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Exploring the role of neuropeptide S in the regulation of arousal: a functional anatomical study

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Abstract

Neuropeptide S (NPS) is a regulatory peptide expressed by limited number of neurons in the brainstem. The simultaneous anxiolytic and arousal-promoting effect of NPS suggests an involvement in mood control and vigilance, making the NPS–NPS receptor system an interesting potential drug target. Here we examined, in detail, the distribution of NPS-immunoreactive (IR) fiber arborizations in brain regions of rat known to be involved in the regulation of sleep and arousal. Such nerve terminals were frequently apposed to GABAergic/galaninergic neurons in the ventro-lateral preoptic area (VLPO) and to tyrosine hydroxylase-IR neurons in all hypothalamic/thalamic dopamine cell groups. Then we applied the single platform-on-water (mainly REM) sleep deprivation method to study the functional role of NPS in the regulation of arousal. Of the three pontine NPS cell clusters, the NPS transcript levels were increased only in the peri-coerulear group in sleep-deprived animals, but not in stress controls. The density of NPS-IR fibers was significantly decreased in the median preoptic nucleus-VLPO region after the sleep deprivation, while radioimmunoassay and mass spectrometry measurements showed a parallel increase of NPS in the anterior hypothalamus. The expression of the NPS receptor was, however, not altered in the VLPO-region. The present results suggest a selective activation of one of the three NPS-expressing neuron clusters as well as release of NPS in distinct forebrain regions after sleep deprivation. Taken together, our results emphasize a role of the peri-coerulear cluster in the modulation of arousal, and the importance of preoptic area for the action of NPS on arousal and sleep.

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Abbreviations

Arc:

Nucleus arcuatus

DMN:

Dorsomedial nucleus of the hypothalamus

DR:

Dorsal raphe

HDB:

Nucleus of the horizontal limb of the diagonal band

KF:

Kölliker-Fuse nucleus

LC:

Locus coeruleus

LDTg/PPTg:

Laterodorsal tegmental/pedunculopontine tegmental nuclei

LPB:

Lateral parabrachial nucleus

LPO:

Lateral preoptic area

LS/MSbo:

Lateral septum/medial septum border zone

LSV:

Lateral septal nucleus, ventral part

MnPO:

Median preoptic nucleus

MPOA:

Medial preoptic area

MS:

Medial septum

PC:

Peri-coerulear cell cluster (of NPS neurons)

PB-PreC:

Parabrachial-precoeruleus region

PVA:

Paraventricular thalamic nucleus, anterior part

PVN:

Paraventricular hypothalamic nucleus

PFA:

Perifornical area of the lateral hypothalamus

SCN:

Suprachiasmatic nucleus

SHy:

Septohypothalamic nucleus

SLD:

Sublaterodorsal tegmental area

VLPO:

Ventro-lateral preoptic nucleus

VLPAG:

Ventro-lateral subdivision of the periaqueductal central gray

VTA:

Ventral tegmental area

VTM:

Ventral tuberomamillary nucleus

ACTH:

Adrenocorticotrophin hormone

CRF:

Corticotrophin releasing factor

ChAT:

Choline acetyltransferase

EDS:

Excessive daytime sleepiness

EEG:

Electroencephalography

HC:

Homecage

HDC:

Histidine decarboxylase

i.c.v.:

Intracerebroventricular

IHC:

Immunohistochemistry

IR:

Immunoreactive

ISH:

In situ hybridization

LPoW:

Large pot-on-water

LPoW-R:

Large pot-on-water plus rebound sleep

MCH:

Melanin concentrating hormone

non-REMS:

Non-rapid eye movement sleep

NPS:

Neuropeptide S

NPSR1:

Neuropeptide S receptor 1

PoW:

Pot-on-water

qISH:

Quantitative in situ hybridization

REMS:

Rapid eye movement sleep

RIA:

Radioimmunoassay

RT:

Room temperature

SPoW:

