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Molecular Brain
Published in: Molecular Brain 1/2016

Open Access 01-12-2016 | Research

Ca2+ in the dorsal raphe nucleus promotes wakefulness via endogenous sleep-wake regulating pathway in the rats

Authors: Su-Ying Cui, Sheng-Jie Li, Xiang-Yu Cui, Xue-Qiong Zhang, Bin Yu, Yuan-Li Huang, Qing Cao, Ya-Ping Xu, Guang Yang, Hui Ding, Jin-Zhi Song, Hui Ye, Zhao-Fu Sheng, Zi-Jun Wang, Yong-He Zhang

Published in: Molecular Brain | Issue 1/2016

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Abstract

Serotonergic neurons in the dorsal raphe nucleus (DRN) are involved in the control of sleep-wake states. Our previous studies have indicated that calcium (Ca2+) modulation in the DRN plays an important role in rapid-eye-movement sleep (REMS) and non-REMS (NREMS) regulation during pentobarbital hypnosis. The present study investigated the effects of Ca2+ in the DRN on sleep-wake regulation and the related neuronal mechanism in freely moving rats. Our results showed that microinjection of CaCl2 (25 or 50 nmol) in the DRN promoted wakefulness and suppressed NREMS including slow wave sleep and REMS in freely moving rats. Application of CaCl2 (25 or 50 nmol) in the DRN significantly increased serotonin in the DRN and hypothalamus, and noradrenaline in the locus coeruleus and hypothalamus. Immunohistochemistry study indicated that application of CaCl2 (25 or 50 nmol) in the DRN significantly increased c-Fos expression ratio in wake-promoting neurons including serotonergic neurons in the DRN, noradrenergic neurons in the locus coeruleus, and orxinergic neurons in the perifornical nucleus, but decreased c-Fos expression ratio of GABAergic sleep-promoting neurons in the ventrolateral preoptic nucleus. These results suggest that Ca2+ in the DRN exert arousal effects via up-regulating serotonergic functions in the endogenous sleep-wake regulating pathways.
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Literature
1.
Monti JM. The structure of the dorsal raphe nucleus and its relevance to the regulation of sleep and wakefulness. Sleep Med Rev. 2010;14:307–17.CrossRefPubMed
2.
Monti JM. The role of dorsal raphe nucleus serotonergic and non-serotonergic neurons, and of their receptors, in regulating waking and rapid eye movement (REM) sleep. Sleep Med Rev. 2010;14:319–27.CrossRefPubMed
3.
4.
Sakai K. Sleep-waking discharge profiles of dorsal raphe nucleus neurons in mice. Neuroscience. 2011;197:200–4.CrossRefPubMed
5.
Trulson ME, Jacobs BL. Raphe unit activity in freely moving cats: correlation with level of behavioral arousal. Brain Res. 1979;163:135–50.CrossRefPubMed
6.
Portas CM, Bjorvatn B, Ursin R. Serotonin and the sleep/wake cycle: special emphasis on microdialysis studies. Prog Neurobiol. 2000;60:13–35.CrossRefPubMed
7.
8.
Ghosh A, Greenberg ME. Calcium signaling in neurons: molecular mechanisms and cellular consequences. Science. 1995;268:239–47.CrossRefPubMed
9.
10.
Kohlmeier KA, Inoue T, Leonard CS. Hypocretin/orexin peptide signaling in the ascending arousal system: elevation of intracellular calcium in the mouse dorsal raphe and laterodorsal tegmentum. J Neurophysiol. 2004;92:221–35.CrossRefPubMed
11.
