Brain Structure and Function

, Volume 221, Issue 7, pp 3521–3546 | Cite as

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

  • Csaba Adori
  • Swapnali Barde
  • Szilvia Vas
  • Karl Ebner
  • Jie Su
  • Camilla Svensson
  • Aleksander A. Mathé
  • Nicolas Singewald
  • Rainer R. Reinscheid
  • Mathias Uhlén
  • Kim Kultima
  • György Bagdy
  • Tomas Hökfelt
Original Article


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.


Neuropeptide S (NPS) Arousal Glutamate Dopamine Preoptic area Septum Sleep Substance P Transmitter release Wakefulness 


Anatomical terms


Nucleus arcuatus


Dorsomedial nucleus of the hypothalamus


Dorsal raphe


Nucleus of the horizontal limb of the diagonal band


Kölliker-Fuse nucleus


Locus coeruleus


Laterodorsal tegmental/pedunculopontine tegmental nuclei


Lateral parabrachial nucleus


Lateral preoptic area


Lateral septum/medial septum border zone


Lateral septal nucleus, ventral part


Median preoptic nucleus


Medial preoptic area


Medial septum


Peri-coerulear cell cluster (of NPS neurons)


Parabrachial-precoeruleus region


Paraventricular thalamic nucleus, anterior part


Paraventricular hypothalamic nucleus


Perifornical area of the lateral hypothalamus


Suprachiasmatic nucleus


Septohypothalamic nucleus


Sublaterodorsal tegmental area


Ventro-lateral preoptic nucleus


Ventro-lateral subdivision of the periaqueductal central gray


Ventral tegmental area


Ventral tuberomamillary nucleus

Other non-trivial abbreviations


Adrenocorticotrophin hormone


Corticotrophin releasing factor


Choline acetyltransferase


Excessive daytime sleepiness






Histidine decarboxylase








In situ hybridization


Large pot-on-water


Large pot-on-water plus rebound sleep


Melanin concentrating hormone


Non-rapid eye movement sleep


Neuropeptide S


Neuropeptide S receptor 1




Quantitative in situ hybridization


Rapid eye movement sleep




Room temperature


Small pot-on-water


Small pot-on-water plus rebound sleep


Slow-wave sleep


Tyrosine hydroxylase


Obstructive sleep apnea syndrome


Vesicular glutamate transporter 2



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).

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interests.


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© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Csaba Adori
    • 1
  • Swapnali Barde
    • 1
  • Szilvia Vas
    • 2
    • 3
  • Karl Ebner
    • 4
  • Jie Su
    • 5
  • Camilla Svensson
    • 5
  • Aleksander A. Mathé
    • 6
  • Nicolas Singewald
    • 4
  • Rainer R. Reinscheid
    • 7
  • Mathias Uhlén
    • 8
    • 9
  • Kim Kultima
    • 10
  • György Bagdy
    • 2
    • 3
  • Tomas Hökfelt
    • 1
  1. 1.Retzius Laboratory, Department of NeuroscienceKarolinska InstitutetStockholmSweden
  2. 2.Department of PharmacodynamicsSemmelweis UniversityBudapestHungary
  3. 3.Neuropsychopharmacology and Neurochemistry Research GroupHungarian Academy of SciencesBudapestHungary
  4. 4.Department of Pharmacology and Toxicology, Institute of Pharmacy, Center for Molecular Biosciences Innsbruck (CMBI)Leopold-Franzens-University of InnsbruckInnsbruckAustria
  5. 5.Department of Physiology and PharmacologyKarolinska InstitutetStockholmSweden
  6. 6.Section of Psychiatry, Department of Clinical NeuroscienceKarolinska InstitutetStockholmSweden
  7. 7.Department of Pharmaceutical SciencesUniversity of California IrvineIrvineUSA
  8. 8.Science for Life Laboratory, Department of NeuroscienceKarolinska InstitutetStockholmSweden
  9. 9.Science for Life Laboratory, Albanova University CenterRoyal Institute of TechnologyStockholmSweden
  10. 10.Department of Medical Science Cancer Pharmacology and Computational Medicine, Academiska SjukhusetUppsala UniversityUppsalaSweden

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