Neuropeptide-S (NPS) Receptor Genotype Modulates Basolateral Amygdala Responsiveness to Aversive Stimuli

Abstract

Recent studies point to a role of neuropeptide-S (NPS) in the etiology of anxiety disorders. In animal models, NPS and its receptor (NPSR) were shown to be highly expressed in the amygdala, a central structure in the fear circuit, also known to be hyper-responsive in anxiety disorders. Recently, a functional polymorphism in the NPSR gene (rs324981 A/T) has been associated with panic disorder and anxiety sensitivity. However, the role of NPSR gene variation in the modulation of fear-related amygdala responsiveness remains to be clarified. In 79 healthy subjects genotyped for NPSR rs324981, amygdala responses were assessed by means of fMRI. The participants were presented with fear-relevant faces in a robust emotion-processing paradigm frequently used to study amygdala responsiveness. We observed a strong association of NPSR T-alleles with right amygdala responsiveness to fear-relevant faces. The association peak was located in the BLA. Furthermore, responsiveness to aversive stimuli within this BLA cluster predicted a participant's self-reported harm avoidance but not depression level. We conclude that NPSR genotype is associated with increased amygdala responsiveness to fear-relevant stimuli. Thereby, NPSR rs324981 apparently causes an indirect effect on anxiety-related traits and potentially contributes to the pathogenesis of anxiety disorders by shaping fear-related limbic activity.

Context conditioning in virtual reality as a model for pathological anxiety

“…More recent studies have shown a relation between panic disorder and the T allele of neuropeptide S (NPS) receptor gene (NPSR1; rs324981; [14]). In addition, fear relevant stimuli (fearful faces) trigger stronger amygdala activation in healthy T allele carriers compared to A allele carriers [12]. The S allele of the 5-HTTLPR polymorphism and the T allele of NPSR1, thus, seem to be risk alleles for anxiety disorders.…”

Prefrontal brain responsiveness to negative stimuli

“…[22][23][24] To activate brain regions associated with emotional processing, we used a series of negative (angry and fearful) faces. More precisely, the paradigm comprised 5 blocks of a sensorimotor control task alternating with 4 blocks of a face-processing task.…”

Prevention of Stress-Impaired Fear Extinction Through Neuropeptide S Action in the Lateral Amygdala

“…Within this theme it is interesting to note that neuropeptide (NPS), a neuropeptidergic transmitter acting via G protein-coupled receptors (NPS-Rs) to modulate anxiety and arousal (Xu et al, 2004;Jüngling et al, 2008;, increases responsiveness of intercalated GABAergic neurons in the murine amygdala and thereby facilitates fear extinction learning and recall (Jüngling et al, 2008). Furthermore, a functional polymorphism in the NPS-R gene (rs324981 A/T) has been associated with overinterpretation of learned fear and panic disorders in humans and is associated with increased amygdala responsiveness to fear-relevant stimuli (Raczka et al, 2010;Dannlowski et al, 2011;Domschke et al, 2011;Donner et al, 2010). Of particular interest, here is that forced swim stress results in increased c-fos activity in NPS-synthesizing neurons in the brain stem (Liu et al, 2011) and increase extracellular levels of NPS in the BLA (Ebner et al, 2011), implying that the NPS system may be stimulated on stress exposure.…”