by Courtney Whilden
figures by Arianna Lord

Imagine this: it’s the peak of winter, and you wake up not feeling well. You touch your face, it feels warm, and your thermometer tells you that you have a fever. As the day goes on, you don’t have much of an appetite, you’re exhausted, and you crave the warmth of a blanket and a cup of hot tea. Unfortunately, most of us have experienced this scenario. But have you ever wondered how our bodies produce these symptoms when we are sick? We know that pathogens—including viruses or bacteria—activate the immune system. The immune system communicates with the brain which, in turn, coordinates a body-wide response to fight the pathogen and allow our bodies to heal. For a long time, though, it was not known how the immune system and the brain work together to generate sickness behaviors. However, this year, two studies led by Osterhout and Illanges, made major breakthroughs toward an answer.

Identifying sickness-responsive neurons in mice

Fortunately for scientific research, mice have a similar set of sickness behaviors as humans, allowing them to be used as models for human illness response. Sick mice get fevers, avoid eating, get sleepy, seek warmth, and avoid socializing. So, to understand how the brain generates these sickness behaviors, both studies induced illness in mice and observed the effects on the brain. To do this, they injected mice with “LPS,” a molecule found on bacterial membranes that activates immune cells and leads to inflammation. After receiving LPS, the mice showed sickness symptoms including fever, loss of appetite, warmth-seeking, and less running around their cages. Both studies then sought to identify which cells in the brain control the mice’s behavioral responses to LPS injection (Figure 1).

Figure 1: How to determine which neurons are active during sickness. Neurons that are active produce c-FOS. When mice are injected with LPS, they become sick. Therefore, to see which neurons are active during sickness, mice were injected with LPS to make them sick, and then neurons with high levels of c-FOS were labeled. Two of these populations were located in the hypothalamus and in the brainstem.

The brain receives information about the body and, in turn, sends signals back to the body to coordinate an appropriate response. This information is transmitted via the electrical activity of cells in the brain called neurons. So, to figure out which neurons coordinate sickness behavior, a good first step is to see which neurons are activated during sickness, as these active neurons could be sending signals to the rest of the brain and the body to coordinate sickness behavior. When neurons are active, they produce a protein called “c-FOS.” c-FOS is a protein that influences cellular pathways to respond to changes in a cell’s conditions, including neuronal activity. Therefore, to see which neurons are active during sickness, the scientists induced sickness in mice and identified neurons by their increased levels of c-FOS

The first study identified a population of neurons in the hypothalamus, a brain region known to influence hormone release, while the second study focused on a population of neurons in the brainstem, a region known to control basic survival functions (Figure 1). Both studies then used combinations of clever experiments to show that their respective populations of neurons control specific aspects of sickness behavior.

How does the brain generate fever?

While having a fever can be an unpleasant experience, fevers help the body fight off infections.  The hypothalamus is thought to work like a thermostat to keep the body at a set temperature—controlling the release of hormones to increase or decrease heat conservation as needed. When you get sick, this set point is increased, allowing your body temperature to rise higher than normal. Previously, we did not know which neurons in the hypothalamus control the onset of fever during sickness. Osterhout et al. noticed that one of the populations of neurons activated by LPS is positioned next to the brain’s communication center with the blood system, an optimal location to receive immune signals and tell the rest of the body to generate a fever (Figure 2). We know that this population of neurons becomes active when mice are sick, but how can we know that they are generating the fever and not just responding to it? 

Figure 2: LPS-responsive neurons in the hypothalamus are responsible for fever. When the “sickness” neurons in the hypothalamus are artificially activated in healthy mice, the mice develop a fever. If you eliminate “sickness” neurons in the hypothalamus and then try to induce sickness by injecting LPS, the mice do not develop a fever.

