A faster way to trigger sickness

The starting point was a small chemical messenger called prostaglandin E2, or PGE2. When an infection develops, the immune system produces this molecule naturally, and it acts like an alarm system, triggering the symptoms we associate with illness: fatigue, chills, fever and loss of appetite. What scientists didn't know was whether PGE2 produces these effects by activating specific parts of the brain's autonomic system — the network that controls involuntary bodily functions — or whether the effects emerge from activation spread across a much wider area.

The researchers injected PGE2 directly into the mice's brains and found that symptoms began almost immediately, compared with hours or days for classic laboratory methods that mimic infections. The symptoms also faded quickly, lasting only 30–45 minutes.

That brevity turned out to be a technical advantage. The team could analyze the mice's behavior, map brain activity and record individual neurons within a single, compact window of sickness.

"Gretel found an approach to study sickness with many technical advantages over previous techniques," said Prevedel, the paper's senior author. "We were able to essentially get a very comprehensive picture of sickness in a much shorter period of time."

The insular cortex takes center stage

The injected mice quickly developed fever, became sluggish and ate less — the classic sickness profile. When the researchers mapped which brain areas switched on, they found that PGE2 had activated many parts of a network known for monitoring the body's internal state. Among them, individual groups of nerve cells in the insular cortex — a region involved in interpreting the body's condition — were clearly engaged, pointing to a central role for this area in how the brain responds to illness.

The study's conclusions rest on mice, and mouse findings do not always translate directly to humans. Still, the work both broadens the scientific view of how the brain handles infection and provides a practical new tool for studying it.

A collaborative effort

Kamm emphasized the role of EMBL Rome in the project. "Our colleagues at EMBL Rome were crucial for our work. Cornelius Gross (head of EMBL Rome) and Hiroki Asari (former EMBL Rome group leader) are well connected within the neuroscience research community, and thus provided important links to key people and resources," she said, adding that close interactions during seminars led to important knowledge exchange.

Gross introduced the team to Nicola Renier, who pioneered a method called iDISCO, which visualizes neuronal activation across the entire brain using activity markers.

Prevedel also credited EMBL's EIPOD fellowship program, which supports interdisciplinary postdocs with their own ambitious ideas. "Gretel is taking a different look at a common problem, and she's a great example of what the EIPOD program looks for," he said. "In her case, the various methods we had established over time in our lab — imaging, electrophysiology, plus others — helped make her idea a reality."

For Kamm, the implications reach beyond the lab. "Many people associate sickness with the bacteria or viruses attacking you, but most symptoms we associate with being sick are actually produced by the brain," she said. "So the main takeaway is that the whole brain is probably involved in changing our decisions and behavior when we have an infection."