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Direct pyrogenic input from prostaglandin EP3 receptor-expressing preoptic neurons to the dorsomedial hypothalamus

Authors

  • Yoshiko Nakamura,

    1. Neurological Sciences Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA
    2. Department of Morphological Brain Science, Graduate School of Medicine
    3. Department of Intelligence Science and Technology, Graduate School of Informatics
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  • Kazuhiro Nakamura,

    1. Neurological Sciences Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA
    2. Department of Morphological Brain Science, Graduate School of Medicine
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  • Kiyoshi Matsumura,

    1. Department of Intelligence Science and Technology, Graduate School of Informatics
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    • *

      Present address: Department of Information Science and Technology, Osaka Institute of Technology, 1-79-1 Kitayama, Hirakata-City, Osaka 573-0196, Japan.

  • Shigeo Kobayashi,

    1. Department of Intelligence Science and Technology, Graduate School of Informatics
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  • Takeshi Kaneko,

    1. Department of Morphological Brain Science, Graduate School of Medicine
    2. Core Research for Evolution Science and Technology, Japan Science and Technology, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan
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  • Shaun F. Morrison

    1. Neurological Sciences Institute, Oregon Health & Science University, 505 NW 185th Avenue, Beaverton, OR 97006, USA
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Dr K. Nakamura, 1Neurological Sciences Institute, as above.
E-mail: nakamura@ohsu.edu

Abstract

Fever is induced by a neuronal mechanism in the brain. Prostaglandin (PG) E2 acts as a pyrogenic mediator in the preoptic area (POA) probably through the EP3 subtype of PGE receptor expressed on GABAergic neurons, and this PGE2 action triggers neuronal pathways for sympathetic thermogenesis in peripheral effector organs including brown adipose tissue (BAT). To explore pyrogenic efferent pathways from the POA, we determined projection targets of EP3 receptor-expressing POA neurons with a special focus on rat hypothalamic regions including the dorsomedial hypothalamic nucleus (DMH), which is known as a center for autonomic responses to stress. Among injections of cholera toxin b-subunit (CTb), a retrograde tracer, into hypothalamic regions at the rostrocaudal level of the DMH, injections into the DMH, lateral hypothalamic area (LH) and dorsal hypothalamic area (DH) resulted in EP3 receptor immunolabelling in substantial populations of CTb-labeled neurons in the POA. Bilateral microinjections of muscimol, a GABAA receptor agonist, into the DMH and a ventral region of the DH, but not those into the LH, inhibited thermogenic (BAT sympathetic nerve activity, BAT temperature, core body temperature and expired CO2) and cardiovascular (arterial pressure and heart rate) responses to an intra-POA PGE2 microinjection. Further immunohistochemical observations revealed a close association of POA-derived GABAergic axon swellings with DMH neurons projecting to the medullary raphe regions where sympathetic premotor neurons for febrile and thermoregulatory responses are localized. These results suggest that a direct projection of EP3 receptor-expressing POA neurons to the DMH/DH region mediates febrile responses via a GABAergic mechanism.

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