When you have an infection, you feel tired and lethargic, food and drink become distasteful, you don’t feel like moving about, and you might experience pains and chills. These physiological responses collectively called “sickness behaviors” allow the body to cope with the infection and reallocate resources to combat disease. The brain drives these responses, but the underlying neural mechanisms have remained unclear, until now.

A mouse model study published in the journal Nature Brainstem ADCYAP1+ neurons control several aspects of sickness behavior” by a team led by Jeffrey Friedman, PhD, professor of genetics at the Rockefeller University, New York, NY, and an investigator of the Howard Hughes Medical Institute, has identified a specific subset of neurons in the brainstem that regulates these diverse adaptive responses. The neurons can be recognized by their expression of a neuropeptide called ADCYAP1.

To model infection in mice, the investigators injected mice with different doses of the bacterial endotoxin, lipopolysaccharide (LPS), instead of infecting them to specific live pathogenic bacteria.

“We studied the sickness responses using LPS, which yields a more consistent response than does bacterial infection,” the authors noted. “The use of LPS also enables one to control for variability in individual animal responses to an infection while also dissociating host responses from pathogen-induced effects that damage and alter organ function.”

At several timepoints following LPS treatment (0.5 to 24 hours), the researchers mapped brain activity throughout the mouse brain by monitoring the expression of a marker called FOS using whole-mount immunostaining and light-sheet imaging. This revealed activation of a distinct subset of neurons in regions of the brainstem called NTS (nucleus of the solitary tract) and AP (area postrema) within one to three hours of LPS injection.

The NTS receives inputs from the vagus nerve—the longest cranial nerve that runs from the large intestines to the brain. The AP located at the boundary of the brain ventricles is bathed by humoral factors, such as immune signaling cytokines.

“Early increases in FOS expression were most prominent in the NTS with a greater than twofold increase at one hour post LPS,” the authors noted.

The authors next used a technology called TRAP2 to reactivate LPS-responsive neurons in the NTS and AP in mice that were not treated with LPS. They found reactivation of specific neurons in these regions recapitulated all the components of sickness behavior.  On the other hand, they found inhibiting the specific LPS-activated neurons diminished all symptoms of sickness behavior in response to LPS.

The authors then conducted single-nucleus RNA sequencing on the NTS and AP regions to identify molecular signatures of the LPS-activated neurons. They identified several clusters of neurons expressing excitatory or inhibitory markers and evaluated each to identify the cluster responsible for sickness behaviors. When they activated neurons in the NTS and AP regions of the brainstem that expressed ADCYAP1, the mice showed all symptoms of sickness behavior as they did when treated with LPS. Inhibition of the same neurons decreased the tendencies of disinclination to eat, drink and move.

These findings establish a previously unknown link between the brain and the body’s response to infection and could pave the way for the identification of better targets for anti-sickness medications.

Masha Prager-Khoutorsky, PhD, an assistant professor of physiology at McGill University in Montreal, who was not involved in the study noted that a logical next step to the current study would be to identify downstream areas in the brain that fire as a result of the activation of ADYAP1 neurons in the NTS and AP and investigate how these influence sickness behaviors. Prager-Khoutorsky  noted, “An open question is how the duration of the sickness response is controlled, and whether the same neuronal circuits are involved in mediating prolonged, chronic symptoms of viral infections, such as long COVID.”

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