Fevers, chills, an appetite that vanishes – we can tell when we’re getting sick. Many people chalk these symptoms of illness up to the immune system fighting off infection. But there’s another player involved when we feel woefully under the weather.
“All of this is orchestrated by the brain,” says neurobiologist Catherine Dulac, who is a Howard Hughes Medical Institute Investigator at Harvard University. Now research from Dulac’s team, published June 8, 2022, in Nature, pins this broad response on a previously uncharacterized population of neurons in the brain.
How exactly the brain serves as an infection ringleader has been unclear. Earlier research had identified receptors in the brain that were required for animals to develop a fever. But fever is only part of the story. One of the bigger mysteries is: Where does ultimate control for the symptoms and behaviors associated with sickness lie?
Dulac, her postdoctoral fellow, Jessica A. Osterhout, and colleagues injected mice with molecules that mimic bacterial or viral infections to investigate that question. As the mice’s immune systems reacted to these inflammatory molecules, the researchers homed in on which neurons jumped into action. The team watched neurons’ gene expression through single-cell RNA sequencing and mapped the whereabouts of those neurons using a visualization technique called MERFISH, which was developed in the lab of HHMI Investigator Xiaowei Zhuang at Harvard, a collaborator in this work.
The researchers focused on an area of the brain’s hypothalamus, the region that regulates most physiological functions. One neuronal population that responded to the immune agitators looked particularly promising. These cells, which the team called LPS-activated VMPO (VMPOLPS) neurons, sat near the blood/brain barrier where they could quickly catch wind of an infection and communicate with the circulatory system. “We thought this would be the perfect area,” Dulac says.
“More and more studies are showing communication between these two systems that are very complex.”
Catherine Dulac, HHMI Investigator at Harvard University
Next, the team turned to parsing the VMPOLPS neurons’ role in regulating sickness symptoms. In some mice, the scientists artificially activated these neurons thanks to a genetic strategy called TRAP2 developed by HHMI Investigator Liqun Luo from Stanford University, also a collaborator in this work, and observed that those rodents’ body temperatures rose while their appetites diminished. When this happened, these mice moved to warmer parts of their enclosures – akin to how people may huddle under a blanket when ill. In another set of mice, the team killed off the VMPOLPS neurons. When those mice were injected with the bacterial molecules or viral mimics, they didn’t develop fevers or move to warmer climes, suggesting the neurons were necessary for those behaviors.
The scientists traced how VMPOLPS neurons in the hypothalamus tether to twelve areas of the brain, including ones related to stress, avoidance, appetite control and thermoregulation. Using pulses of laser light, the scientists activated the neural connection to a region known for regulating temperature and observed that the mice’s body temperatures rise. Similarly, when the link to an area related to appetite were turned on, mice ate less chow.
Together, the experiments showed that the VMPOLPS neuron population serves as sickness symptom headquarters. This illness response crew turns on with infection triggers, is required for some symptoms to arise and directly connects to areas of the brain that control how illness manifests. Because of VMPOLPS neurons’ proximity to the blood brain barrier, the scientists suspect that these cells help relay messages between the brain and the immune system.
At the outset, her team was most concerned with figuring out fever, Dulac says. Ultimately, “we realized that there was this really interesting dialogue between non-neuronal cells and neurons,” she says. “It became a way more complex story.”
The researchers identified immune cells that make signaling molecules such as cytokines, chemokines and prostaglandins. Some of those molecules affect the signals sent by VMPOLPS neurons, suggesting a route by which the brain and the immune system communicate during disease. Based on their results, the team developed a model of how VMPOLPS neurons act as a sickness symptom control center.
“The authors show that this neuronal population can directly sense local immune signals and trigger changes in thermoregulation and appetite, raising the fascinating possibility that it is the keystone in a pathway linking the immune system to adaptive behavior,” say graduate student Maddy Junkins and Elena Gracheva, a neurophysiologist at Yale University, who weren’t part of this work. “One of the major strengths of this study is that the authors look at this interaction at different levels from animal behavior to single gene analysis,” they say.
There’s still a lot to learn about how the brain responds to inflammation, from the acute variety investigated in this work, to chronic inflammation from aging, obesity and degenerative diseases such as Alzheimer’s. “More and more studies are showing communication between these two systems that are very complex,” Dulac says.