To summarize: A new mouse study sheds light on how the brain processes sensory information from internal organs, revealing that feedback from the organs activates distinct clusters of neurons in the brainstem.
Most of us seldom think about why we feel pleasantly full after a holiday meal, why we start coughing after accidentally inhaling campfire smoke, or why we suddenly feel sick after ingesting a toxic substance. Such feelings, however, are essential for survival: they tell us what our bodies need at any given moment so that we can quickly adjust our behavior.
Historically, however, very little research has been devoted to understanding these basic bodily sensations (also known as internal sensations), which arise when the brain receives and interprets input from internal organs.
Now, a team led by Harvard Medical School researchers has made new progress in understanding the fundamental biology of internal organ perception, which involves a complex cascade of communication between cells in the body.
In a study in mice, published Aug. 31 in naturethe team used high-resolution imaging to reveal a spatial map of how neurons in the brainstem respond to feedback from internal organs.
They found that feedback from different organs activates discrete clusters of neurons, whether the information is mechanical or chemical in nature — groups of neurons representing different organs are topographically organized in the brainstem. In addition, they found that inhibition within the brain plays a key role in helping neurons selectively respond to organs.
“Our study revealed the fundamentals of different internal organs in the brainstem,” said lead author Ran Chen, a researcher in cell biology at HMS.
This research is just the first step toward elucidating how internal organs communicate with the brain. However, if the findings are confirmed in other species, including humans, they could help scientists develop better therapeutic strategies for eating disorders, overactive bladder, diabetes, lung cancer caused by faulty internal perception diseases and high blood pressure.
“I think understanding how the brain encodes sensory input is one of the big mysteries of how the brain works,” said senior author Stephen Lieberles, HMS Blavatnik Professor of Cell Biology and a Howard Hughes Medical Institute Investigator. “It helps to understand how the brain generates perception and evokes behavior.”
Insufficient research and little understanding
For nearly a century, scientists have been studying how the brain processes external information to form the basic senses of sight, smell, hearing, taste and touch we use to navigate the world. Over time, they aggregated their findings to show how various sensory areas in the brain are organized to represent different stimuli.
For example, in the mid-1900s, research into touch led scientists to develop the cortical homunculus for the somatosensory system—an illustration depicting cartoon body parts overlaid on the surface of the brain, each positioned in relation to where it is located. Position-aligned processing and scaled according to sensitivity.
In 1981, Harvard professors David Hubel and Torsten Wiesel, who won the Nobel Prize for their work on vision, methodically mapped the brain’s visual cortex 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 work on the olfactory system, where they discovered hundreds of olfactory receptors and revealed exactly how odor input is arranged in the nose and brain.
However, until now, the process by which the brain senses and organizes feedback from internal organs to regulate basic physiological functions such as hunger, satiety, thirst, nausea, pain, breathing, heart rate and blood pressure has remained a mystery.
“How the brain receives inputs from within the body and how it processes those inputs is very little and poorly understood,” Liberles said.
This may be because internal sensing is more complex than external sensing, Ran adds. External senses tend to receive information in a single format, he explained. Vision, for example, is entirely based on the detection of light.
In contrast, internal organs transmit information through mechanical forces, hormones, nutrients, toxins, temperature, etc.—each of which can act on multiple organs and translate into multiple physiological responses. Mechanical stretching, for example, signals the need to urinate when it occurs in the bladder, but translates to satiety when it occurs in the stomach and triggers a reflex to stop inhalation in the lungs.
group of neurons
In their new study, Liberles, Ran and colleagues focused on an area of the brainstem called the nucleus tractus solitarius, or NTS.
It is known that the NTS receives sensory information from internal organs via the vagus nerve. It relays this information to higher-order brain regions that regulate physiological responses and generate behavior. In this way, the NTS acts as the brain’s internal sensory channel.
The researchers used a powerful technique called two-photon calcium imaging, which measures calcium levels in individual neurons in the brain as a proxy for neuronal activity.
The team applied the technique to mice exposed to different types of internal organ stimulation and used microscopy to simultaneously record the responses of thousands of neurons in the NTS over time. The resulting video shows neurons throughout the NTS glowing like stars twinkling in the night sky.