Small pot-on-water

SPoW-R:

Small pot-on-water plus rebound sleep

SWS:

Slow-wave sleep

TH:

Tyrosine hydroxylase

OSAS:

Obstructive sleep apnea syndrome

VGlut2:

Vesicular glutamate transporter 2

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Acknowledgments

This study was supported by the Swedish Research Council, Grants from Karolinska Institutet, the Rut&Arvid Wolff foundation for insomnia research, the National Hungarian Development Agency (Grant No. KTIA-NAP-13-1-2013-0001), the Hungarian Brain Research Program (Grant No. KTIA 13 NAP-A-II/14) and the Austrian Science Fund (FWF, Grant No. P25375). We are grateful for the excellent technical assistance of Blanca Silva-Lopez, Szilvia Deak and Agnes Ruzsits. We acknowledge the generous donation of antisera/antibodies to tyrosine hydroxylase (the late Dr. Menek Goldstein, NYU, New York, NY); orexin (Dr. Luis de Lecea, The Salk Institute, La Jolla, CA); histidine decarboxylase (the late Dr. John Walsh, CURE core facility, UCLA, Las Angeles, CA); vesicular glutamate transporter 2 (Dr. Masahiko Watanabe, Hokkaido University School of Medicine, Sapporo, Japan); galanin (Dr. Elvar Theodorsson, Linköping University, Linköping, Sweden); substance P (Dr. Ingrid Nylander, Uppsala University, Uppsala, and Dr. Lars Terenius, Karolinska Institutet, Stockholm, Sweden; choline acetyltransferase (Dr. Boyd Hartman, Department of Psychiatry, University of Minnesota, Minneapolis, MN).

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Authors and Affiliations

  1. Retzius Laboratory, Department of Neuroscience, Karolinska Institutet, Retzius väg 8, 17177, Stockholm, Sweden

    Csaba Adori, Swapnali Barde & Tomas Hökfelt

  2. Department of Pharmacodynamics, Semmelweis University, Nagyvarad ter 4, 1089, Budapest, Hungary

    Szilvia Vas & György Bagdy

  3. Neuropsychopharmacology and Neurochemistry Research Group, Hungarian Academy of Sciences, Nagyvarad ter 4, 1089, Budapest, Hungary

    Szilvia Vas & György Bagdy

  4. Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck (CMBI), Leopold-Franzens-University of Innsbruck, Innrain 80-82/III, 6020, Innsbruck, Austria

    Karl Ebner & Nicolas Singewald

  5. Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, 17177, Stockholm, Sweden

    Jie Su & Camilla Svensson

  6. Section of Psychiatry, Department of Clinical Neuroscience, Karolinska Institutet, Tomtebodavägen 18A, 17177, Stockholm, Sweden

    Aleksander A. Mathé

  7. Department of Pharmaceutical Sciences, University of California Irvine, Irvine, CA, 92697, USA

    Rainer R. Reinscheid

  8. Science for Life Laboratory, Department of Neuroscience, Karolinska Institutet, 17165, Stockholm, Sweden

    Mathias Uhlén

  9. Science for Life Laboratory, Albanova University Center, Royal Institute of Technology, 17165, Stockholm, Sweden

    Mathias Uhlén

  10. Department of Medical Science Cancer Pharmacology and Computational Medicine, Academiska Sjukhuset, Uppsala University, 75185, Uppsala, Sweden

    Kim Kultima

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  1. Csaba Adori
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  2. Swapnali Barde
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  3. Szilvia Vas
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  7. Aleksander A. Mathé
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  8. Nicolas Singewald
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Correspondence to Csaba Adori.

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Adori, C., Barde, S., Vas, S. et al. Exploring the role of neuropeptide S in the regulation of arousal: a functional anatomical study. Brain Struct Funct 221, 3521–3546 (2016). https://doi.org/10.1007/s00429-015-1117-5

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  • DOI: https://doi.org/10.1007/s00429-015-1117-5

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