Most of us don’t think much about why we feel full after a big holiday meal, why we cough when we breathe in campfire smoke by accident, or why we feel sick all of a sudden after eating something poisonous.

Such sensations are essential for survival, though, as they let us know what our bodies are in need of at any particular time, allowing us to swiftly alter our behavior.

Basic physical sensations, also known as internal senses, are produced when the brain receives and interprets information from internal organs. However, traditionally, very little research has been devoted to comprehending these internal senses.

The basic biology of internal organ sensing, which involves a complex cascade of intracellular communication between cells, has now been better understood by a team led by experts at Harvard Medical School.

In a study performed on mice and published today in Nature, the team used high-resolution imaging to show spatial maps of how neurons in the brain stem react to input from internal organs.

Whether the information is mechanical or chemical in origin, they discovered that feedback from various organs activates distinct clusters of neurons. These clusters of neurons, which correspond to various organs, are topographically organized in the brain stem. Additionally, scientists found that the brain’s inhibition plays a crucial part in enabling neurons to respond to organs specifically.

Leading author Chen Ran, a research fellow in cell biology at HMS, said, “Our study reveals the fundamental principles of how different internal organs are represented in the brain stem.”

Understanding the communication between internal organs and the brain will take more investigation. However, if the results are replicated in additional species, such as humans, they may enable researchers to create more effective treatment plans for illnesses brought on by malfunctioning internal sensing, such as eating disorders, hypertension, diabetes, pulmonary conditions, and overactive bladder.

According to senior author Stephen Liberles, professor of cell biology at the Blavatnik Institute at HMS and a researcher at the Howard Hughes Medical Institute, “understanding how sensory inputs are encoded by the brain is one of the great mysteries of how the brain works.” It advances knowledge of how perceptions are produced and behaviors are elicited by the brain.

Poorly studied

Scientists have been researching how the basic senses of sight, smell, hearing, taste, and touch—which we use to navigate the world—are formed by the brain’s processing of external information for almost a century. They’ve gathered their research over time to demonstrate how the brain’s many sensory regions are set up to represent distinct stimuli.

In the mid-1900s, for example, study on touch led scientists to create the cortical homunculus for the somatosensory system. This is an illustration of cartoonish body parts draped over the surface of the brain, with each part aligned with the area where it is processed and drawn to scale based on sensitivity. David Hubel and Torsten Wiesel, both professors at Harvard, won a Nobel Prize in 1981 for their work on vision. They carefully mapped the visual cortex of the brain by recording the electrical activity of individual neurons in response to visual stimuli. In 2004, another pair of scientists won the Nobel Prize for their research on the olfactory system. They found hundreds of olfactory receptors and showed exactly how odor inputs are arranged in the nose and brain.

But up until now, it has been unclear how the brain perceives and organizes feedback from the body’s organs to control fundamental physiological processes like breathing, heart rate, blood pressure, nausea, and pain.

It has been remarkably understudied and poorly understood how the brain receives information from the body and how it interprets those impulses, according to Liberles.

“How the brain receives inputs from within the body and how it processes those inputs have been vastly understudied and poorly understood,” Liberles adds.

Contrarily, internal organs transmit information via mechanical forces, hormones, nutrition, toxins, temperature, and more—each of which can operate on several organs and result in a variety of physiological reactions. Mechanical stretch, for instance, communicates the need to urinate when it affects the bladder, but it signifies satiation when it affects the stomach and sets off a reflex to halt breathing when it affects the lungs.

A group of nerve cells.

The nucleus of the solitary tract, or NTS, is a part of the brain stem that Liberles, Ran, and associates focused on in their most recent study.

The vagus nerve is known to transmit sensory data from internal organs to the NTS. Higher-order brain areas that control physiological reactions and produce behaviors receive this information from it and pass it to them. Thus, the NTS acts as the brain’s internal sensory gateway.

Two-photon calcium imaging is a potent method that monitors calcium levels in individual brain neurons as a stand-in for neuronal activity.

The team used this method on mice that were exposed to different kinds of internal organ stimulation. They used a microscope to record the responses of thousands of neurons in the NTS at the same time over time. The resulting clips show neurons lighting up all over the NTS, just like stars in the night sky that blink on and off.

Traditional imaging methods, such as inserting an electrode to record a small group of neurons at a single time point, “are like seeing only a couple pixels at a time,” Ran said.

“Our technique is like seeing all the pixels at once to reveal the entire image in high resolution.”

The team found that different parts of the body, like the stomach or the larynx, tend to stimulate different groups of neurons in the NTS. On the other hand, the researchers found several cases in which mechanical and chemical stimuli in the same organ that often cause the same physiological response (like coughing or feeling full) activated neurons in the brain stem that was already active. These results imply that certain neural networks may be dedicated to representing different organs.

The researchers also found that responses in the NTS were organized in the form of a spatial map, which they called the “visceral homunculus” as a reference to the similar cortical homunculus that was discovered decades ago.

Lastly, the scientists found that neurons need to be turned off for signals to be sent from organs to the brain stem. When they employed medications to block inhibition, neurons in the brain stem lost their prior selectivity and started to respond to a variety of organs.

According to Ran, the discovery lays the groundwork for “systematically studying the coding of internal senses throughout the brain.”

The groundwork for the years to come

The results bring up a lot of fresh issues, some of which the HMS team would like to address.

Ran is interested in determining how the brain stem transmits sensory data from within to higher-order brain areas, which then cause the associated sensations, such as thirst, discomfort, or hunger.

Liberles is interested in finding out more about the molecular mechanisms of the internal sensory system. He is interested in finding out specifically which organs’ main sensory receptors are responsible for detecting mechanical and chemical stimuli.

The configuration of the system throughout embryonic development is another topic for further study. According to the current research, it is important for scientists to take into account neurons’ locations throughout the brain as well as their type.

To comprehend how the circuits are wired and what the various cell types accomplish in the context of various circuits, he stated that it is necessary to investigate how different neuron types and their placements interact.

Liberles is particularly curious to see whether the results apply to people as well as other animals. He pointed out that while many sensory pathways are shared by numerous species, there are also significant evolutionary variances. Some animals, for instance, don’t display simple actions like coughing or throwing up.

If the research findings are validated in humans, they may potentially aid in the development of better treatments for illnesses that develop when the internal sensory system is impaired.

“Oftentimes these diseases occur because the brain receives abnormal feedback from internal organs,” Ran adds. “If we have a good idea of how these signals are differentially encoded in the brain, we may someday be able to figure out how to hijack this system and restore normal function.”

Source: 10.1038/s41586-022-05139-5

Image Credit: Getty

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