The rostral raphe pallidus nucleus mediates pyrogenic transmission from the preoptic area - PubMed (original) (raw)

The rostral raphe pallidus nucleus mediates pyrogenic transmission from the preoptic area

Kazuhiro Nakamura et al. J Neurosci. 2002.

Abstract

Fever is the widely known hallmark of disease and is induced by the action of the nervous system. It is generally accepted that prostaglandin (PG) E(2) is produced in response to immune signals and then acts on the preoptic area (POA), which triggers the stimulation of the sympathetic system, resulting in the production of fever. Actually, the EP3 subtype of PGE receptor, which is essential for the induction of fever, is known to be localized in POA neurons. However, the neural pathway mediating the pyrogenic transmission from the POA to the sympathetic system remains unknown. To identify the neuronal groups involved in the fever-inducing pathway, we first investigated Fos expression in medullary regions of rats after central administrations of PGE(2). PGE(2) application to the lateral ventricle or directly to the POA strikingly increased the number of Fos-positive neurons in the rostral part of the raphe pallidus nucleus (rRPa). Most of these neurons did not exhibit serotonin immunoreactivity. Microinjection of muscimol, a GABA(A) receptor agonist, into the rRPa blocked fever and thermogenesis in brown adipose tissue induced by intra-POA as well as by intracerebroventricular PGE(2) applications. Furthermore, neural tract tracing studies revealed a direct projection from EP3 receptor-expressing POA neurons to the rRPa. Our results demonstrate that the rRPa, which has never been associated with the fever mechanism, mediates the pyrogenic neurotransmission from the POA to the peripheral sympathetic effectors contributing to fever development.

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Figures

Fig. 1.

Fig. 1.

Central PGE2 stimulations induce Fos expression in rRPa neurons. a, Distribution of Fos-immunoreactive cells (dots) in the ventral medulla after intracerebroventricular injection of saline or PGE2. Fos-immunoreactive cells in a 20-μm-thick frontal section of the corresponding rostrocaudal position were plotted on a drawing. Sections set in a row were taken from the same rostrocaudal position, and their (Figure legend continued.) distances from the interaural line are indicated based on the brain atlas of Paxinos and Watson (1998). b, The numbers of Fos-positive cells in ventral medullary regions after intracerebroventricular injection of saline (white bars) or PGE2 (black bars). The numbers were counted in every sixth 20-μm-thick frontal section throughout the medulla oblongata. Each_bar_ represents the mean ± SEM of three rats per group. Asterisks indicate statistically significant differences between PGE2- and saline-injected groups (p < 0.05). c, Double-immunoperoxidase staining of Fos (blue-black) and serotonin (brown) in the rRPa (Interaural_−_2.30 mm) after intracerebroventricular PGE2 injection. Arrows and_arrowheads_ indicate cells with serotonin and Fos immunoreactivity, respectively. d, A representative view of an intra-MPO microinjection site. The injection site was clearly identified as a cluster of fluorescent beads (arrow) in the section counterstained with toluidine blue. e, Fos immunoreactivity in the rRPa (Interaural −2.30 mm) after intra-MPO microinjection of saline or PGE2. 3V, Third ventricle;DAO, dorsal accessory olivary nucleus;MAO, medial accessory olivary nucleus;ox, optic chiasm; PIO, principal inferior olivary nucleus; py, pyramidal tract. Scale bars:a, d, 500 μm; c, 100 μm; e, 50 μm.

Fig. 2.

Fig. 2.

Projections from POA neurons to the rRPa.a, Sindbis virus injection into the POA. Infected cells exhibited EGFP fluorescence and formed a cluster (enclosed with a_broken line_), and many neuronal fibers with fluorescence extended from the cell cluster. b, The location of the Sindbis virus injection. A section adjacent to the one shown in_a_ was immunostained for EP3 receptor. The location of the cluster of the infected cells is indicated by a broken line. The cell cluster was located over the EP3 receptor-immunoreactive neuronal cell group in the MPO (arrows). c, d, Infection of EP3 receptor-expressing POA neurons with the Sindbis virus. There were POA neuronal cell bodies double labeled with EGFP fluorescence (c) and EP3 receptor immunoreactivity (d) (arrow). The photomicrographs were taken at the same site under different conditions of excitation.e, EGFP immunoreactivity in the caudal one-third of the rRPa. The immunoreactivity was localized in fibers (arrows) and boutons (arrowheads).ac, Anterior commissure. Scale bars: a, 100 μm; b, 500 μm; c,d, 10 μm; e, 20 μm.

