Scientists Reveal How Prostaglandin E₂ Drives Chills and Warmth-Seeking Behavior During Fever
Fever is a hallmark response to infection, serving as a powerful evolutionary mechanism to curb pathogenic growth and enhance immune functions. Yet, accompanying fever, we often experience chills—an intense sensation of cold that compels behavioral responses such as bundling up or seeking warmth. While the autonomic mechanisms underlying fever are well characterized, the neural basis for chills and warming behaviors has remained elusive—until now.
In a groundbreaking study published in The Journal of Physiology, researchers from Nagoya University have identified critical neural circuits and molecular actors responsible for these chills, shedding light on how prostaglandin E₂ (PGE₂), a pyrogenic mediator, orchestrates warmth-seeking behavior during infection. Their findings suggest that chills are not merely uncomfortable symptoms but adaptive responses driven by precise brain mechanisms aimed at restoring thermal homeostasis.
When mammals fall ill, immune cells induce the production of PGE₂ in vascular cells of the brain. This lipid compound is well-known for acting within the preoptic area (POA) of the hypothalamus to trigger autonomic fever responses such as shivering, increased heat generation by brown adipose tissue, and vasoconstriction, all geared towards elevating core body temperature. However, PGE₂’s role extends beyond these autonomic pathways. It also drives behavioral thermoregulatory strategies—chiefly, warmth-seeking triggered by chills, although the mechanisms underlying this were unclear prior to this study.
Professor Kazuhiro Nakamura and his colleagues, including Dr. Takaki Yahiro and Dr. Yoshiko Nakamura, hypothesized that PGE₂ targets the lateral parabrachial nucleus (LPB), a brain region relaying peripheral sensory inputs, to mediate chills and warmth-seeking behaviors. This proposition was grounded in their previous research showing that LPB neurons transmit skin temperature information to higher brain centers involved in thermoregulation. To verify this, they designed a series of meticulous experiments using rat models.
The team employed thermal plate preference tests (TPPTs), placing rats on adjoining metal plates at controlled temperatures of 28°C (neutral) and 39°C (warm). Initially, healthy rats showed a consistent preference for the neutral plate, indicative of regular thermoregulatory behavior. Strikingly, rats injected with PGE₂ directly into the LPB displayed a marked shift, opting for the warmer surface and consequently elevating their core body temperature. Importantly, these PGE₂-treated rats exhibited no signs of autonomous thermogenic activity such as shivering, indicating that PGE₂ action in the LPB selectively modulates voluntary behavioral responses rather than involuntary mechanisms.
Delving deeper into receptor pharmacology, the researchers identified that among the four subtypes of prostaglandin E₂ receptors (EP1-EP4), the EP3 receptor subtype within the LPB is the key mediator of this warmth-seeking behavior. Administration of receptor subtype-specific agonists revealed that activation of EP3 receptors was both necessary and sufficient to modify thermal preference in rats. This receptor-specific effect underscores the precise molecular control within these thermosensory pathways.
Anatomical tracing of neurons expressing EP3 receptors in the LPB further revealed that their axonal projections predominantly target the central nucleus of the amygdala (CeA), a brain area classically associated with emotional processing, including the modulation of aversive states like discomfort and fear. Conversely, minimal projections reached the preoptic area, emphasizing distinct neural circuits for autonomic versus behavioral fever responses.
Physiological mapping showed that this EP3-expressing parabrachial-amygdala pathway is activated when the animal experiences cold ambient temperatures. Such activation likely amplifies cold signals relayed from the periphery to the amygdala, generating the sensation of chills that drives the animal to seek warmth behaviorally. Hence, during infection, PGE₂ acts on the LPB to potentiate these cold signals through EP3 receptors, engaging emotional circuits to promote adaptive warmth-seeking behavior.
These findings offer profound insights into the neurobiology of fever. PGE₂ exerts dual, complementary actions—on the one hand, engaging the POA to trigger autonomic heat production, and on the other, modulating the LPB to elicit chilling sensations that compel behavioral adaptations. This delineation of separate but convergent neural pathways advances our understanding of how the brain integrates physiological and emotional aspects of sickness to optimize survival.
Professor Nakamura emphasizes that this work “illuminates part of the neural basis for emotional symptoms during infection.” By revealing the brain’s emotional circuitry involvement, the research redefines chills not as merely unpleasant side effects but as evolutionarily conserved strategies enhancing fever efficacy. These behavioral responses aid infected organisms in maintaining elevated body temperatures conducive to immune defense.
Looking forward, the team highlights the need to determine whether this neural circuit architecture is conserved in humans and to explore its implications in chronic inflammatory and thermoregulatory disorders beyond infectious disease. Given the profound intersection of sensory processing, emotion, and autonomic regulation uncovered here, such research promises to expand our understanding of febrile pathophysiology and pave the way for novel therapeutic interventions targeting maladaptive fever responses.
This seminal study was supported by multiple funding bodies, including Japan’s Moonshot R&D program and the Ministry of Education, Culture, Sports, Science and Technology, underscoring the high priority of deciphering fundamental brain-body interactions during sickness states.
Subject of Research: Animals
Article Title: The pyrogenic mediator prostaglandin E₂ elicits warmth seeking via EP3 receptor-expressing parabrachial neurons: a potential mechanism of chills
News Publication Date: 10 February 2026
Web References: DOI:10.1113/JP289466
References: Takaki Yahiro, Yoshiko Nakamura, and Kazuhiro Nakamura. (2026) The pyrogenic mediator prostaglandin E₂ elicits warmth seeking via EP3 receptor-expressing parabrachial neurons: a potential mechanism of chills. The Journal of Physiology
Image Credits: Kazuhiro Nakamura
Keywords: Fever, chills, prostaglandin E₂, EP3 receptor, lateral parabrachial nucleus, warmth-seeking behavior, preoptic area, central amygdala, thermoregulation, sickness behavior, behavioral fever, neuroimmunology
Tags: adaptive responses to infectionchills and warmth-seeking behaviorevolutionary mechanisms of feverimmune system and temperature regulationNagoya University research on chillsneural circuits in fever responsephysiological effects of chillsprostaglandin E₂ and immune responsepyrogenic mediators in the brainrole of hypothalamus in chillsstudy on chills and feverthermoregulation during infection
