Activation of neuropeptide S-expressing neurons in the locus coeruleus by corticotropin-releasing factor

J Physiol. 2012 Aug 15;590(16):3701-17. doi: 10.1113/jphysiol.2011.226423. Epub 2012 May 8.


A recently discovered neurotransmitter system, consisting of neuropeptide S (NPS), NPS receptor, and NPS-expressing neurons in the brain stem, has received considerable interest due to its modulating influence on arousal, anxiety and stress responsiveness. Comparatively little is known about the properties of NPS-expressing neurons. Therefore in the present study, a transgenic mouse line expressing enhanced green fluorescent protein (EGFP) in NPS neurons was used to characterize the cellular and functional properties of NPS-expressing neurons located close to the locus coeruleus. Particular emphasis was on the influence of corticotropin-releasing factor (CRF), given previous evidence of stress-related activation of the NPS system. Upon acute immobilization stress, an increase in c-fos expression was detected immunocytochemically in brain stem NPS-EGFP neurons that also expressed the CRF receptor 1 (CRF1). NPS-EGFP neurons were readily identified in acute slice preparations and responded to CRF application with a membrane depolarization capable of triggering action potentials. CRF-induced responses displayed pharmacological properties indicative of CRF1 that were mediated by both a reduction in membrane potassium conductance and an increase in a non-specific cation conductance different from the hyperpolarization-activated cation conductance Ih, and involved protein kinase A signalling. In conclusion, stress exposure results in activation of brain stem NPS-expressing neurons, involving a CRF1-mediated membrane depolarization via at least two ionic mechanisms. These data provide evidence for a direct interaction between the CRF and the NPS system and thereby extend previous observations of NPS-modulated stress responsiveness towards a mechanistic level.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials
  • Animals
  • Corticotropin-Releasing Hormone / pharmacology*
  • Electrophysiological Phenomena
  • Gene Expression Regulation
  • Green Fluorescent Proteins
  • Immobilization
  • Locus Coeruleus / cytology*
  • Locus Coeruleus / drug effects
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / cytology
  • Neurons / metabolism*
  • Neuropeptides / genetics
  • Neuropeptides / metabolism*
  • Polymerase Chain Reaction
  • Stress, Physiological


  • Neuropeptides
  • enhanced green fluorescent protein
  • neuropeptide S, mouse
  • Green Fluorescent Proteins
  • Corticotropin-Releasing Hormone