Fig. 3.

Fig. 3.

EP3 receptor-expressing POA neurons directly project to the rRPa. a, Fluoro-Gold injection centered on the caudal one-third of the rRPa (arrow). b, POA neuronal cell bodies double labeled with Fluoro-Gold fluorescence and EP3 receptor immunoreactivity (arrows). The photomicrographs were taken at the same site under different conditions of excitation.c, Distributions of POA neurons labeled with Fluoro-Gold (open circles) and with both Fluoro-Gold and EP3 receptor immunoreactivity (filled circles). All Fluoro-Gold-labeled cells distributed in the shown regions were drawn. The distribution area of EP3 receptor-immunoreactive cells is colored_gray_. Scale bars: a, c, 500 μm; b, 50 μm.

Fig. 4.

Fig. 4.

Muscimol microinjection into the rRPa blocks fever and BAT thermogenesis stimulated by intracerebroventricular administration of PGE2. a, b, Changes in T_BAT (a) and T_rec (b) after intracerebroventricular PGE2 injection in rats microinjected with muscimol or saline into the caudal one-third of the rRPa. The sites of muscimol and saline microinjections are shown in_d (Interaural −_2.30 mm). Each value represents the mean ± SEM of three rats per group. The changes in T_BAT and_T_rec were significantly different between muscimol- and saline-pretreated (Figure legend continues.) (Figure legend continued.) groups at least during the time period denoted by bars with_asterisks (p < 0.05). The muscimol microinjections for showing in a and_b_ were selected from the ones shown in d_using anatomical criteria: the three microinjections closest to the midline in the rRPa. The data shown in a and_b are from the same animals. c, A representative view of muscimol microinjection. The injection site is clearly identified as a cluster of fluorescent beads (arrow) in the section counterstained with toluidine blue. d, Composite drawing of the effect of muscimol or saline microinjections into ventral medullary regions on BAT thermogenesis stimulated by intracerebroventricular PGE2injection. Each symbol represents the injection site and corresponding change in T_BAT 30 min after PGE2 administration. The symbols located outside the brain parenchyma indicate the cases of injections with penetration of the capillary tip. Note the correlation with the distribution of Fos-positive cells in the brain of PGE2-administered rats shown in Figure 1_a. 7, Facial nucleus; 7n, descending root of the facial nerve; Am, ambiguus nucleus; g7, genu of the facial nerve; _Gi_α, alpha part of the gigantocellular reticular nucleus; Giv, ventral part of the gigantocellular reticular nucleus; Pr, prepositus nucleus; Sol, nucleus of the solitary tract. Scale bar, 500 μm.

Fig. 5.

Fig. 5.

Fever and BAT thermogenesis induced by intra-MPO microinjection of PGE2 are blocked by muscimol microinjection into the rRPa. a, b, Changes in _T_BAT (a) and T_rec (b) after intra-MPO PGE2 microinjection in rats microinjected with muscimol or saline into the caudal one-third of the rRPa. The sites of muscimol and saline microinjections are shown in c(Interaural −_2.30 mm). Each value represents the mean ± SEM of three rats per group. The changes in_T_BAT and _T_recwere significantly different between muscimol- and saline-pretreated groups at least during the time period denoted by bars_with asterisks (p < 0.05). The data shown in a and b are from the same animals. c, Composite drawing of the effect of muscimol or saline microinjections into ventral medullary regions on BAT thermogenesis stimulated by intra-MPO PGE2microinjection. Each symbol represents the site of muscimol microinjection (filled circles and_crosses) or of saline microinjection (open circles) and corresponding change in_T_BAT 40 min after PGE2microinjection: ≤0.7°C (filled circles); ≥2.0°C (crosses and open circles).

Fig. 6.

Fig. 6.

A population of EP3 receptor-expressing POA neurons are GABAergic. a, Double labeling with EP3 receptor immunoreactivity (brown) and GAD67 mRNA hybridization (blue) in the POA. _Arrows_indicate EP3 receptor immunoreactive neurons exhibiting signals for GAD67 mRNA. Filled and _open arrowheads_indicate neurons single labeled with GAD67 mRNA hybridization and EP3 receptor immunoreactivity, respectively. b, Our current hypothesis on the neural pathway mediating PGE2-induced fever. See Discussion for details. Blue,red, and black circles denote cell bodies of activated inhibitory neurons, activated excitatory neurons, and suppressed neurons, respectively. IML, Intermediolateral cell column. Scale bar, 30 μm.

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