When someone gets an infection, most people think it’s the immune system kicking into gear when they feel some of the body’s natural defenses like a fever, chills, or fatigue. But what many of us don’t know is that it’s actually the brain behind all of this. Researchers led by teams from the Harvard University labs of Catherine Dulac, PhD, and Xiaowei Zhuang, PhD, have now identified a small population of neurons near the base of the brain in mice that can induce symptoms of sickness, including fever, appetite loss, and warm-seeking behavior. The neurons, which have not been previously described, are found in an area of the hypothalamus, a part of the brain known for controlling key homeostatic functions that keep the body in a balanced, healthy state. The researchers found that these neurons have receptors that are capable of directly detecting molecular signals coming from the immune system, an ability most neurons don’t have.

“It was important for us to establish this general principle that the brain can even sense these immune states,” said Jessica Osterhout, PhD, a postdoctoral researcher in the Dulac Lab and the study’s lead author. “This was poorly understood before.” The hope is that scientists can one day use the knowledge from how this mechanism works to target the process in humans and potentially reverse it when it impacts badly on health.

Zhuang, Dulac and colleagues reported on their findings in Nature, in a paper titled “A preoptic neuronal population controls fever and appetite during sickness.”

During infection, the brain talks to the immune system and orchestrates physiological and behavioral changes that manifest as the unpleasant symptoms of sickness, and which are designed to help eliminate the pathogen and increase survival, the authors explained. “Symptoms include fever, lethargy, appetite loss, warmth-seeking, social withdrawal and increased pain sensitivity.” However, the team pointed out for neuroscientists, the long-standing questions have been, how and where does this happens in the brain?, “ … exactly how the nervous system alters body temperature and triggers sickness behaviors to coordinate responses to infection remains unknown,” they acknowledged.

Through their studies in mice, the researchers have now identified a previously uncharacterized population of neurons in the ventral medial preoptic area (VMPO) of the hypothalamus that are activated after sickness. “These neurons are crucial for generating a fever response and other sickness symptoms such as warmth-seeking and loss of appetite,” they wrote.

This key area of the hypothalamus is located right next to a permeable section of the brain called the blood-brain barrier, which helps circulates blood to the brain. “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.

The new knowledge could one day help scientists to develop new strategies for targeting the process when it is harmful, rather than helpful, to health. A fever, for instance, is typically a healthy reaction that helps eliminate a pathogen. But when it gets too high, it can also become dangerous. The same can be said for loss of appetite or a lowered thirst, which can, at first, be beneficial. But a continued or sustained lack of nutrients or hydration then start to impede recovery.

“If we know how it works, perhaps we can help patients who have difficulty with these kinds of symptoms, like chemo patients or cancer patients, for example, who have a very low appetite but there’s really nothing we can do for them,” Osterhout said.

The reported work originally started as an effort to look at what is known as the fever effect in autism patients. It’s a phenomenon where autistic patients have a reduction in autistic symptoms when they have symptoms of an infection, such as a fever. The investigators set out to find the neurons that generate fever and link them to the neurons that are involved with social behavior.

Instead, Osterhout found many populations of neurons that are activated when an animal is sick. She focused on about 1,000 neurons in ventral medial preoptic area of the hypothalamus, because of their location next to the blood-brain barrier.

To find the different areas of neurons that become activated, Osterhout injected mice with pro-inflammatory agents, lipopolysaccharide or polycytidylic acid, which mimic bacterial or viral infection. She analyzed the areas of the brain that lit up in the brain scans.

Osterhout and colleagues then used a powerful and precise set of methods called chemo- and optogenetics to control and investigate the connectivity between the different neuronal populations. Using these tools, they were able to activate or silence these neurons on command in the brains of mice and pin down their function by seeing what happened.

The researchers found that using these tools they could increase body temperature in the mice, increase warmth-seeking behavior, and decrease appetite. They reported that the identified VMPO neurons that were activated by LPS (VMPOLPS neurons) project to 12 brain areas, some of which are known to control thirst, pain sensation, and social interactions. This suggests that other sickness behaviors may also be affected by the activity of the same neurons.

During their experiments, the investigators also noticed increased activity and activation in this population of neurons when molecules from the immune system gave off increased signals. That suggests that the brain and the immune system were communicating with each other through paracrine signaling at the location they focused on—the ventral medial preoptic area and the blood-brain barrier right next to it. Paracrine signaling is when cells produce a signal to trigger changes in nearby cells. “Together, these results uncover VMPOLPS neurons as a control hub that integrates immune signals to orchestrate multiple sickness symptoms in response to infection,” the team stated.

Osterhout said the process expanded her understanding of how neurons work. “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,” she said. “It changed how I thought about the problem.”

The authors concluded in their paper, “Altogether, our data showed that VMPOLPS neurons are necessary and sufficient to generate fever, directly sense immune signals and coordinate sickness-induced increases in body temperature, warmth-seeking behaviour and appetite suppression … we show that VMPOLPS neurons exert a broad influence on the activity of brain areas associated with behavioural and homeostatic functions and are synaptically and functionally connected to circuit nodes controlling body temperature and appetite.”

The scientists plan to further explore the other areas to which the neurons project and apply their findings to revisit the fever effect in autism patients. “There is way more for us to look at in the future,” Dulac said.

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