Cell reveals the neurobiological mechanism by which the brain initiates the "nausea-vomiting" response

The "nausea-vomiting" reaction is a kind of self-protective defense response produced by the human body after encountering pathogenic invasion, which is of great significance for survival; Nausea and vomiting are also major side effects of cancer chemotherapy and have important clinical significance; The "nausea-vomiting" reaction is also common
in everyday life.
Unfortunately, for more than three decades, the study of the mechanism of the "nausea-vomiting" response has been difficult because of the lack of suitable animal models and research paradigms
in the field.
To elucidate the mechanism by which the brain initiates the "nausea-vomiting" response, in addition to appropriate animal models and research paradigms, three long-unsolved mysteries
need to be solved.

The laboratory of Beijing Institute of Biological Sciences/Tsinghua University Institute of Biomedical Sciences has established a new paradigm for studying the "nausea-vomiting" response using mice as animal models, and preliminarily revealed the molecular cell and neural circuit mechanism
of the brain sensing pathogenic invasion and initiating the "nausea-vomiting" response.
This achievement opens up a new direction for the study of the molecular cellular mechanism and neural circuit mechanism of the "nausea-vomiting" response, and is expected to provide new targets for the development of
new chemotherapy antiemetic drugs.

According to the World Health Organization, about 600 million people worldwide suffer from food poisoning caused by ingesting food contaminated with pathogens every year, resulting in about 420,000 deaths [1].

After food poisoning, the brain initiates a series of defense responses
such as nausea and vomiting.
Through vomiting, the body excretes the poisonous food ingested from the digestive tract to prevent pathogens from further invading the body
.
Through nausea, the brain can form long-term memories of the characteristics of toxic foods, thereby avoiding future ingestion of toxic foods
.
It can be seen that the "nausea-vomiting" reaction is a kind of self-protection defense response produced by the human body after encountering pathogenic invasion, which is of great significance
for survival.

Nausea and vomiting are also major side effects of cancer chemotherapy and have important clinical significance [2].

Chemotherapy drugs can kill rapidly dividing tumor cells, but they also have a strong killing effect
on normal cells.
The chemotherapy drugs ingested into the body are recognized as "toxins" by the body and initiate a defense response to nausea and vomiting, helping the body to excrete these "toxins"
as soon as possible.
As a result, cancer patients undergoing chemotherapy have to suffer from extremely painful "nausea-vomiting" side effects and must take large doses of antiemetics to barely survive the chemotherapy process
.
Because the specific mechanism of the "nausea-vomiting" response is unknown, only a handful of antiemetics can be used clinically
.
Only by deeply analyzing the fine mechanism of the body's "nausea-vomiting" response can it be possible to develop more effective chemotherapy antiemetic drugs
.

The "nausea-vomiting" reaction also occurs in everyday life
.
For example, pregnant "mothers-to-be" experience varying degrees of "nausea-vomiting" reactions
.
In long-distance passenger transport, some passengers with motion sickness and seasickness will also experience a "nausea-vomiting" reaction
due to long bumps.
In these life scenarios, highly safe antiemetics are needed to suppress excessive "nausea-vomiting" reactions
.

Unfortunately, for more than three decades, the study of the mechanism of the "nausea-vomiting" response has been difficult because of the lack of suitable animal models and research paradigms
in the field.
Rodents commonly used in laboratories, such as mice and rats, do not exhibit vomiting behavior
.
The inability of rodents to spit out food in the stomach is thought to be due to insufficient development of smooth muscles in the digestive tract [3].

Previous studies
could only be conducted with animals with vomiting behavior, such as dogs and ferrets.
They found that cutting the subphrenic vagus nerve was effective in blocking the vomiting response, indicating that vomiting relies on the "gut-to-brain axis"
between the gastrointestinal tract and the brain.
Using these animals, some brain regions involved in vomiting were also identified by means of destruction and electrical stimulation [4].

Through pharmacological methods, antagonists of 5-HT3R and NK1R have been found to be effective in inhibiting vomiting [5].

