Nature Brainstem ADCYAP1+ neurons mediate pathological behavior

Written by | Jun

infection is one of the serious threats that organisms need to face in survival [1], while inducing immune cell responses, infection will also trigger a series of changes in the body, including anorexia, obesity, drowsiness, body temperature changes, etc.
, which are collectively referred to as pathological behaviors [2, 3].

。 If forced feeding or changing the ambient temperature increases mortality [4, 5], indicating that pathological behavior is an adaptive change made by the body in the face of infection, but the relevant neural mechanisms of pathological behavior have not been elucidated [6, 7], and it is not clear
whether different pathological behaviors are controlled by the same neuron cluster.

On September 7, 2022, the Jeffrey M.
Friedman team at the Howard Hughes Medical Institute at Rockefeller University in New York published an article in the journal Nature Brainstem ADCYAP1+ neurons control multiple aspects of sickness behaviour , Explaining that endotoxin-induced pathological behavior is controlled by clusters of neurons expressing ADCYAP1 neuropeptide within the dorsal brainstem vagus complex, this paper identifies key nodes that link the immune response to the nervous system, providing a new perspective on the relationship between infection, inflammation, and behavior – the nervous system
.


The authors first induced the pathological behavior
of mice by a single intraperitoneal injection of bacterial endotoxin lipopolysaccharide (LPS).
The lethal dose of LPS is 10mg/kg, and three doses are selected in this article, namely 0.
1, 0.
5 and 2.
5 mg/kg
.
The results of real-time monitoring showed that the pathological behavior showed a dose-dependent relationship, and the food intake, water intake, exercise ability, and body weight of the mice after LPS injection decreased rapidly, while the core temperature showed significant differences only in medium and high doses
.
Overall, the behavioral responses induced by the three doses are very similar, but higher doses of LPS result in longer durations
.
The effect of high doses at 48 hours after injection remains significant, the effect of medium doses can last for 24 hours, while the effects of low doses begin to disappear
at 12 hours.
Since the qualitative responses of the three doses were highly consistent, the authors chose to use the medium dose (0.
5 mg/kg) to study the neural mechanisms
of pathological behavior in later experiments.

Using whole tissue embedded immunofluorescence staining technology and light film technology, the authors realized the expression observation
of the whole brain, that is, early gene Fos after LPS injection.
To identify key clusters of neurons that regulate the pathological effects, the authors chose to focus on brain regions that exhibit high expression of FOS early after LPS injection, namely the solitary bundle nucleus (NTS) and the posterior region (AP)
located in the dorsal brainstem.
Further use of the TRAP2 system to label LPS-activated neurons, and three weeks later, with the help of chemical genetic methods, the labeled neurons were reactivated, and it was found that their food intake, water intake, exercise capacity, body weight, and core temperature
could be significantly reduced.
In addition, if the activity of these neurons is suppressed before the re-injection of LPS, it is found that the pathological behavior that should have occurred is disturbed, and only the temperature is reduced
as usual.
These results suggest that activation of labeled neurons in NTS-AP brain regions is necessary for pathological behavior caused by LPS, while body temperature responses appear to be mediated
by other brain regions.

Next, the authors identified specific neuron types within NTS-AP that respond to LPS through single-cell nuclear RNA sequencing, and finally found that clusters of four types of excitatory neurons (expressing VGLUT2) and four groups of inhibitory neurons (expressing VGAT) changed
after LPS injection.
Activation of excitatory neurons within NTS-AP can induce significant pathological behavior, but activation of inhibitory neurons does not trigger pathological responses
.
Further regulating different clusters of excitatory neurons, the authors first focused on ADCYAP1+ neurons, which account for 65.
45% of LPS-activated NTS neurons and 76.
4%
of AP neurons.
The results showed that chemical genetics induced significant pathological behavior
after activating ADCYAP1+ neurons.

Since ADCYAP1+ neurons are distributed in both NTS and AP, in order to distinguish the different roles of the two brain regions, the authors also focus on DBH+ neurons, which coincide with ADCYAP1+ neuron clusters at APs up to 97.
5%, while DBH+ neurons in NTS rarely respond
to LPS.
The results showed that activating DBH+ neurons induced weak pathological behavior, and the effect could only last for 6-12 hours, while the action of ADCYAP1+ neurons could last for 24 hours
.
The above results suggest that ADCYAP1+ neurons of NTS may play a more important role
in pathological behavior.

To study the ADCYAP1+ neurons of NTS, the authors also focused on PHOX2B+ neurons, which also coincide with ADCYAP1+ neuron clusters up to 97.
5% at AP (the same neurons as DBH+), but are only expressed
in NTS in some ADCYAP1+ neurons.
Therefore, the role of ADCYAP1+ PHOX2B+ neurons in NTS can be obtained by comparing the roles of ADCYAP1+ neurons and PHOX2B+ neurons
.
The results also showed that activation of PHOX2B+ neurons induced weak pathological behavior, indicating that the pathological behavior was mainly controlled
by ADCYAP1+PHOX2B-neurons within NTS.

The results of inhibition of specific types of neurons by chemical genetics showed that inhibition of ADCYAP1+ neurons can interfere with LPS-induced pathological behavior, but inhibition of DBH+ neurons or PHOX2B+ neurons did not have an effect, indicating that these two types of neuron clusters that label almost all AP neurons are not necessary for pathological behavior, compared with ADCYAP1+ neurons, which have a key role in pathological behavior
。
Taken together, this paper demonstrates that ADCYAP1+ neurons in NTS-AP are key agents in regulating LPS-induced pathological behavior, and this study has important implications
for understanding how the immune system interacts with the nervous system.

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Maker: Eleven

References

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