When we are ill, we often feel tired and drained, have no appetite and often have an elevated body temperature. These symptoms are regulated by our brain. But how does our brain learn about the infection and which region exactly is responsible for the reactions? Researchers have now studied this in mice. It turned out that an area of the hypothalamus close to the blood-brain barrier communicates directly with the immune system. If the researchers activated the corresponding neurons experimentally, the mice also developed symptoms of the disease.
Our bodies respond to infections of various types with a series of evolutionarily conserved adaptations aimed at fighting off the pathogens and increasing our chances of survival: we get fevers, lose our appetite and feel tired. All of these reactions are controlled by our brain. However, how exactly it learns about the infection and how it produces the changes in behavior and physiology has so far been unclear.
Direct communication between the brain and the immune system
A team led by Jessica Osterhout from Harvard University in Cambridge has now used mice to investigate exactly how the disease reaction is initiated and proceeds in the brain. To do this, they first injected the test animals with pro-inflammatory substances that imitated a bacterial or viral infection. As expected, the animals developed fever, loss of appetite and other signs of illness. Using various methods of fluorescent labeling and optogenetic analysis, the researchers then examined which areas and cells in the mouse brain reacted to this.
The result: The so-called ventral-medial preoptic area (VMPO), a region of the hypothalamus that lies directly next to the blood-brain barrier, was strongly activated by the infection. “What happens is that the blood-brain barrier cells, which are in contact with the blood and the peripheral immune system, become activated. These non-neuronal cells then secrete messenger substances, which in turn activate the population of neurons that we found,” explains Osterhout’s colleague Catherine Dulac. This is how the brain communicates directly with the immune system.
reverse disease responses?
Next, the researchers studied the responses elicited as a result of activation by artificially activating the appropriate brain region without an underlying infection. And indeed: if they stimulated the corresponding neurons, the body temperature of the mice rose, they ate less and preferred to stay in an area of their cage that was heated to 30 degrees Celsius. “In addition, the corresponding neurons projected onto 12 brain areas, some of which are known to control thirst, pain sensation, or social interactions, suggesting that other disease behaviors may also be influenced by the activity of these neurons,” the researchers said.
Although all of these responses have evolved to promote individual survival, they can be overly harmful. Fever, for example, can help fight the pathogens. However, if it gets too high, it damages the body and can even become life-threatening. The same applies to a reduced feeling of hunger and thirst. With a more detailed understanding of the underlying mechanisms, the researchers hope to be able to specifically reverse certain processes. “If we know how this works, we might be able to help patients who are struggling with these types of symptoms, for example cancer patients undergoing chemotherapy,” says Osterhout.
Source: Jessica Osterhout (Harvard University, Cambridge) et al., Nature, doi: 10.1038/s41586-022-04793-z