The neurons behind Nature's illness

Infections are often associated with symptoms that are not directly related to the pathogen, such as drowsiness and loss
of appetite.

"I think it's really a major step forward," said Keith Kelley, professor emeritus of immunophysiology at the University of Illinois and former longtime editor-in-chief of the journal Brain, Behavior, and Immunity, who was not involved in the work
.

Focus on the neurons that make us feel sick

Our bodies are always trying to maintain a balance that controls our body temperature, how often we feel hungry, how often we sleep, and so on
.

When we get sick, this balance changes, triggering a range of symptoms and physiological changes, collectively known as disease behaviors, that can help us recover
.

Previous studies have shown that at least some of the signals that lead to disease-causing behavior originate in the brainstem, but do not pinpoint specific locations
in the brainstem structure.

The scientists then detected neuronal activity
by looking for a protein called FOS in the brains of mice that were euthanized after LPS injections.

But to determine whether neurons in these areas are really responsible for disease behavior, they need to activate them without using LPS, as toxins are known to cause other changes in
the body and brain.

To do this, they injected a virus into the NTS-AP region of the brainstem of a particular mouse that delivers a molecular switch
sensitive to the antipsychotic drug clozapine.

The researchers then injected the transgenic mice with LPS and tamoxifen
that switched on and took pictures.
A few weeks after recovery, the researchers injected the mice with clozapine, and the NTS-AP neurons produced FOS again, and the mice exhibited sick behavior, even if there was no LPS
in their system.
For the team, this confirmed that neurons in the NTS-AP region help with feeling uncomfortable
.
Further experiments using mononuclear RNA sequencing narrowed the specificity of LPS-activated neurons further to those regions that
also express the ADCYAP1 protein.

Ilanges' team also found that inhibiting neurons expressing ADCYAP1 reduced disease behavior in response to LPS injections, although it did not completely eliminate them
.

Kelley noted that he thinks the mouse model developed by the team to reactivate specific groups of neurons is "very clever
.

Patricia C.

Lopes noticed an interesting problem in both papers: All the animals used were males
.

Ilanges' team was also unable to investigate what specific bodily signals these neurons responded to, although they noted that NTS is thought to be transmitting signals from the vagus nerve — an important line of communication between the brain and internal organs — while APs are thought to be sensing fluid signals, such as proteins
released into the bloodstream.

Still, they hope others can use the data and methods they've already developed to continue exploring how the brain and immune system interact, and Ilanges plans to continue this research direction
in Janelia.

More broadly, Friedman said, this study shows that the brain plays a key role in fighting infections and is an active participant
.