Cell: Cao Peng's team at the Beijing Institute of Biological Sciences reveals the neurobiological mechanism of the "nausea-vomiting" response

*For medical professionals only

Everyone knows that ingesting spoiled food can trigger a series of unpleasant reactions
such as nausea and vomiting.

Nausea and vomiting are both part of the body's defense response to prevent pathogens from attacking the body
.
Through vomiting, the body can promote the excretion of toxic substances; The negative emotion of nausea allows us to avoid ingesting similar toxic substances again [1].

Nausea and vomiting, as defensive behaviors and emotions, are actually inseparable from the regulation
of the nervous system.
So, how does our brain sense toxic substances in the gut and then respond to nausea and vomiting?

Previous studies have attempted to answer this question through animal models of vomiting responses, such as dogs and ferrets [2].

These studies found that nausea and vomiting responses are strongly associated with the gut-brain axis [3].

Previous studies have also found that enterotoxin and the chemotherapy drug cisplatin activate the solitary bundle nucleus of the brainstem, while vagus neurectomy is effective in blocking the nausea and vomiting caused by enterotoxin and cisplatin [4-5].

In addition to this, pharmacological methods have demonstrated that nausea and vomiting responses are associated with serotonin type 3 receptors and tachykinin type 1 receptors[6].

However, because molecular genetic manipulation is difficult to implement in these animal models, the specific neural circuitry of the gut-brain axis that regulates nausea and vomiting is still unknown
.

Recently, the Cao Peng laboratory from the Beijing Institute of Biological Sciences/Tsinghua University Interdisciplinary Institute of Biomedical Sciences answered this question
through a mouse model.
This work was published in the prestigious journal Cell [7].

They found that the toxin activates intestinal chromaffin cells (EC) in the gut, causing these cells to release serotonin, which activates the vagus nerve
in the gut.
The vagus nerve then transmits signals to neurons expressing tachykinin (Tac1+) in the dorsal vagus complex (DVC) of the medulla oblongata, which is activated to regulate nausea and retching behavior in mice through two neural pathways, respectively.

Screenshot of the paper cover

Then let's follow the singularity cake to see how Cao Peng and his team carry out research
.

Based on the advantages of mouse models in molecular genetic manipulation techniques, they first successfully established a model simulating food poisoning in mice to study the neuroregulatory mechanisms
of nausea and retching responses.

They found that enterotoxin (SEA) produced by Staphylococcus aureus could cause mice to exhibit "retching-like behavior," that is, behaviors similar to retching; Then, through conditioned flavor avoidance (CFA), they also demonstrated that SEA could cause mice to exhibit aversion
similar to "nausea.
"

SEA can cause mice to exhibit reactions similar to nausea and retching

Since previous studies have shown that the vagus nerve is closely related to nausea and vomiting response, they first performed vagus nerve resection on mice, and the results showed that these mice after vagus nerve resection had significant relief of nausea and retching response to SEA
.
Because one of the main brain regions of vagus projection is DVC in the medulla oblongata, including the nucleus of the solitary bundle (NTS) and the posterior region (AP), they next explored whether DVC had an important regulatory effect
on SEA-induced nausea and retching.

They found that neurons in the DVC region were highly activated after SEA administration, and that specific inhibition of these neurons significantly alleviated the nausea and retching response
caused by SEA.

So, what neurons of DVC are responsible for regulating nausea and retching response?

Previous studies have shown that the DVC region is enriched with neurons expressing tachykinin (Tac1+), and studies have also shown that if the tachykin receptor, neurokinin type 1 receptor, is inhibited, it can effectively block the vomiting response, so the authors suspect that Tac1+ neurons in the DVC region are responsible for regulating the nausea and retching response
caused by enterotoxin.

To prove this hypothesis, they specifically inhibited Tac1+ neurons in the DVC region by chemogenetic techniques, and found that this can significantly inhibit the nausea and retching response
induced by SEA.

Specific inhibition of Tac1+ neurons in the DVC region can significantly alleviate the nausea and vomiting response triggered by SEA

In addition, it was found that these Tac1+ neurons secrete Tac1-related neurotransmitters and glutamate that are necessary for this group of neurons to induce nausea and retching reactions
.

The next question is, how do DVC's Tac1+ neurons pick up signals for enterotoxins?

Using retrograde tracing viruses to label Tac1+ neurons in DVC, the authors found labeled vagus nerve fibers
at mucosal endingings in the antrum and villi of the small intestine.
At the mucosal endings in the small intestine, there is a group of cells called enteric chromaffin cells (EC).

The authors were surprised to find that these labeled vagus nerve fibers were very close to EC cells
.

Therefore, they guessed that these EC cells could activate vagus neurons
.

They first used staining to show that most labeled vagus neurons expressed serotonin receptors, serotonin type 3 receptors
.
They then found that specifically knocking out serotonin in EC cells significantly inhibited SEA-induced nausea and retching
.
That is, EC cells do activate vagus neurons in the SEA model, and this pathway is necessary to trigger nausea and retching
.

