Elsevier

Neuroscience

Volume 161, Issue 2, 30 June 2009, Pages 614-620
Neuroscience

Systems Neuroscience
Research Paper
Different populations of prostaglandin EP3 receptor-expressing preoptic neurons project to two fever-mediating sympathoexcitatory brain regions

https://doi.org/10.1016/j.neuroscience.2009.03.041Get rights and content

Abstract

The central mechanism of fever induction is triggered by an action of prostaglandin E2 (PGE2) on neurons in the preoptic area (POA) through the EP3 subtype of prostaglandin E receptor. EP3 receptor (EP3R)-expressing POA neurons project directly to the dorsomedial hypothalamus (DMH) and to the rostral raphe pallidus nucleus (rRPa), key sites for the control of thermoregulatory effectors. Based on physiological findings, we hypothesize that the febrile responses in brown adipose tissue (BAT) and those in cutaneous vasoconstrictors are controlled independently by separate neuronal pathways: PGE2 pyrogenic signaling is transmitted from EP3R-expressing POA neurons via a projection to the DMH to activate BAT thermogenesis and via another projection to the rRPa to increase cutaneous vasoconstriction. In this case, DMH-projecting and rRPa-projecting neurons would constitute segregated populations within the EP3R-expressing neuronal group in the POA. Here, we sought direct anatomical evidence to test this hypothesis with a double-tracing experiment in which two types of the retrograde tracer, cholera toxin b-subunit (CTb), conjugated with different fluorophores were injected into the DMH and the rRPa of rats and the resulting retrogradely labeled populations of EP3R-immunoreactive neurons in the POA were identified with confocal microscopy. We found substantial numbers of EP3R-immunoreactive neurons in both the DMH-projecting and the rRPa-projecting populations. However, very few EP3R-immunoreactive POA neurons were labeled with both the CTb from the DMH and that from the rRPa, although a substantial number of neurons that were not immunoreactive for EP3R were double-labeled with both CTbs. The paucity of the EP3R-expressing neurons that send collaterals to both the DMH and the rRPa suggests that pyrogenic signals are sent independently to these caudal brain regions from the POA and that such pyrogenic outputs from the POA reflect different control mechanisms for BAT thermogenesis and for cutaneous vasoconstriction by distinct sets of POA neurons.

Section snippets

Animals

All experimental animal protocols were reviewed and approved by Animal Care and Use Committee of Oregon Health and Science University and conform to the National Institutes of Health Guide for the Care and Use of Laboratory Animals. All efforts were made to minimize the number of animals used and their suffering. Male Sprague-Dawley rats (200–250 g, Charles River, Indianapolis, IN, USA) were housed two per cage with ad libitum access to feed and water in a room air-conditioned at 24±2 °C with a

Results

Following injections of CTbs conjugated with different fluorophores into the DMH and the rRPa (Fig. 1), many neuronal cell bodies in the POA were retrogradely labeled with CTb (Fig. 2, Fig. 3). Neurons labeled with cholera toxin b-subunit derived from the dorsomedial hypothalamus (DMH-CTb) and those labeled with cholera toxin b-subunit derived from the rostral raphe pallidus nucleus (rRPa-CTb) showed similar distributions in the MnPO and MPO, both of which overlapped EP3R-immunoreactive regions

Discussion

The major finding in the present study is that although the DMH and the rRPa receive projections from many POA neurons that express prostaglandin EP3Rs, only a very small number of EP3R-expressing POA neurons project to both the DMH and the rRPa. In light of the critical role of EP3Rs in POA neurons as a sensor of the pyrogenic mediator, PGE2 (Lazarus et al., 2007), the present result indicates that fever signaling to the DMH and to the rRPa from the POA is mediated by separate populations of

Conclusion

In conclusion, the results from the present anatomical study using a molecular marker for pyrogen-receptive neurons indicate that separate sets of projection neurons mediate pyrogenic signaling from the POA to neurons in two different caudal brain sites: the DMH and the rRPa. These separate outflow pathways from the POA potentially mediate differential inhibitory control of the sympathoexcitatory drive determining BAT thermogenesis and cutaneous vasoconstriction during fever development, and

Acknowledgments

This work was supported by National Institutes of Health (NIH) grants NS40987 and DK57838 to S.F.M. K.N. was a fellow for research abroad supported by the Japan Society for the Promotion of Science. Acquisition of confocal images was supported by NIH instrumentation grant RR016858.

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