When we have a cold and a fever, we often feel cold: we suffer from chills and instinctively try to warm ourselves. A research team has now investigated how chills occur and why they also influence our behavior. In experiments with rats, they found that our immune system initiates this typical fever reaction using a special messenger substance, prostaglandin E2. This affects two different areas in the brain. The first is the temperature control center in the diencephalon, which then causes fever and, in the case of chills, triggers tremors. The second area activated by prostaglandin E2 is a nucleus in the brainstem that sends signals to the amygdala and triggers heat-seeking behavior in those affected. This makes us want to hide under thick blankets.
When we have the flu, cold or other illnesses, we often develop a fever: our body temperature rises to inhibit the growth of invading pathogens and increase the activity of immune cells. Despite this internal heat, when we have a fever, paradoxically we don’t feel warm, but rather cold: we freeze despite the warm environment, try to keep ourselves warm with hot tea, thick blankets or hot water bottles and, in extreme cases, we even start to shiver like we do in extreme cold. However, what lies behind this behavioral reaction and how it is triggered neuronally was previously unclear.
A messenger substance causes the fever
Takaki Yahiro and his colleagues from the University of Nagoya have now investigated in more detail why we feel cold when we have a fever. The starting point of their study was a specific messenger substance, prostaglandin E2 (PGE2). “This messenger substance is the main trigger of fever,” they explain. “It is produced and released in the vessels throughout the brain and spinal cord during systemic infections.” It was already known how the prostaglandin E2 triggers the autonomic fever reaction: The messenger substance is sent to the preoptic area in the diencephalon, which acts as the temperature control center of our body. When prostaglandin E2 docks on the receptors in this center, this sets in motion a cascade of reactions that up-regulate our body temperature: the vessels in the skin constrict in order to lose less heat to the outside, fat burning in the brown adipose tissue increases and, when we have chills, muscle tremors are also triggered as an additional source of heat.
Researchers have long suspected that prostaglandin E2 not only causes these autonomous, physiological fever reactions, but also the associated subjective sensations and behavioral changes – the feeling of freezing and the increased need for warmth. “Studies in animals with deactivated preoptic areas have shown that this center is not responsible for these behavioral changes,” report Yahiro and his colleagues. However, another brain region could be responsible instead, the so-called lateral parabrachial nucleus in the brainstem. “This area is a critical junction where temperature signals arrive from the skin’s thermoreceptors and which then initiates physiological and behavioral responses. For example, this nucleus ensures that we feel cold and uncomfortable when the skin and limbs become too cold by sending signals to the amygdala, the center of the brain associated with fears, avoidance reactions and negative emotions.
…and also our freezing
To find out whether the parabrachial nucleus might also be involved in the sensation of cold during fever, Yahiro and his colleagues carried out experiments with rats. They injected this fever messenger prostaglandin E2 directly into the switching point in the brain stem and then gave the animals the choice between a floor plate at a normal temperature and a warming plate heated to 39 degrees. It turned out that the rats that had received the prostaglandin preferred to stay on the warmer plate. Control animals without messenger substance injection, on the other hand, chose the neutral temperature plate. Further analyzes revealed that a special receptor, EP3R, in this brainstem area reacts to the messenger substance. This activates a signaling pathway that, like the normal cold response, extends to the amygdala and triggers heat-seeking and cold-avoiding behavior. “However, this reaction of the parabrachial nucleus to prostaglandin E2 does not trigger fever or increased burning of brown fat,” report Yahiro and his team. This suggests that the brainstem’s reaction to the messenger substance only specifically influences behavior in the event of a fever.
Taken together, the results show that fever, chills and our fever-related shivering are due to one messenger substance, but to two different brain areas and circuits. In the preoptic area, prostaglandin E2 triggers the autonomic fever reaction and ensures that our body temperature rises. In the brainstem, however, prostaglandin E2 acts on the parabrachial nucleus, which triggers the subjective feeling of cold and our heat-seeking behavior. “This discovery provides new insights into the causes of chills and heat-seeking behavior by elucidating the role of emotional circuits in the brain,” says senior author Kazuhiro Nakamura. “From an evolutionary perspective, our results also suggest that behavioral changes associated with fever are adaptive survival strategies and not just simple symptoms of infection.”
Source: Takaki Yahiro (Nagoya University) et al., The Journal of Physiology, doi: 10.1113/JP289466