Why are you cold if you burn with fever? The reason for the chills

A recent study with rats carried out by a team from Nagoya University (Japan) has identified the neural mechanism that causes chillsa sensation of cold that favors the body’s response to infection, as published in The Journal of Physiology.

When mammals become infected, their immune system produces a pyrogenic mediator, prostaglandin E2 (PGE2)in the vascular cells of the brain. The PGE2 acts on the preoptic area, the thermoregulatory center of the brain, and triggers febrile autonomic responsessuch as chills, increased heat production in brown adipose tissue, and constriction of blood vessels in the skin.

PGE2 is known to trigger not only febrile autonomic responses, but also febrile behavioral responsesincluding warming behaviors with shivering, but the mechanism remains unclear.

To investigate this mechanism, Professor Kazuhiro Nakamura and Drs Takaki Yahiro (now at Oregon Health and Science University) and Yoshiko Nakamura of Nagoya University School of Medicine conducted a study in which they hypothesized that PGE2 acts in the lateral parabranchial nucleus (LPB) of the brainwhich transmits sensory signals, to trigger shivering and heat-seeking behaviors during infection. This was based on their 2023 study showing that LPB neurons transmit skin temperature sensations to the forebrain and influence body temperature regulation. To test this hypothesis, the team performed thermal plate preference testing (TPPT) placing rats on two metal plates at 28 °C (neutral) and 39 °C (hot). This allowed the rats to choose their preferred temperature.

Normal rats preferred the neutral plate, while rats injected with PGE2 in the LPB chose the warmer plate.which increased its core temperature. Rats treated with PGE2 did not show autonomous thermogenic responses such as shivering, indicating that PGE2 in the LPB specifically modulates behavioral responses.

They then investigated which of the four PGE2 receptor subtypes (EP1-EP4) trigger heat-seeking behavior. Their findings suggest that, during infection, PGE2 enhances cold signals from the lateral parabranchial nucleus (LPB) to the central nucleus of the amygdala via EP3 receptorswhich triggers chills and promotes heat seeking.

This study demonstrates that PGE2 increases body temperature by acting on two brain regions: the preoptic areawhich drives autonomous thermogenic responses, and the lateral parabranchial nucleus (LPB)which mediates behavioral responses.

“We have identified part of the neural basis of emotional symptoms during infection,” says Nakamura. “This discovery provides new insight into the causes of shivering and heat seeking by elucidating the role of emotional circuits in the brain. From an evolutionary physiological perspective, our findings suggest that behavioral changes related to fever They are adaptive survival strategies, rather than simple symptoms of infection“.

The authors note that future research should determine whether this circuit is conserved in humans and clarify its role in chronic inflammation and thermoregulatory disordersas well as in infectious diseases.