Researchers have identified the brain structures that induce and control certain symptoms of sickness such as fever and loss of appetite.

When our bodies first notice an infection taking hold, our nervous systems first take the news to the immune system, to ready it for the battle ahead. But it also informs our brains, which play an important role in orchestrating the defense. They do this by starting a series of behavioral and physiological changes to the normal workings of our bodies in order to make it more difficult for the pathogens to survive and develop.

However, these changes are manifested as the unpleasant symptoms of sickness — they’re most of what we understand as ‘feeling sick’. This is why neuroscientists have been keen to find out which areas of the brain drive these changes, and how they do it, for quite a long time now. New research on the brains of mice may have found the answer.

Emergency buttons

The team has identified a group of neurons in the hypothalamus, a group that has not been described previously, which controls key homeostatic functions of the body. Homeostatic processes are those involved in maintaining the normal internal conditions required for our bodies to function properly such as temperature, blood pressure, blood sugar levels, and so on.

These neurons, they say, are responsible for inducing symptoms of sickness, including fever and appetite loss. They can receive molecular signals directly from the immune system, the authors explain, an ability that the vast majority of other neurons lack. The contact between these neurons and the immune system is made possible by their position in the hypothalamus. They are placed close to the permeable blood-brain barrier, which allows for chemical messengers from the immune system to reach these neurons.

“It was important for us to establish this general principle that the brain can even sense these immune states,” said Jessica Osterhout, a postdoctoral researcher in the Dulac Lab and the study’s lead author. “This was poorly understood before.”

“What’s happening is that the cells of the blood-brain barrier that are in contact with the blood and with the peripheral immune system get activated and these non-neuronal cells secrete cytokines and chemokines that, in turn, activate the population of neurons that we found,” said Dulac, Lee and Ezpeleta Professor of Arts and Sciences and Higgins Professor of Molecular and Cellular Biology.

A fever, for example, is not caused by the pathogen (bacteria, virus etc.) itself but is rather a reaction that our bodies have to being infected. And fevers can definitely help kill a pathogen – but if it gets too high, a fever can become dangerous to the patient itself. Loss of appetite and thirst work the same way, but if they are sustained for too long, they can also impede recovery. So understanding how these processes occur and how we may reverse them could be of value for doctors and patients around the world. One particular area of applicability for these findings is for chemotherapy or cancer patients, who suffer from chronic loss of appetite.

The study was prompted by the observation that autism symptoms recede in patients as they are experiencing the symptoms of an infection. The team set out to identify the link between neurons that generate fevers and those involved in modeling social behavior; instead, they found that many different populations of neurons are activated when an animal is sick.

The work started as an effort to examine the “fever effect” in autism patients, a phenomenon in which autism symptoms fade as a patient experiences symptoms of infection. The goal was to find the neurons that generate fever and link them to the neurons that are involved with social behavior.

The team injected lab mice with inflammatory agents that mimic bacterial or viral infections. They then analyzed the brain activity of the mice to record which areas showed activation. Instead of finding a single link between two different groups of neurons, they saw many populations of neurons that are activated when an animal is sick. About 1,000 neurons in the hypothalamus were earmarked because of their proximity to the blood-brain barrier. The authors also noted that these neurons were activated when the levels of messenger molecules from the immune system increased.

Using various approaches, the team activated and inactivated these neurons to observe their effect. All in all, they report that these neurons could increase body temperature in the mice, increase warmth-seeking behavior, and decrease appetite. They communicate with 12 distinct brain areas, whose known roles include controlling thirst, pain sensations, and social interactions.

Overall, the finding suggests that the population of neurons they identified in the hypothalamus mediates chemical communications between the brain and immune system. The results give us valuable insight into how these two systems coordinate and could pave the way toward more effective treatment for cases of excessive anti-pathogen responses.

“As a neuroscientist, we often think of neurons activating other neurons and not that these other paracrine-type or secretion-type methods are really critical,” Osterhout said. “It changed how I thought about the problem.”

The paper “A preoptic neuronal population controls fever and appetite during sickness” has been published in the journal Nature.