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.2009 Sep 23;29(38):11954-64.
doi: 10.1523/JNEUROSCI.2643-09.2009.

Parallel preoptic pathways for thermoregulation

Affiliations

Parallel preoptic pathways for thermoregulation

Kyoko Yoshida et al. J Neurosci..

Abstract

Sympathetic premotor neurons in the rostral medullary raphe (RMR) regulate heat conservation by tail artery vasoconstriction and brown adipose tissue thermogenesis. These neurons are a critical relay in the pathway that increases body temperature. However, the origins of the inputs that activate the RMR during cold exposure have not been definitively identified. We investigated the afferents to the RMR that were activated during cold by examining Fos expression in retrogradely labeled neurons after injection of cholera toxin B subunit (CTb) in the RMR. These experiments identified a cluster of Fos-positive neurons in the dorsomedial hypothalamic nucleus and dorsal hypothalamic area (DMH/DHA) with projections to the RMR that may mediate cold-induced elevation of body temperature. Also, neurons in the median preoptic nucleus (MnPO) and dorsolateral preoptic area (DLPO) and in the A7 noradrenergic cell group were retrogradely labeled but lacked Fos expression, suggesting that they may inhibit the RMR. To investigate whether individual or common preoptic neurons project to the RMR and DMH/DHA, we injected CTb into the RMR and Fluorogold into the DMH/DHA. We found that projections from the DLPO and MnPO to the RMR and DMH/DHA emerge from largely separate neuronal populations, indicating they may be differentially regulated. Combined cell-specific lesions of MnPO and DLPO, but not lesions of either one alone, caused baseline hyperthermia. Our data suggest that the MnPO and DLPO provide parallel inhibitory pathways that tonically inhibit the DMH/DHA and the RMR at baseline, and that hyperthermia requires the release of this inhibition from both nuclei.

