Fever, loss of appetite and seeking warmth are common responses to infections, and the discovery of the brain cells responsible for this behaviour in mice could help treat chronic illnesses
8 June 2022
The brain cells responsible for generating fever and other symptoms of sickness have been discovered in mice, a finding that could improve treatments for chronic illnesses.
Animals all largely respond to being ill in the same way, experiencing symptoms such as fever, fatigue, loss of appetite and seeking warmth. Previous studies have suggested that fever helps animals survive bouts of sickness by increasing body temperature – making it harder for pathogens to survive – while fatigue and loss of appetite have been linked to energy regulation.
To pin down the parts of the brain responsible for coordinating these behaviours, Catherine Dulac at Harvard University and her colleagues injected mice with molecules that induce similar effects to a genuine illness. They used such molecules to avoid the risk of a real pathogen spreading uncontrollably.
One molecule, lipopolysaccharide, mimics the effects of a bacterial infection, while the other, polyinosinic-polycytidylic acid, mimics a viral infection. Both molecules trigger an acute inflammatory response that, in turn, causes symptoms like fever.
The researchers used sequencing and fluorescent imaging to determine which neurons were most active in the brains of the mice during the induced sickness. They suspected that the neurons responsible for regulating sickness symptoms would be in the hypothalamus. “That’s where all the control of appetite and thermoregulation occurs,” says Dulac.
The team found a population of neurons that fit the bill in the hypothalamus’s ventral medial preoptic area, which is generally responsible for thermoregulation. These neurons were significantly activated by the sickness-producing molecules, in comparison with the brains of mice that hadn’t been given the molecules.
To confirm the findings, the team then genetically inhibited these neurons within mice so they wouldn’t be activated during sickness. The altered mice didn’t develop a fever when given one of the sickness-producing molecules, while also experiencing a smaller drop in their appetites and not seeking as much warmth. They were still fatigued, however, suggesting that this symptom is regulated by another part of the brain.
Dulac says she is confident that humans have a similar population of neurons that control sickness symptoms. “The hypothalamus in mammals is extremely conserved,” she says.
She also hopes that these findings help researchers develop treatments to reduce the symptoms of chronic sickness. “One can also use our findings to ask questions that may benefit human health,” says Dulac. “For example, what happens if these sickness neurons are activated frequently – including during early life – do they become more sensitive to illness?”
“One of the biggest threats to survival is infection,” says Marysia Placzek at the University of Sheffield in the UK. “If cells in our bodies are infected, they start to make ‘immune’ signals, but if that was all that happened, it would be too small a response, too local.”
“This study has found a new group of hypothalamic neurons that are activated by immune signals,” says Placzek. “These then marshal the huge response that is necessary to fight the infection.”
Journal reference: Nature, DOI: 10.1038/s41586-022-04793-z
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