In a groundbreaking advancement in neurophysiology, researchers have unveiled a specialized population of neurons in the brain that orchestrate the body’s dramatic shifts between fever and torpor, two opposing physiological states critical for survival. The discovery highlights the prostaglandin EP3 receptor (EP3R)-expressing neurons in the median preoptic nucleus (MnPO) as a pivotal biological switch, capable of toggling the body’s temperature and metabolic responses with remarkable precision and duration. This revelation not only deepens our understanding of thermoregulatory control but opens new avenues for therapeutic intervention in disorders related to body temperature dysregulation.
Torpor is an adaptive state characterized by a controlled and reversible decrease in body temperature and metabolic rate, enabling animals to survive periods of food scarcity and harsh environmental conditions. This hypometabolic condition is especially prevalent among small mammals and certain bird species, acting as a short-term alternative to hibernation. Conversely, fever represents the body’s hypermetabolic defensive mechanism against infections and systemic inflammation. Until now, the neuronal circuitry underlying these dichotomous physiological responses had remained largely elusive, hindered by the complexity and diversity of preoptic neurons known to express numerous peptides and receptors.
The investigation conducted by Machado and colleagues sheds light on this mystery by identifying EP3R-positive neurons within the MnPO as both necessary and sufficient for initiating and maintaining fever and torpor. Unlike prior studies that mapped various neuronal subpopulations associated with thermoregulation, this research uniquely isolates EP3R expression as a genetic marker exclusive to the two-way thermoregulatory switch. By combining chemogenetic and optogenetic techniques, the team demonstrated that stimulating these neurons induces prolonged hypothermia reminiscent of torpor, whereas inhibiting them triggers sustained fever, even after brief interventions.
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This bi-directional control mechanism relies on persistent intracellular signaling cascades within the EP3R-expressing MnPO neurons. Elevations in cyclic AMP (cAMP) and calcium ion concentrations post-stimulation suggest that these neurons maintain prolonged activity states far beyond the initial triggering stimulus. Such persistent signaling may underlie the extended durations of fever or torpor observed behaviorally, offering a cellular explanation for how rapid changes in thermoregulation can translate into lasting physiological states.
The MnPO, located in the anterior hypothalamus, has long been recognized as a crucial hub for thermoregulatory processes, integrating peripheral temperature signals with central control pathways. However, the heterogeneity of preoptic neurons has complicated efforts to pin down specific molecular drivers of temperature modulation. The identification of EP3R as a unique marker simplifies this landscape, providing a clear genetic handle on a functionally coherent neuronal group linking inflammation-induced pyrexia and hypothermic torpor.
Importantly, the study’s findings align with and expand upon prior research indicating the involvement of preoptic neurons expressing various peptides and receptors, such as those sensitive to estrogen or leptin, in temperature regulation. The convergence upon EP3R neurons underscores the receptor’s role as a final integrator of thermogenic and hypothermic signals, adding a new dimension to the neurochemical orchestration of body temperature. Furthermore, it bridges the gap between immune signaling and neural control mechanisms, given that prostaglandin E2-mediated fever is a well-established response to infection and inflammation.
Beyond the fundamental scientific intrigue, the discovery carries potential clinical implications. Disorders of thermoregulation, including hypothermia in critical illness or persistent fevers in autoimmune conditions, could be better targeted through modulation of the MnPO-EP3R neuronal population. The ability to selectively switch these neurons on or off may pave the way for novel treatments that harness the body’s intrinsic temperature control circuitry to restore homeostasis or induce therapeutic hypometabolic states for medical purposes.
Additionally, the revelation of persistent intracellular signaling mechanisms provides crucial insight for developing pharmacological agents capable of achieving durable physiological effects from transient interventions. Drugs designed to influence the cAMP or calcium pathways within EP3R neurons might replicate or dampen fever and torpor states with improved temporal control, minimizing side effects associated with systemic immune activation or metabolic depression.
This study’s innovative use of optogenetics and chemogenetics—a precise manipulation of neuronal activity using light or engineered receptors responsive to designer drugs—further exemplifies the frontier methods propelling neuroscience. These approaches allowed researchers to activate or inhibit EP3R neurons in vivo, conclusively demonstrating their causal role in temperature regulation. The persistence of induced fever or hypothermia following brief stimulation challenges prior assumptions about the immediacy and reversibility of thermoregulatory behavior, suggesting a neural memory component intrinsic to these neurons.
Moreover, understanding the MnPO-EP3R neuronal switch enriches evolutionary perspectives on survival strategies. Torpor and fever represent two ends of an adaptive spectrum balancing energy conservation and immune defense. The capacity of a single neuronal population to govern these states allows rapid, context-dependent transitions, optimized for survival amid fluctuating environmental and pathogenic threats.
Future research will likely explore how peripheral signals—such as nutrient availability and immune mediators—modulate EP3R neuron activity and how these neurons interact with broader hypothalamic and brainstem circuits governing metabolism, cardiovascular function, and behavior. Decoding the network dynamics surrounding the MnPO-EP3R population could reveal further intricacies of systemic thermoregulation and its links to health and disease.
In conclusion, the identification of EP3R-expressing neurons in the median preoptic nucleus as a two-way switch for fever and torpor represents a transformative step in neurobiology. This work not only clarifies longstanding questions about the neural substrates of body temperature control but also highlights how a genetically defined neuronal population integrates metabolic and immunological cues to enact survival-critical physiological states. As the field advances, these insights promise to inspire innovative therapies and deepen our comprehension of the brain’s remarkable capacity to adapt to internal and external challenges.
Subject of Research: Neuronal control of thermoregulation; mechanisms of fever and torpor.
Article Title: Preoptic EP3R neurons constitute a two-way switch for fever and torpor.
Article References:
Machado, N.L.S., Lynch, N., Costa, L.H.A. et al. Preoptic EP3R neurons constitute a two-way switch for fever and torpor. Nature (2025). https://doi.org/10.1038/s41586-025-09056-1
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Tags: adaptive physiological statesbody temperature dysregulation disordersfever and torpor controlfever as a defense mechanismhypometabolic states in small animalsmedian preoptic nucleus functionmetabolic response mechanismsneuronal circuitry of temperature regulationpreoptic EP3 receptor neuronsprostaglandin receptors in neurophysiologyresearch on neurophysiology and temperature regulationthermoregulation in mammals