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Figures

Figure 1.
Figure 1.
Changes in body temperature in cold-exposed rats (at 4°C,n = 7) compared with control rats (at 24°C,n = 7). Stress-induced hyperthermia was observed only in the control group at 15–45 min after animals were transferred to the thermally controlled chamber at time 0, but not in the cold-exposed group. Each point corresponds to the average temperature in a 5 min interval (12 points/h). Significant differences between groups are noted by asterisks (p < 0.05; repeated-measures ANOVA followed by pairedt tests for comparisons at each time point). All values are the mean ± SEM.
Figure 2.
Figure 2.
A photomicrograph showing a CTb injection site into the raphe pallidus nucleus (RPa) and the overlying raphe magnus nucleus (RMg) (A), and a series of line drawings showing the maximal spread of CTb injections in all 17 cases used in our analysis, including three control cases that missed the medullary raphe (B–D). Light blue line indicates injection case RP1 (B), RP9 (C), RP15 (D); blue line: RP3 (B), RP10 (C), RP16 (D); pink line: RP4 (B), RP11 (C), RP17 (D); red line: RP5 (B), RP12 (C), RP19 (D); green line: RP7 (B), RP13 (C), RP20 (D); orange line: RP8 (B), RP14 (C). Scale bar, 500 μm. GiA, Gigantocellular reticular nucleus, α part; LPGi, lateral paragigantocellular nucleus; py, pyramidal tract.
Figure 3.
Figure 3.
A–F, Drawings of brain sections from rostral to caudal levels of preoptic area after CTb injection into the RMR. Each dot represents one retrogradely labeled neuron. The counting box for the MnPO was placed dorsal to the opening of the third ventricle just rostral to the anterior commissure (A, box 1). Neurons in the medial preoptic area were counted by placing a box with the ventral border 300 μm above the surface of the optic chiasm and its medial border along the wall of the third ventricle (D, box 2) at the level of the bed nucleus of the anterior commissure of Gurdjian (BAC). For the DLPO, the counting box was placed just lateral to the medial preoptic box (D, box 3). 3V, Third ventricle; ac, anterior commissure; aca, anterior commissure, anteriot part; AVPe, anteroventral periventricular nucleus; f, fornix; HDB, nucleus of the horizontal limb of the diagonal band; och, optic chiasm; opt, optic tract; PaAP, paraventricular hypothalamic nucleus, anterior parvicellular part; PS, parastrial nucleus; PT, paratenial thalamic nucleus; PVA, paraventricular thalamic, anterior part; SCh, suprachiasmatic nucleus; sm, stria medullaris of the thalamus; SO, supraoptic nucleus; VLPO, ventrolateral preoptic nucleus; VOLT, vascular organ of the lamina terminalis.
Figure 4.
Figure 4.
A–J, Drawings of brain sections from the paraventricular hypothalamic nucleus (A) to the medulla (J) after CTb injection into the RMR (injection site is shown by shading inI). Each dot represents one retrogradely labeled neuron. Scale bar, 1 mm. 7n, Facial nerve; A7, A7 noradrenergic cell group; AP, area postrema; Aq, cerebral aqueduct; Arc, arcuate nucleus; cp, cerebral peduncle, basal part; cu, cuneate fasciculus; DMC, dorsomedial hypothalamic nucleus, compact part; DMV, dorsomedial hypothalamic nucleus, ventral part; f, fornix; fr, fasciculus retroflexus; gr, gracile fasciculus; ic, internal capsule; icp, inferior cerebellar peduncle; LPB, lateral parabrachial nucleus; me5, mesencephalic trigeminal tract; mlf, medial longitudinal fasciculus; mt, mammillothalamic tract; NTS, nucleus of the solitary tract; ox, optic chiasm; PH, posterior hypothalamic area; PS, parastrial nucleus; py, pyramidal tract; RMg, raphe magnus nucleus; Rpa, raphe pallidus nucleus; scp, superior cerebellar peduncle; SON, supraoptic nucleus; sp5, spinal trigeminal tract; TM, tuberomammillary nucleus; VMH, ventromedial hypothalamic nucleus.
Figure 5.
Figure 5.
A–D, A series of photomicrographs illustrating tyroxine hydroxylase (TH)-immunoreactivity (green) and CTb-immunoreactivity (red) in the DMH/DHA cell areaA11/A13 dopaminergic group (A), and the rostral pontine cell group that includes the A7 noradrenergic group (B–D), after injection of CTb into the RMR. Both areas project to the medullary raphe but only A7 noradrenergic neurons were double-labeled. A11/A13 dopaminergic neurons are located dorsally to the DMH/DHA neurons that project to the medullary raphe (CTb-labeled neurons). PhotomicrographsC andD are higher-magnification images of the area indicated by the box inB. Arrows point to doubly labeled neurons (A7 noradrenergic cells that project to the RMR). Scale bars:A, 200 μm;B–D, 100 μm. 3V, Third ventricle. For color-blind readers, a copy of this figure with the red fluorescence converted to magenta is included as supplemental Figure 1, available atwww.jneurosci.org as supplemental material.
Figure 6.
Figure 6.
Cold exposure induces Fos expression in DMH/DHA neurons that project to the RMR. The diagram inA shows the location of the DMH/DHA (box), which contained numerous retrogradely labeled neurons after CTb injection into the RMR. Photomicrographs inC andD show the distribution of doubly labeled neurons for Fos (black nucleus) and CTb (retrogradely labeled white cytoplasm) after exposure to cold (3–4°C) (C) or room temperature (24−5°C (D). There were many more doubly labeled neurons after exposure to cold (C) than to room temperature (D). The line drawing inB shows the injection sites of Fluorogold in the same DMH/DHA area. The green line indicates the injection in case RP17, the red line in case RP19, and the blue line in case RP20. Scale bars:B,C, 100 μm. 3V, Third ventricle; Arc, arcuate nucleus; DMH, dorsomedial hypothalamic nucleus; f, fornix; ic, internal capsule; ml, medial lemniscus; mt, mammillothalamic tract; opt, optic tract; VMH, ventromedial hypothalamic nucleus.
Figure 7.
Figure 7.
Neurons in the MnPO that project to the RMR do not project simultaneously to the DMH/DHA. Photomicrographs inA–C illustrate the median preoptic nucleus after injection of CTb into the RMR (red inA) and Fluorogold into the DMH/DHA (blue inB). The merged image inC shows only one cell in this field that was doubly labeled (at the arrowhead).D–F show the DMH/DHA in the same experiment. Note that the retrogradely labeled neurons that project to the RMR (red inD), are immediately adjacent to the tracer deposit at the core of the injection of Fluorogold into the DMH (marked INJ inE andF). The brightness of the Fluorogold image has been reduced in this set of photographs to avoid oversaturating the images; tracer spreads in all directions at least 500 μm from the center of the injection as shown in Figure 6B, experiment RP20. Scale bar, 100 μm. 3V, Third ventricle; INJ, Fluorogold injection site; OVLT, organum vasculosum of the lamina terminalis.
Figure 8.
Figure 8.
Mean Tb of the combined preoptic (MnPO+DLPO) lesion group (A), MnPO lesion group (B), and DLPO lesion group (C) over 3 consecutive days. Higher Tb was observed throughout the entire day (dark and light periods) in the combined (MnPO+DLPO) lesion group (A) but not in the MnPO lesion (B) or DLPO lesion (C) groups. GraphsD,E, andF show the fever response after LPS injection in control animals compared with the combined (MnPO+DLPO) lesion group (D), MnPO lesion group (E), and DLPO lesion group (F). LPS was injected at time 0. The DLPO lesion group showed a similar pattern of temperature increase as control animals (F), but neither the combined (MnPO+DLPO) nor MnPO lesion groups showed this rise in temperature (D andE, respectively). Significant differences between groups are noted by asterisks (p < 0.05; repeated-measures ANOVA followed by pairedt tests for comparisons at each time point). All values are the mean ± SEM.
Figure 9.
Figure 9.
Elevation of Tb shows a strong negative correlation with the number of remaining neurons in the MnPO+DLPO (A), but not with those in the MnPO+MPA (B) or MPA+DLPO (C), demonstrating that only simultaneous lesions of both MnPO and DLPO are effective in altering baseline Tb.
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