which the brain regulates other body functions, such as the fight-or-flight response, have long eluded scientists.

"The anatomy and function of the autonomic system has been known for over a century, but we have surprisingly little understanding of cellular and functional diversity of autonomic neurons," Oka says.

While the central nervous system comprises neurons in the brain and spinal cord, the sympathetic, or peripheral, autonomic nervous system consists of neurons in ganglia (groups or clusters) throughout the body, innervating regions like the gut and heart. Although advanced techniques have been developed to study neurons in the brain, examining autonomic neurons in the periphery has been more challenging.

Traditionally, the sympathetic nervous system has been seen as a uniform network broadly influencing organ functions. This new research challenges that paradigm and illustrates how specific parts of the sympathetic system do unique jobs.

In the new study, Wang combined two molecular techniques, single-cell RNA sequencing and spatial transcriptomic analysis, to examine the gene expression patterns of cells in the major sympathetic ganglia that innervate abdominal organs, such as the intestines, in mice. Interestingly, the team found at least two distinct neuron populations expressing different sets of genes. Further investigation using genetically modified mice revealed that one of these neuronal groups targets the gastrointestinal tract, while the other projects to secretory areas including the pancreas and bile tract. "Discovering the diverse sympathetic neuron populations with organ-specific innervation was electrifying, because it allows for precise control and modulation of body functions," Wang says.

The team next aimed to understand how these distinct neuron types causally influence physiological processes. They first focused on the secretion of bile, a fluid produced in tiny volumes by the liver and released into the intestine for fat digestion. Collaborating with researchers in the laboratory of Caltech's Wei Gao—professor of medical engineering, Heritage Medical Research Institute Investigator, and Ronald and JoAnne Willens Scholar—the team developed a microfluidic device capable of detecting nuanced changes in bile secretion at the nanoliter level, in vivo. By employing genetic perturbation tools to selectively activate each unique neuron population, they found that one sympathetic neuron class suppressed digestive secretion while increasing release of glucagon, a hormone crucial for boosting blood sugar levels. Notably, the other class of neurons independently inhibited gut motility—the squeezing of intestinal muscles to push food along.

"It was like flipping switches in a complex machine and watching how each part responds," Wang explains.

Oka adds, "The modular arrangement we uncovered means that the body can fine-tune each organ's activity without affecting others. It's a level of control that we did not fully appreciate before."

This discovery has profound implications for understanding and treating various medical conditions. Many diseases involve dysfunction in specific organs, and understanding the dedicated neural pathways opens up new therapeutic possibilities.

Although the sympathetic nervous system is perhaps best known for responding to threats like predators, other stressors such as low glucose levels in the body can also activate sympathetic neurons. More studies are needed to understand the complex brain-to-body signaling pathways that process, integrate, and respond to the various stress signals.

"This work would not have been feasible without the inquisitive, open and collaborative environment at Caltech," Wang says.

The paper is titled "Organ-specific Sympathetic Innervation Defines Visceral Functions." In addition to Wang and Oka, co-authors are Caltech postdoctoral scholar Bochuan Teng, graduate student Dickson (Richard) Yao, and Gao. Funding was provided by Caltech; the New York Stem Cell Foundation; the National Institutes of Health; the Alfred P. Sloan Foundation; the Edward Mallinckrodt, Jr. Foundation; and the Heritage Medical Research Institute. Yuki Oka is an affiliated faculty member with the Tianqiao and Chrissy Chen Institute for Neuroscience at Caltech.