Summary: A new study in mice provides clues about how the brain processes sensory information from internal organs, and reveals feedback from organs that activate different groups of neurons in the brainstem.
Most of us don’t think much about why we feel so full after a big holiday meal, why we start coughing after accidentally inhaling campfire smoke, or why we suddenly feel nauseous after eating something poisonous. However, these sensations are essential for survival: they tell us what our bodies need at any given moment so that we can quickly adjust our behavior.
However, historically, very little research has been devoted to understanding these basic bodily sensations – also known as internal senses – that are generated when the brain receives and interprets input from internal organs.
Now, a team led by researchers at Harvard Medical School has made new strides in understanding the basic biology of sensing internal organs, which involves the complex series of connections between cells within the body.
In a study conducted on mice and published on August 31 temper natureThe team used high-resolution imaging to reveal spatial maps of how neurons in the brainstem respond to feedback from internal organs.
They found that feedback from different organs activates separate groups of neurons, regardless of whether this information is mechanical or chemical in nature — these groups of neurons that represent different topographically organized organs in the brainstem. Furthermore, they discovered that inhibition within the brain plays a key role in helping neurons respond selectively to organs.
“Our study reveals the basic principles of how different internal organs are represented in the brainstem,” said lead author Chen Ran, research fellow in cell biology at HMS.
The research is just the first step in clarifying how internal organs communicate with the brain. However, if the findings are confirmed in other species, including humans, they could help scientists develop better treatment strategies for diseases such as eating disorders, overactive bladder, diabetes, pulmonary disorders, and high blood pressure that arise when the internal sensor is skewed.
“I think understanding how the brain encodes sensory input is one of the great puzzles of how the brain works,” said senior author Stephen Liberlis, professor of cell biology at HMS’s Blavatnik Institute and researcher at Howard Hughes Medical Institute. “It gives advances in understanding how the brain works to generate perceptions and evoke behaviors.”
Thoughtful and misunderstood
For nearly a century, scientists have been studying how the brain processes external information to make up the basic senses of sight, smell, hearing, taste and touch that we use to navigate the world. Over time, they pooled their findings to show how different sensory areas in the brain are organized to represent different stimuli.
In the mid-20th century, for example, research on touch led scientists to develop the cortical homunculus of the somatosensory system—an illustration depicting cartoonish body parts curled up on the surface of the brain, each part positioned in line with where it is located. Extensively processed and painted based on sensitivity.
In 1981 Harvard professors David Hubel and Torsten Wiesel won the Nobel Prize for their research on vision, where they systematically mapped the brain’s visual cortex by recording the electrical activity of individual neurons that respond to visual stimuli.
In 2004, another pair of scientists won the Nobel Prize for their studies of the olfactory system, identifying hundreds of olfactory receptors and revealing precisely how smell inputs are arranged in the nose and brain.
However, until now, the process by which the brain senses and regulates reactions from internal organs to regulate basic physiological functions such as hunger, satiety, thirst, nausea, pain, breathing, heart rate, and blood pressure, has remained obscure.
“How the brain receives inputs from within the body and how it processes those inputs has been largely studied and poorly understood,” Liberliz said.
This may be because internal sensing is more complex than external sensing, Ran added. He explained that the external senses tend to receive information in a single form. Vision, for example, depends entirely on the detection of light.
By contrast, internal organs transmit information through mechanical forces, hormones, nutrients, toxins, temperature, and more—each of which can act on multiple organs and translate into multiple physiological responses. Mechanical expansion, for example, refers to the need to urinate when it occurs in the bladder, but translates to a feeling of fullness when it occurs in the stomach and triggers a reaction to stop inhalation in the lungs.
Constellation of neurons
In their new study, Lieberless, Wran and colleagues focused on a brain stem area called the nucleus of the solitary system, or NTS.
NTS is known to receive sensory information from internal organs via the vagus nerve. It relays this information to higher-level brain regions that regulate physiological responses and generate behaviors. In this way, the NTS acts as an internal sensory gateway to the brain.