The authors then measured the reactivity of Tac1+ neurons at DVC in the SEA model using in vivo fiber optic calcium imaging and compared
it with subphrenic vagotomy and_HT3Rantagonist-treated groups, respectively.
The results showed that the activation of Tac1+ neurons in the SEA model depended on the signal transmission
of vagus nerve →DVC Tac1+ neurons.

In vivo fiber optic calcium imaging demonstrated that Tac1+ neurons at DVC were activated in the SEA model

So, how do DVC's Tac1+ neurons trigger nausea and retching when activated in the SEA model?

To answer this question, the authors tracked the Tac1+ neurons of DVC retrograde tracing virus, and they found that these Tac1+ neurons mainly project to the two brain regions
of the lateral nucleus (LPB) parabrachial (LPB) and the snout of the ventral respiratory group (rVRG).

They also found that the two neural circuits overlapped almost non-existent, meaning that there were two subsets of Tac1+ neurons in the DVC, which projected to LPB and rVRG
, respectively.
Interestingly, the authors found through chemical genetics that these two circuits control the two reactions of nausea and retching:

(1) Specific activation of DVC Tac1+→rVRG neural circuits only caused retching-like behavior in mice, but did not induce conditioned taste avoidance behavior;

(2) Specific activation of DVCTac1+→LPB neural circuits does not cause retching-like behavior, but can induce conditioned taste avoidance behavior
.

Effects of specific activation of DVC Tac1+→rVRG or DVC Tac1+→LPB neural circuits on SEA-induced nausea and retching responses

In addition to food toxins, chemotherapy drugs, such as cisplatin and doxorubicin, can also trigger nausea and gagging
.
Therefore, the authors next explored whether these neural circuits were also involved in the nausea and retching caused by chemotherapy drugs
.

They found that intraperitoneal doxorubicin injection could induce nausea and vomiting in mice, while specific inhibition of DVC Tac1+ neurons, specific knockout of DVC region Tac1 gene or glutamate synthesis-related genes could significantly attenuate this phenomenon
.

In addition, if the DVC Tac1+ →rVRG circuit is specifically inhibited, the gagging response caused by doxorubicin can be specifically attenuated, while the inhibition of the DVC Tac1+→LPB circuit is specifically attenuated nausea
.

In summary, through a variety of cutting-edge techniques, Cao Peng and his team found that EC cells located in the intestinal epithelium can sense enterotoxin
.
When activated, EC cells secrete a large amount of serotonin, which is activated by vagus sensory nerve fibers expressing serotonin type 3 receptors, which in turn transmit the signal to Tac1+ neurons
of DVC located in the medulla oblongata.
Tac1+ neurons then transmit signals to two brain regions, LPB and rVRG, causing nausea and retching, respectively
.
The above neural circuit pathway is also involved in the nausea and retching reaction caused by chemotherapy drugs
.

Summarize the model

This research result not only deepens the understanding of the intestinal-brain axis, but also provides a potential target for the treatment and intervention of nausea and vomiting in the future
.

Comes with a video version ☟

References:

[1].
Horn CC.
Why is the neurobiology of nausea and vomiting so important?.
Appetite.
2008; 50(2-3):430-434.
doi:10.
1016/j.
appet.
2007.
09.
015

[2].
Andrews PL, Horn CC.
Signals for nausea and emesis: Implications for models of upper gastrointestinal diseases.
Auton Neurosci.
2006; 125(1-2):100-115.
doi:10.
1016/j.
autneu.
2006.
01.
008

[3].
Zhong W, Shahbaz O, Teskey G, et al.
Mechanisms of Nausea and Vomiting: Current Knowledge and Recent Advances in Intracellular Emetic Signaling Systems.
Int J Mol Sci.
2021; 22(11):5797.
Published 2021 May 28.
doi:10.
3390/ijms22115797

[4].
Reynolds DJ, Barber NA, Grahame-Smith DG, Leslie RA.
Cisplatin-evoked induction of c-fos protein in the brainstem of the ferret: the effect of cervical vagotomy and the anti-emetic 5-HT3 receptor antagonist granisetron (BRL 43694).
Brain Res.
1991; 565(2):231-236.
doi:10.
1016/0006-8993(91)91654-j

[5].
Wang X, Wang BR, Zhang XJ, Duan XL, Guo X, Ju G.
Fos expression in the rat brain after intraperitoneal injection of Staphylococcus enterotoxin B and the effect of vagotomy.
Neurochem Res.
2004; 29(9):1667-1674.
doi:10.
1023/b:nere.
0000035801.
81825.
2a

[6].
Rojas C, Raje M, Tsukamoto T, Slusher BS.
Molecular mechanisms of 5-HT(3) and NK(1) receptor antagonists in prevention of emesis.
Eur J Pharmacol.
2014; 722:26-37.
doi:10.
1016/j.
ejphar.
2013.
08.
049

[7].
Xie Z, Zhang X, Zhao M, et al.
The gut-to-brain axis for toxin-induced defensive responses.
Cell.
2022; 185(23):4298-4316.
e21.
doi:10.
1016/j.
cell.
2022.
10.
001

Responsible editorEddy Zhang