Abstract
The Neuropeptide S system, consisting of the 20-amino acid peptide neuropeptide S (NPS) and its G-protein coupled receptor (NPSR), modulates arousal, wakefulness, anxiety, and fear-extinction in mice. In addition, recent evidence indicates that the NPS system attenuates stress-dependent impairment of fear extinction, and that NPS-expressing neurons in close proximity to the locus coeruleus region (LC; pericoerulear, periLC) are activated by stress. Furthermore, periLC NPS neurons receive afferents from neurons of the centrolateral nucleus of the amygdala (CeL), of which a substantial population expresses the kappa opioid receptor (KOR) ligand precursor prodynorphin. This study aims to identify the effect of the dynorphinergic system on NPS neurons in the periLC via pre- and postsynaptic mechanisms. Using electrophysiological recordings in mouse brain slices, we provide evidence that NPS neurons in the periLC region are directly inhibited by dynorphin A (DynA) via activation of κ-opioid receptor 1 (KOR1) and a subsequent increase of potassium conductances. Thus, the dynorphinergic system is suited to inactivate NPS neurons in the periLC. In addition to this direct, somatic effect, DynA reduces the efficacy of GABAergic synapses on NPS neurons via KOR1 and KOR2. In conclusion, the present study provides evidence for the interaction of the NPS and the kappa opioid system in the periLC. Therefore, the endogenous opioid dynorphin is suited to inhibit NPS neurons with a subsequent decrease in NPS release in putative target regions leading to a variety of physiological consequences such as increased anxiety or vulnerability to stress exposure.
Highlights
The neuropeptide S (NPS) system, consisting of the 20-amino acid peptide NPS and its G-protein coupled receptor (NPSR), has been shown to be involved in processes of anxiety, fear-extinction, and fear memory consolidation (Xu et al, 2004; Okamura and Reinscheid, 2007; Jüngling et al, 2008; Okamura et al, 2011)
Using electrophysiological recordings in mouse brain slices, we provide evidence that NPS neurons in the periLC region are directly inhibited by dynorphin A (DynA) via activation of κ-opioid receptor 1 (KOR1) and a subsequent increase of potassium conductances
Gene expression profiling of isolated NPS neurons from the periLC of NPS-enhanced green fluorescent protein (EGFP) mice indicates the expression of kappa opioid receptor (KOR) in these neurons (Liu et al, 2011)
Summary
The neuropeptide S (NPS) system, consisting of the 20-amino acid peptide NPS and its G-protein coupled receptor (NPSR), has been shown to be involved in processes of anxiety, fear-extinction, and fear memory consolidation (Xu et al, 2004; Okamura and Reinscheid, 2007; Jüngling et al, 2008; Okamura et al, 2011). Recent evidence suggests that the NPS system is involved in stress coping and that stressful events increase the release of NPS in the amygdala of rodents (Ebner et al, 2011; Chauveau et al, 2012). Immobilization stress induces an up-regulation of c-fos in NPS-expressing neurons, indicating an activation of these neurons during periods of stress (Liu et al, 2011; Jüngling et al, 2012). The NPS neurons express the corticotropin-releasing factor receptor 1 (CRF1) and depolarize following CRF1 activation by CRF or stressin I (Liu et al, 2011; Jüngling et al, 2012). NPS-expressing neurons in the periLC region have recently been shown to receive central amygdalar afferents originating from dynorphin- and somatostatin-expressing neurons (Jüngling et al, 2015). NPS neurons are inactivated by application of DynA or somatostatin, indicating a negative control of NPSexpressing neurons by these peptide systems (Jüngling et al, 2015)
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