Think about the last time you were sick. Maybe you ran a fever, had body chills, felt lethargic and lost your appetite.
But your brain probably played a key role as well and controlled many of the symptoms you felt.
Two recent studies published in Nature report that specific parts of the brain rapidly respond to illness and coordinate how the body counters it. Although the studies were in mice, this new understanding may also hold clues about why some people continue to have chronic problems such as long covid months after a bout of infection.
“When we are ill, we imagine that if we are feeling crappy, it’s because our immune system is going into overdrive, and somehow this is impairing our function,” said Catherine Dulac, a professor of molecular and cellular biology at Harvard and an author of one of the studies. “But the idea that it’s actually the brain that orchestrates this was extraordinarily intriguing.”
With a still-raging pandemic, an upcoming flu season and other more common pathogens threatening our health, our immune system has an ally in the brain.
“I think it’s really an interplay between the two that’s fairly intimate and requires a lot of coordination,” said Anoj Ilanges, a biologist at the Janelia Research Campus. “Figuring out this coordination and what it really means is a big question in better understanding our response to infection in general.”
The new research shows that by making us feel bad temporarily, our brain is both telling us to rest and helping us feel better faster.
Feeling bad helps us — and other animals — feel better
Humans are not alone in getting sick and feeling crummy.
Big or small, warm or coldblooded, vertebrate or invertebrate, animals also contend with life-threatening infections from viruses, bacteria and other pathogens and “have some sort of response that’s very similar to this,” said Ilanges, who co-wrote one of the studies.
To understand how sickness affects the body and brain, researchers injected mice with pro-inflammatory agents that mimic bacterial or viral infections.
Mice get sick in much the same way that we do. They become lethargic and move around much less. Their body temperature changes, and they spike a fever. They seek out warmth when they can. They drink less water.
And just as we tend to not want food when we fall ill, mice also drastically reduce their feeding when they are sick even with unrestricted access to food, and can drop a dramatic 10 percent of their body weight in days — the equivalent of “humans being starved for, like, a week,” Ilanges said.
Many of these behaviors appear to be adaptive to help us survive the infection, even though exactly why they help is still somewhat mysterious.
For example, losing one’s appetite seems counterproductive for winning against a pathogen. But earlier research found if the mice are given supplementary food directly to their stomach when they were sick, they were more likely to die during a bacterial infection. We still do not quite know why.
Other adaptations appear more intuitively helpful. Moving around less helps us conserve energy. And fevers may make the pathogen less effective while simultaneously boosting our immune system’s activity.
But making these shifts in eating habits or body temperature is no trivial task and requires the brain to intervene.
For warm-blooded mammals such as mice and humans, body temperature is “extremely strictly controlled,” staying in the same range whether we are in a cozy room or in the cold, said Dulac. But for a fever to occur, the brain inhibits those controls.
Ideally, “the response has to be controlled. So you’ll stop eating, but you need to start eating again,” said Jeffrey Friedman, professor of molecular genetics at the Rockefeller University and co-author of one of the studies.
“It seems like all these symptoms — conserving energy, raising temperature to be able to better fight pathogen and not eating — is actually very beneficial for the animal and orchestrated by the brain, which I think is really a fabulous phenomenon,” Dulac said.
What a sick brain looks like
We tend to look like we are not doing much when we are sick — we are, after all, probably in bed and not moving — but the brain is hard at work. The researchers looked for genetic markers of activity in the brain soon after they injected their mice with a pro-inflammatory agent. “Surprisingly, if you look at the brain, there’s high levels of activity across many regions,” Ilanges said.
By focusing on a few prominently activated brain regions, the two research groups uncovered dedicated neurons in areas involved with different aspects of how animals respond to sickness.
The first study found that specific neurons in the hypothalamus, a brain structure crucial for regulating basic bodily functions, control fever and appetite during sickness. When Dulac and her colleagues specifically stimulated these hypothalamic neurons without making the mice sick, the mice still spiked a fever, sought out warmer temperatures and lost their appetite. These neurons in the hypothalamus were able to generate aspects of the sickness symptoms without sickness.
If these hypothalamic neurons were selectively destroyed, the mice did not get a fever or prefer warmth when sick, suggesting that they are necessary for these symptoms.
These neurons are probably able to detect sickness from signals released by the immune system in the body, Dulac said. This particular part of the hypothalamus is located where the blood-brain barrier is somewhat permeable, which allows immune molecules to leak through. Non-neuronal cells may amplify these signals, which in turn activate the hypothalamic neurons that trigger the loss of appetite, fever and warmth-seeking.
Notably, the hypothalamus is not involved in lethargy or lack of movement. Instead, neurons in two parts of the brainstem — the nucleus of the solitary tract and the area postrema — step in to mediate the symptoms of reduced movement, feeding and drinking.
When Ilanges, Friedman and their colleagues activated neurons in these brainstem areas, the mice reduced their eating, drinking and moving even when they were not sick. But if the researchers inhibited the brainstem neurons when the mice were ill, the mice had much weaker symptoms, and still ate, drank and moved.
Together, the two new studies underscore the underappreciated role our brain plays when we are sick.
There is still much to discover about what the brain does when we are sick. We still do not know why some people have chronic symptoms long after the body has seemingly cleared the pathogen that once plagued it, like in the case of the millions of long-covid sufferers.
Our sickness behaviors “are adaptive when they’re turned on for short periods of time during these really potent infections,” Ilanges said. “You know, let’s just shut down everything. Let’s focus on fighting the infection.” But he speculates it is possible that these responses may accidentally stay on in chronic cases where “they might be doing more harm than good at that point,” he said.
But when the sickness response is well-regulated, understanding why we feel bad — and how the brain is involved — may help us work with our body and brain to get better.
“It really reinforces the advice that people are given when they are sick: rest, get a lot of hot tea or hot soup, and go under the blanket, and just rest, eat light,” Dulac said. “Just let your body and your brain fight the infection.”
“It’s helpful to know that the brain is doing this on purpose,” she added.
Do you have a question about human behavior or neuroscience? Email BrainMatters@washpost.com, and we may answer it in a future column.