Neuropeptide S Activates Paraventricular Oxytocin Neurons to Induce Anxiolysis

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 Ca 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. 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 Ca 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.

A Nonpeptide Oxytocin Receptor Agonist for a Durable Relief of Inflammatory Pain

“…In this regard, to target the oxytocinergic system, in particular with specific OTR agonist such as LIT-001, may be particularly relevant. Indeed, activation of OTR is known to induce a variety of molecular cascades 24 resulting in an important modulation of nociception 25 , social recognition and interactions 26,27 , anxiety 28 , feeding behavior 29 , and stress 30 , all important comorbidity factors in painful patients. www.nature.com/scientificreports www.nature.com/scientificreports/ Interestingly, a previous study has also shown that LIT-001 improved social interaction in a mouse model of autism 20 , reinforcing its putative interest as an analgesic molecule.…”

A Fear Memory Engram and Its Plasticity in the Hypothalamic Oxytocin System

“…Next, an AAV equipped with bidirectional tet promoter (P tet bi) expressing the Cre-recombinase was linked to a genetically-encoded calcium indicator (YC3.60) (Virus 2, rAAV-P tet bi-Cre/YC3.60, (L€ utcke et al, 2010)). As the last component of our viral technique (Virus 3), we generated rAAVs under the OT promoter to drive expression of hChR2-mCherry, GFP or hM4D(Gi)-mCherry (Eliava et al, 2016;Grund et al, 2017) in a Cre-dependent manner.…”

Acute and long-lasting effects of oxytocin in cortico-limbic circuits: consequences for fear recall and extinction

“…In addition to acting as an acute anxiolytic to diminish fear responses, mainly in the CeA and other areas (Litvin et al 2016;Viviani et al 2011;de la Mora et al 2016;Sabihi et al 2017;Grund et al 2017;Menon et al 2018), OTcould also act on fear learning, and fear extinction learning in a longlasting manner. In other words, it could work on neuronal plasticity in the fear-related neural networks.…”