Tuckwell HC. Biophysical properties and computational modeling of calcium spikes in serotonergic neurons of the dorsal raphe nucleus. Biosystems. 2013;112:204–13.CrossRefPubMed
12.
Tuckwell HC, Penington NJ. Computational modeling of spike generation in serotonergic neurons of the dorsal raphe nucleus. Prog Neurobiol. 2014;118:59–101.CrossRefPubMed
13.
Cui SY, Cui XY, Zhang J, Wang ZJ, Yu B, Sheng ZF, et al. Ca2+ modulation in dorsal raphe plays an important role in NREM and REM sleep regulation during pentobarbital hypnosis. Brain Res. 2011;1403:12–8.CrossRefPubMed
14.
Cui SY, Cui XY, Zhang J, Wang ZJ, Yu B, Sheng ZF, et al. Diltiazem potentiates pentobarbital-induced hypnosis via 5-HT1A and 5-HT2A/2C receptors: role for dorsal raphe nucleus. Pharmacol Biochem Behav. 2011;99:566–72.CrossRefPubMed
15.
Del Cid-Pellitero E, Garzón M. Medial prefrontal cortex receives input from dorsal raphe nucleus neurons targeted by hypocretin1/orexinA-containing axons. Neuroscience. 2011;172:30–43.CrossRefPubMed
16.
Lee HS, Kim MA, Waterhouse BD. Retrograde double-labeling study of common afferent projections to the dorsal raphe and the nuclear core of the locus coeruleus in the rat. J Comp Neurol. 2005;481:179–93.CrossRefPubMed
17.
Samuels ER, Szabadi E. Functional neuroanatomy of the noradrenergic locus coeruleus: its roles in the regulation of arousal and autonomic function part I: principles of functional organisation. Curr Neuropharmacol. 2008;6:235–53.CrossRefPubMedPubMedCentral
18.
Sherin JE, Shiromani PJ, McCarley RW, Saper CB. Activation of ventrolateral preoptic neurons during sleep. Science. 1996;271:216–9.CrossRefPubMed
19.
20.
Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, et al. The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. Cell. 1999;98:365–76.CrossRefPubMed
21.
22.
Ito H, Yanase M, Yamashita A, Kitabatake C, Hamada A, Suhara Y, et al. Analysis of sleep disorders under pain using an optogenetic tool: possible involvement of the activation of dorsal raphe nucleus-serotonergic neurons. Mol Brain. 2013;6:59.CrossRefPubMedPubMedCentral
23.
Nelson LE, Guo TZ, Lu J, Saper CB, Franks NP, Maze M. The sedative component of anesthesia is mediated by GABA(A) receptors in an endogenous sleep pathway. Nat Neurosci. 2002;5:979–84.CrossRefPubMed
24.
Celada P, Puig MV, Casanovas JM, Guillazo G, Artigas F. Control of dorsal raphe serotonergic neurons by the medial prefrontal cortex: Involvement of serotonin-1A, GABA(A), and glutamate receptors. J Neurosci. 2001;21:9917–29.PubMed
25.
de Kock CP, Cornelisse LN, Burnashev N, Lodder JC, Timmerman AJ, Couey JJ, et al. NMDA receptors trigger neurosecretion of 5-HT within dorsal raphe nucleus of the rat in the absence of action potential firing. J Physiol. 2006;577:891–905.CrossRefPubMedPubMedCentral
26.
Barbosa R, Scialfa JH, Terra IM, Cipolla-Neto J, Simonneaux V, Afeche SC. Tryptophan hydroxylase is modulated by L-type calcium channels in the rat pineal gland. Life Sci. 2008;82:529–35.CrossRefPubMed
27.
Li SJ, Cui SY, Zhang XQ, Yu B, Sheng ZF, Huang YL, et al. PKC in rat dorsal raphe nucleus plays a key role in sleep-wake regulation. Prog Neuropsychopharmacol Biol Psychiatry. 2015;63:47–53.CrossRefPubMed
28.
