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@ARTICLE{Grund:181223,
      author       = {T. Grund and S. Goyon and Y. Li$^*$ and M. Eliava and H.
                      Liu$^*$ and A. Charlet and V. Grinevich$^*$ and I. D.
                      Neumann},
      title        = {{N}europeptide {S} {A}ctivates {P}araventricular {O}xytocin
                      {N}eurons to {I}nduce {A}nxiolysis.},
      journal      = {The journal of neuroscience},
      volume       = {37},
      number       = {50},
      issn         = {0270-6474},
      address      = {Washington, DC},
      publisher    = {Soc.},
      reportid     = {DKFZ-2022-01871},
      pages        = {12214 - 12225},
      year         = {2017},
      note         = {DKFZ-ZMBH Alliance},
      abstract     = {Neuropeptides, such as neuropeptide S (NPS) and oxytocin
                      (OXT), represent potential options for the treatment of
                      anxiety disorders due to their potent anxiolytic profile. In
                      this study, we aimed to reveal the mechanisms underlying the
                      behavioral action of NPS, and present a chain of evidence
                      that the effects of NPS within the hypothalamic
                      paraventricular nucleus (PVN) are mediated via actions on
                      local OXT neurons in male Wistar rats. First, retrograde
                      studies identified NPS fibers originating in the brainstem
                      locus coeruleus, and projecting to the PVN. FACS identified
                      prominent NPS receptor expression in PVN-OXT neurons. Using
                      genetically encoded calcium indicators, we further
                      demonstrated that NPS reliably induces a transient increase
                      in intracellular Ca2+ concentration in a subpopulation of
                      OXT neurons, an effect mediated by NPS receptor. In
                      addition, intracerebroventricular (i.c.v.) NPS evoked a
                      significant somatodendritic release of OXT within the PVN as
                      assessed by microdialysis in combination with a highly
                      sensitive radioimmunoassay. Finally, we could show that the
                      anxiolytic effect of NPS seen after i.c.v. or intra-PVN
                      infusion requires responsive OXT neurons of the PVN and
                      locally released OXT. Thus, pharmacological blockade of OXT
                      receptors as well as chemogenetic silencing of OXT neurons
                      within the PVN prevented the effect of synthetic NPS. In
                      conclusion, our results indicate a significant role of the
                      OXT system in mediating the effects of NPS on anxiety, and
                      fill an important gap in our understanding of brain
                      neuropeptide interactions in the context of regulation of
                      emotional behavior within the hypothalamus.SIGNIFICANCE
                      STATEMENT Given the rising scientific interest in
                      neuropeptide research in the context of emotional and
                      stress-related behaviors, our findings demonstrate a novel
                      intrahypothalamic mechanism involving paraventricular
                      oxytocin neurons that express the neuropeptide S receptor.
                      These neurons respond with transient Ca2+ increase and
                      somatodendritic oxytocin release following neuropeptide S
                      stimulation. Thereby, oxytocin neurons seem essential for
                      neuropeptide S-induced anxiolysis, as this effect was
                      blocked by pharmacological and chemogenetic inhibition of
                      the oxytocin system.},
      keywords     = {Animals / Anxiety: physiopathology / Axonal Transport /
                      Bacterial Proteins: analysis / Calcium Signaling: physiology
                      / Dependovirus: genetics / Exploratory Behavior: drug
                      effects / Genes, Reporter / Genetic Vectors / Luminescent
                      Proteins: analysis / Male / Microdialysis / Motor Activity:
                      drug effects / Neuropeptides: pharmacology / Neuropeptides:
                      physiology / Oxytocin: agonists / Oxytocin: physiology /
                      Paraventricular Hypothalamic Nucleus: drug effects /
                      Paraventricular Hypothalamic Nucleus: physiology / Rats /
                      Rats, Wistar / Receptors, Neuropeptide: drug effects /
                      Receptors, Neuropeptide: physiology / Receptors, Oxytocin:
                      antagonists $\&$ inhibitors / Receptors, Oxytocin:
                      physiology / Synaptic Transmission: drug effects / DREADD
                      (Other) / GCaMP6s (Other) / anxiety (Other) / microdialysis
                      (Other) / neuropeptide S (Other) / oxytocin (Other) /
                      Bacterial Proteins (NLM Chemicals) / Luminescent Proteins
                      (NLM Chemicals) / Neuropeptides (NLM Chemicals) / Receptors,
                      Neuropeptide (NLM Chemicals) / Receptors, Oxytocin (NLM
                      Chemicals) / neuropeptide S receptor, rat (NLM Chemicals) /
                      neuropeptide S, rat (NLM Chemicals) / oxytocin receptor, rat
                      (NLM Chemicals) / red fluorescent protein (NLM Chemicals) /
                      yellow fluorescent protein, Bacteria (NLM Chemicals) /
                      Oxytocin (NLM Chemicals)},
      cin          = {A240 / V078},
      ddc          = {610},
      cid          = {I:(DE-He78)A240-20160331 / I:(DE-He78)V078-20160331},
      pnm          = {311 - Signalling pathways, cell and tumor biology
                      (POF3-311)},
      pid          = {G:(DE-HGF)POF3-311},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:29118105},
      pmc          = {pmc:PMC6596824},
      doi          = {10.1523/JNEUROSCI.2161-17.2017},
      url          = {https://inrepo02.dkfz.de/record/181223},
}