If activity of these hypothalamic neurons generates a fever, then activating them in healthy mice should cause a fever even when the mice are not sick. To do this, Osterhout et. al used an artificial receptor that increases neuron activity when the receptor is bound by a specific chemical. They expressed this receptor specifically in hypothalamic neurons activated by LPS and then delivered the chemical to activate these neurons. When they performed this experiment with healthy mice, remarkably, the mice developed a fever and increased warmth-seeking behavior. Then, the scientists delivered a toxin to specifically kill these neurons, and then tried to induce sickness with LPS. When they did this, the mice did not develop a fever or warmth-seeking behavior (Figure 2). This is a striking finding—even after activating the immune system with LPS, the mice cannot develop a fever if they don’t have this single population of neurons

So, how do these neurons recognize sickness and in turn generate a fever? Osterhout et al. hypothesized that these neurons might be directly activated by immune signals that the body releases when we get sick. To test this, they cultured these neurons in a dish and monitored their activity while exposing them to different immune signals, finding that the neurons became active in response to these immune signals. This strongly suggests that during sickness, the immune signals that the body produces directly activate a population of neurons in the hypothalamus, and those neurons then coordinate a fever response

Why don’t I feel like eating when I’m sick?

In addition to fever, it is common to experience a loss of appetite during sickness. Therefore, both studies asked if their respective populations of neurons are involved in appetite. Ilanges et al. activated the population of neurons in the brainstem (that they found earlier to be LPS-responsive) in healthy mice, and the mice almost completely stopped eating. This shows that activation of LPS-responsive brainstem neurons is enough to curb appetite, even if the mice are not sick. Then, Ilanges et al. chemically stopped the activity of these neurons and tried to make the mice sick with LPS. Even though they had been given LPS, they continued to eat normally. This suggests that the LPS-responsive neurons in the brainstem play an essential role in the loss of appetite that occurs with sickness.

Osterhout et. al also explored the role of their fever-driving, hypothalamic neuron population in loss of appetite during sickness, and found similar results to Illanges et. al. To make these results even more interesting, Osterhout et. al also found that these neurons are directly connected to neurons in the brain known to control hunger. To determine if this specific connection drives loss of appetite, they activated LPS-responsive neurons that project to hunger-driving neurons using an artificial channel that increases neuron activity when exposed to light (Figure 3). When they activated the region where LPS-responsive neurons contact hunger-driving neurons, the mice consumed less food. This suggests that the connection between fever-driving neurons and hunger-driving neurons is directly responsible for loss of appetite during sickness.

Figure 3: The connection between “fever” neurons and “feeding” neurons in the hypothalamus underlies loss of appetite. “Fever” neurons are directly connected to “feeding” neurons in the hypothalamus. Artificial activation of the fever neurons’ connection onto feeding neurons causes mice to stop eating, even though they are not sick.

Overall, both studies identified neuron populations whose activity controls different aspects of sickness behavior. While one study identified a population of neurons in the hypothalamus that controls fever and appetite during sickness, the other study identified a population of neurons in the brainstem that controls appetite during sickness. It is important to note that these studies were done in mice, which may not perfectly reflect the mechanisms the human brain uses to control sickness behaviors, and we don’t yet know how these two populations could be working together to coordinate sickness. Finding these answers in future research will be important for understanding more about how the brain makes us feel sick, and to develop medicines to effectively treat the unpleasant side effects of sickness.

Courtney Whilden is a Ph.D. candidate in the Program in Neuroscience at Harvard University, where she is studying how small RNAs affect neuron function and behavior.

Arianna Lord is a PhD student in Organismic and Evolutionary biology. She studies the natural history and biogeography of invertebrates. You can find her on instagram as @thingsdoingsbeings.

Cover image by guvo59 from pixabay.

For More Information:

  • To learn more about the scientists who led these studies and their ongoing research, check out Dr. Illanges’ and Dr. Osterhout’s lab websites.
  • This video from MIT explains how scientists can use light to activate cells
  • Check out this article to learn more about sickness behavior and the specific molecules and pathways that are involved.

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