Cui SY, Li SJ, Cui XY, Zhang XQ, Yu B, Sheng ZF, et al. Phosphorylation of CaMKII in the rat dorsal raphe nucleus plays an important role in sleep-wake regulation. J Neurochem. 2016;136:609–19.CrossRefPubMed
29.
Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature. 2005;437:1257–63.CrossRefPubMed
30.
Marston OJ, Williams RH, Canal MM, Samuels RE, Upton N, Piggins HD. Circadian and dark-pulse activation of orexin/hypocretin neurons. Mol Brain. 2008;1:19.CrossRefPubMedPubMedCentral
31.
Jacobs BL, Azmitia EC. Structure and function of the brain serotonin system. Physiol Rev. 1992;72:165–229.PubMed
32.
Monti JM, Jantos H. The role of serotonin 5-HT7 receptor in regulating sleep and wakefulness. Rev Neurosci. 2014;25:429–37.CrossRefPubMed
33.
Giulietti M, Vivenzio V, Piva F, Principato G, Bellantuono C, Nardi B. How much do we know about the coupling of G-proteins to serotonin receptors? Mol Brain. 2014;7:49.CrossRefPubMedPubMedCentral
34.
Petersen SL, Hartman RD, Barraclough CA. An analysis of serotonin secretion in hypothalamic regions based on 5-hydroxytryptophan accumulation or push-pull perfusion. Effects of mesencephalic raphe or locus coeruleus stimulation and correlated changes in plasma luteinizing hormone. Brain Res. 1989;495:9–19.CrossRefPubMed
35.
Kaehler ST, Singewald N, Philippu A. Dependence of serotonin release in the locus coeruleus on dorsal raphe neuronal activity. Naunyn Schmiedebergs Arch Pharmacol. 1999;359:386–93.CrossRefPubMed
36.
Hamamura T, Lee Y, Fujiwara Y, Kuroda S. Serotonin1A receptor agonists induce Fos protein expression in the locus coeruleus of the conscious rat. Brain Res. 1997;759:156–9.CrossRefPubMed
37.
Ortega JE, Mendiguren A, Pineda J, Meana JJ. Regulation of central noradrenergic activity by 5-HT(3) receptors located in the locus coeruleus of the rat. Neuropharmacology. 2012;62:2472–9.CrossRefPubMed
38.
Gallopin T, Fort P, Eggermann E, Cauli B, Luppi PH, Rossier J, et al. Identification of sleep-promoting neurons in vitro. Nature. 2000;404:992–5.CrossRefPubMed
39.
Tabuchi S, Tsunematsu T, Kilduff TS, Sugio S, Xu M, Tanaka KF, et al. Influence of inhibitory serotonergic inputs to orexin/hypocretin neurons on the diurnal rhythm of sleep and wakefulness. Sleep. 2013;36:1391–404.PubMedPubMedCentral
40.
Wang ZJ, Zhang XQ, Cui XY, Cui SY, Yu B, Sheng ZF, et al. Glucocorticoid receptors in the locus coeruleus mediate sleep disorders caused by repeated corticosterone treatment. Sci Rep. 2015;5:9442.CrossRefPubMedPubMedCentral
41.
Paxinos G, Watson C. The Rat Brain in Stereotaxic Coordinates. 4th ed. San Diego: Academic; 1986.
42.
Zhang J, Yu B, Zhang XQ, Sheng ZF, Li SJ, Wang ZJ, et al. Tetrandrine, an antihypertensive alkaloid, improves the sleep state of spontaneously hypertensive rats (SHRs). J Ethnopharmacol. 2014;151:729–32.CrossRefPubMed
Metadata
Title
Ca2+ in the dorsal raphe nucleus promotes wakefulness via endogenous sleep-wake regulating pathway in the rats
Authors
Su-Ying Cui
Sheng-Jie Li
Xiang-Yu Cui
Xue-Qiong Zhang
Bin Yu
Yuan-Li Huang
Qing Cao
Ya-Ping Xu
Guang Yang
Hui Ding
Jin-Zhi Song
Hui Ye
Zhao-Fu Sheng
Zi-Jun Wang
Yong-He Zhang
Publication date
01-12-2016
Publisher
BioMed Central
Published in
Molecular Brain / Issue 1/2016
Electronic ISSN: 1756-6606
DOI
https://doi.org/10.1186/s13041-016-0252-0

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