As sniffles and sneezing set in, the last thing anyone wants to do is leave the house to socialize with people. When feeling sick, hunkering down in bed under a cozy pile of blankets is often the only thing that sounds good.
This desire to avoid other people when feeling under the weather is an evolutionary one: It both helps the sick person rest and recover more quickly, while also preventing their infection from spreading to more people. The societal benefits of socially isolating when sick are well understood, but researchers have wondered what molecular mechanisms underly this behavior.
In a new study published today in Cell, neuroimmunologist Gloria Choi at the Massachusetts Institute of Technology, immunologist Jun Huh at Harvard University, and their teams have begun to answer that question.1 Using mice, they discovered that the cytokine interleukin-1 beta (IL-1β) signals through its receptor on neurons in a specific brain region to promote the social withdrawal behavior during an illness, revealing greater insight into the neural mechanisms that underlie this response.
“Our findings show that social isolation following immune challenge is self-imposed and driven by an active neural process, rather than a secondary consequence of physiological symptoms of sickness, such as lethargy,” said Choi in a statement.
Cytokines are signaling proteins secreted by immune cells that—due to their ability to move through the blood and cerebral spinal fluid (CSF)—can act as molecular go-betweens for the immune and nervous systems.2 To identify cytokines that might be involved in social withdrawal due to an infection, Choi, Huh, and their teams performed a social behavior test in mice. They injected mice with lipopolysaccharide (LPS), which is an outer membrane component of bacteria that stimulates the immune system in a similar way that an infection would. They saw that these mice were less social and more lethargic than uninfected control mice. The team then injected mice with different cytokines, and they found that only one cytokine led to the same behavioral symptoms as the LPS-injected mice: IL-1β.
Since IL-1β binds to interleukin-1 receptor type 1 (IL-1R1), the team used fluorescence in situ hybridization to find where in the brain this receptor is expressed. They saw a brain region called the dorsal raphe nucleus (DRN), which is involved in regulating social behaviors, light up with IL-1R1-expressing neurons. The DRN is also located near the cerebral aqueduct—through which CSF flows—giving it access to molecules like cytokines that are present there, so the team decided to focus on the IL-1R1-expressing neurons there.
The team found that activating these neurons in the absence of IL-1β led to social withdrawal behaviors in mice, indicating that these neurons are sufficient to lead to this response. To test if these neurons are required for social withdrawal, the researchers blocked the neurons’ activity, and they found that even in the presence of IL-1β, the mice didn’t isolate themselves. The team saw the same results when they specifically knocked out IL-1R1 in these neurons. Notably, the researchers reported that while these mice did not withdraw socially, they were still lethargic, indicating that the IL-1R1-expressing neurons in the DRN regulate social withdrawal behavior but not the tired feeling that also comes along with an infection.
“Collectively, these results reveal a role for IL-1R1-expressing DRN neurons in mediating social withdrawal in response to IL-1β during systemic immune challenge,” the researchers wrote.
The researchers plan to study this circuit further and to investigate other neurons in the DRN that may also play a role in the behavior. In the meantime, it’s clear that the desire to isolate and hunker down with hot tea and lots of blankets is a hard-wired one.
- Yang L, et al. IL-1R-positive dorsal raphe neurons drive self-imposed social withdrawal in sickness. Cell. 2025.
- Yang L, et al. One messenger shared by two systems: How cytokines directly modulate neurons. Curr Opin Neurobiol. 2023;80:102708.