However, these model animals lack the matching molecular genetic tools to systematically elucidate the molecular cell and neural circuit mechanisms
by which the brain senses pathogenic invasion and initiates the "nausea-vomiting" response.

To elucidate the mechanism by which the brain initiates the "nausea-vomiting" response, in addition to appropriate animal models and research paradigms, three long-unsolved mysteries
need to be solved.
First, after the gastrointestinal tract is invaded by pathogens, what kind of intestinal cells give this important information to the vagus nerve? Second, what are the identities and characteristics of sensory neurons in the vagus nerve responsible for docking with the intestinal "informant"? Third, when the brain receives information about pathogen invasion from the vagus nerve, how to quickly and synchronously initiate a series of defense responses such as nausea and vomiting?

On November 1, 2022, the Beijing Institute of Biological Sciences/Laboratory of the Institute of Biomedical Sciences of Tsinghua University published a research paper entitled The gut-to-brain axis for toxin-induced defensive responses online on Cell [6].

The study established a new paradigm for studying the "nausea-vomiting" response using mice as animal models, and solved the above three mysteries, preliminarily revealing the molecular cell and neural circuit mechanisms
by which the brain senses pathogenic invasion to initiate the "nausea-vomiting" response.

In this research project, the neurobiological mechanism of the "nausea-vomiting" response was studied (Fig.
1).

First, they established a research paradigm
for food poisoning in mice using Staphylococcal enterotoxin-produced by Staphylococcus aureus.
They were surprised to find that mice ingesting enterotoxin could not vomit, but could exhibit "open-mouthed" retching-like behavior (video-1).

Ingested enterotoxin can also cause "nausea" aversion in mice, resulting in conditioned flavor avoidance of beverages containing enterotoxin
.
Therefore, the conditioned taste avoidance and retching behaviors of mice simulated the "nausea" and "vomiting" defense responses triggered by human food poisoning, respectively, and could be used as a research paradigm
for food poisoning in mice.
Figure 1 Neurobiological mechanism by which the brain senses toxins and initiates a "nausea-vomiting" response

In the intestinal epithelium, there is a class of intestinal endocrine cells called enterochromaffin cells
.
Applying the newly established food poisoning research paradigm, Cao Peng's team found that enteric chromaffin cells play an important role in the "nausea-vomiting" response, and may be "informants"
that help the brain sense pathogenic invasion.
When the gastrointestinal tract is invaded by enterotoxins, these cells are activated and release serotonin (5-HT)
in large quantities.
Around the intestinal chromaffin cells, vagus sensory endings expressing the serotonin type 3 receptor gene (Htr3a+) are distributed around the intestinal chromophilocytes, which receive important information
about pathogenic invasion in response to serotonin.
This information is transmitted via the vagus nerve to the brainstem lone bundle nucleus, where it is received by a group of neurons expressing the tachykinin gene (Tac1+
).
The researchers activated these solitary bundle nucleus Tac1+ neurons through optogenetics (video-2) and chemogenetics (video-3), which directly triggered retching behavior and conditioned taste avoidance
in mice.
Inactivation of these neurons, or knocking out the Tac1 gene, can prevent retching behavior and conditioned taste avoidance
caused by pathogenic invasion.
Interestingly, these solitary nucleus Tac1+ neurons are divided into two ways, on the one hand, they activate the parabrachial nucleus in the pons, producing disgust associated with "nausea"; On the other hand, activating the ventral respiratory group of the medulla oblongata may trigger retching by regulating the motor behavior
of the "retching" neurons responsible for simultaneous contraction of the diaphragm and abdominal muscles.

Further digging deeper revealed that these molecular cell and neural circuit mechanisms were also involved in the "nausea-vomiting" side effects
induced by chemotherapy drugs (doxorubicin).
The finding suggests that the "nausea-vomiting" side effects of chemotherapy drugs may have been achieved
by hijacking the evolutionarily conservative "food poisoning" mechanism.
The reviewers believe that this achievement opens up a new direction for the study of the molecular cellular mechanism and neural circuit mechanism of the "nausea-vomiting" response, and is expected to provide a new target for the development of
new chemotherapy antiemetic drugs.