The researchers used a powerful technique called two-photon calcium imaging that 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 stimuli and used a microscope to record the responses of thousands of NTS neurons simultaneously over time. The resulting videos show neurons lighting up throughout the NTS, like stars blinking and closing in the night sky.
Conventional imaging techniques, which involve inserting an electrode to record a small group of neurons at a single point in time, are “like seeing only a few pixels of an image at a time,” Ran said. “Our approach is like seeing all the pixels at once to show the whole image in high definition.”
The team discovered that stimuli in different internal organs — for example, the stomach versus the larynx — generally activate different groups of neurons in the NTS. By contrast, researchers have identified several instances in which mechanical and chemical stimuli in the same organ that often elicit the same physiological response (such as coughing or satiety) activate overlapping neurons in the brainstem. These results suggest that certain groups of neurons may be customized to represent specific organs.
Furthermore, the researchers found that responses in the NTS were organized as a spatial map, which they named “visceral homunculus” in reference to a similar cortical homunculus that had been developed decades ago.
Finally, scientists have demonstrated that sending signals from internal organs to the brain stem requires inhibition of neurons. When they used drugs to block inhibition, neurons in the brainstem began responding to multiple organs, losing their prior selectivity.
Ran said the work lays the foundation for “a systematic study of the encoding of internal senses throughout the brain.”
foundation of the future
The findings raise many new questions, some of which the HMS team would like to answer.
Ran is interested in investigating how the brain stem transmits internal sensory information to higher-order brain regions that produce the resulting sensations, such as hunger, pain or thirst.
Liberles wants to explore how the internal sensing system works at the molecular level. In particular, he would like to identify the primary sensory receptors that detect mechanical and chemical stimuli within organs.
Another area of future research is how to set up the system during embryonic development. Lieberles said the new findings suggest that looking at the type of neuron alone is not enough; Researchers must also consider where the neurons are located in the brain.
“We need to study the interaction between neuron types and locations to understand how circuits are connected and what different cell types do in the context of different circuits,” he said.
Liberles is also interested in how generalized the findings are 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 display basic behaviors such as coughing or vomiting.
If the results of the research in humans are confirmed, the research findings could eventually benefit the development of better treatments for diseases that arise when the internal sensory system is disrupted.
“These diseases often occur because the brain receives abnormal responses from internal organs,” Ran said. “If we have a good idea 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 Butcher, Judith Kay, and Catherine Gallory of HMS.
Financing: The work was supported by the National Institutes of Health (grant DP1AT009497; R01DK122976; R01DK103703), the Food Allergy Science Initiative, the Leonard and Isabel Goldenson Postdoctoral Fellowship, the Harvard Brain Science Initiative, and the American Diabetes Association.
About this Neuroscience Research News
author: Dennis Neylon
Contact: Dennis Nealon – Harvard
picture: The image is in the public domain
original search: open access.
“Brainstem map of visceral sensationsWritten by Chen Ran et al. temper nature
Brainstem map of visceral sensations
The nervous system uses different coding strategies to process sensory input. For example, the olfactory system uses a large receptor repertoire and is wired to recognize various odors, while the optical system provides high acuity for body position, shape and movement.
Compared with the external sensory systems, the principles underlying sensory processing by the internal nervous system remain poorly defined.
Here we have developed a two-photon calcium imaging preparation to understand internal organ representations in the nucleus of the solitary tract (NTS), a sensory gateway in the brainstem that receives vagal and other inputs from the body.
Focusing on gut and upper airway stimuli, we observed that individual NTS neurons are tuned to detect signals from specific organs and are topographically organized based on body position. Moreover, some mechanosensory and chemosensory inputs from the same organ converge centrally.
Sensory input enters specific NTS domains with specific sites, each of which contains heterogeneous cell types. Spatial representations of different organs are augmented in the NTS beyond what is achieved by vagal axonal sorting alone, in which blockade of brainstem inhibition broadens neuronal tuning and perturbs visceral representations.
These findings reveal key regulatory features that the brain uses to process sensory input.