EP3R-Expressing Glutamatergic Preoptic Neurons Mediate Inflammatory Fever

Area of Science:

• Neuroscience
• Physiology
• Immunology

Background:

• Fever, a rise in body temperature, is a common response to infection and inflammation.
• It is regulated by the central nervous system (CNS), specifically neurons in the median preoptic nucleus (MnPO) that express prostaglandin E2 (EP3) receptors.

Purpose of the Study:

• To identify the specific type of MnPO neurons involved in fever responses.
• To investigate the role of EP3 receptor-expressing neurons in thermoregulation and fever.

Main Methods:

• In situ hybridization to identify coexpression of EP3 receptors and VGluT2 (a marker for excitatory neurons) or Vgat (a marker for inhibitory neurons) in MnPO neurons.
• Retrograde tracing to map projections from MnPO neurons to the raphe pallidus.
• Selective ablation of MnPO^VGluT2 or MnPO^Vgat neurons.
• Generation of EP3 receptor conditional knockout mice crossed with VGluT2-IRES-cre or Vgat-IRES-cre mice.

Main Results:

• MnPO^EP3R neurons were found to coexpress the excitatory marker VGluT2, not the inhibitory marker Vgat.
• MnPO^VGluT2 neurons project extensively to the raphe pallidus, a key fever-regulating area, while MnPO^Vgat neurons have limited projections.
• Ablation of MnPO^VGluT2 neurons abolished fever but did not affect body temperature changes due to stress or thermal challenges.
• Confirmation that EP3 receptor-expressing neurons mediating fever are glutamatergic, not GABAergic.

Conclusions:

• The findings demonstrate that excitatory MnPO^VGluT2 neurons, not inhibitory ones, are responsible for mediating fever.
• This discovery necessitates a reevaluation of current models of central thermoregulation, particularly the role of MnPO^EP3R neurons.