Traditional imaging techniques involve inserting electrodes to record a small group of neurons at a single point in time, “like seeing only a few pixels of the image at a time,” Ran said. “Our technology is like seeing all the pixels at once, displaying the entire image in high resolution.”
The team found that stimulation in different internal organs, such as the stomach and larynx, often activates different clusters of neurons in the NTS. In contrast, the researchers found several situations in which mechanical and chemical stimuli in the same organ often elicited the same physiological response (such as coughing or satiety), activating overlapping neurons in the brainstem. These findings suggest that specific groups of neurons may be specialized to represent specific organs.
In addition, the researchers found that responses in the NTS are organized into a spatial map, which they dubbed the “visceral homunculus,” in homage to the cortical-like homunculus developed decades ago.
Finally, the scientists determined that inhibitory neurons are required for signaling from internal organs to the brainstem. When they blocked inhibition with drugs, neurons in the brainstem began to respond to multiple organs, losing their previous selectivity.
Ran said the work lays the groundwork for a “systematic study of the encoding of senses within the entire brain.”
Lay the foundation for the future
These findings raise many new questions, some of which the HMS team wants to address.
Ran is interested in studying how the brainstem transmits internal sensory information to higher-level brain regions that generate sensations such as hunger, pain or thirst.
Liberles wants to explore how the internal sensing system works at the molecular level. In particular, he wanted to identify the main sensory receptors that detect mechanical and chemical stimuli in organs.
Another area for future research is how to build systems during embryonic development. The new findings show that looking at neuron types alone isn’t enough, Liberus said. Researchers must also consider where neurons are located in the brain.
“We need to study the interactions between neuron types and their locations to understand how these circuits are connected and the roles of different cell types in different circuits,” he said.
Liberles is also interested in how these findings generalize to other animals, including humans. He noted that while many sensory pathways are conserved across species, there are also important evolutionary differences. For example, some animals do not exhibit basic behaviors such as coughing or vomiting.
If confirmed in humans, the findings could eventually inform the development of better treatments for diseases that arise when internal sensory systems malfunction.
“These diseases often occur because the brain receives abnormal feedback from internal organs,” Ran said. “If we have a good understanding of how these signals are differentially encoded in the brain, we may one day be able to figure out how to hijack this system and restore normal function.”
Additional authors include Jack Boettcher, Judith Kaye and Catherine Gallori of HMS.
funds: This work was supported by the National Institutes of Health (grants DP1AT009497; R01DK122976; R01DK103703), the Food Allergy Science Initiative, a Leonard and Isabelle Goldenson Postdoctoral Fellowship, the Harvard Brain Science Initiative, and the American Diabetes Association.
About this Neuroscience Research News
author: Dennis Nealon
touch: Dennis Neillon – Harvard
picture: Image is in the public domain
Original research: Open access.
“A Brainstem Map of Visceral Sensation” by Chen Ran et al. nature
Brain stem map of visceral senses
The nervous system uses various coding strategies to process sensory input. For example, the olfactory system uses a large library of receptors and is connected to recognize different odors, while the visual system provides a high degree of sensitivity to object position, form and movement.
In contrast to the external sensory system, the mechanism of sensory processing by the interoceptive nervous system remains unclear.
Here, we developed a two-photon calcium imaging preparation to understand internal organ representations in the nucleus tractus solitarius (NTS), a sensory channel in the brainstem that receives vagal and other bodily inputs.
Focusing on gut and upper airway stimulation, we observed that individual NTS neurons are tuned to detect signals from specific organs and are topologically organized according to body location. In addition, some mechanosensory and chemosensory inputs from the same organ converge.
Sensory input binds to specific NTS domains with defined locations, each of which contains heterogeneous cell types. Spatial representations of different organs sharpened further in the NTS beyond what was achieved by vagal axonal sorting alone, as blockade of brainstem inhibition expanded neuromodulation and disrupted visceral representations.
These findings reveal fundamental organizational features that the brain uses to process interoceptive input.