Identification of a Neuropeptide S Responsive Circuitry Shaping Amygdala Activity via the Endopiriform Nucleus

Abstract

Neuropeptide S (NPS) and its receptor are thought to define a set of specific brain circuits involved in fear and anxiety. Here we provide evidence for a novel, NPS-responsive circuit that shapes neural activity in the mouse basolateral amygdala (BLA) via the endopiriform nucleus (EPN). Using slice preparations, we demonstrate that NPS directly activates an inward current in 20% of EPN neurons and evokes an increase of glutamatergic excitation in this nucleus. Excitation of the EPN is responsible for a modulation of BLA activity through NPS, characterized by a general increase of GABAergic inhibition and enhancement of spike activity in a subset of BLA projection neurons. Finally, local injection of NPS to the EPN interferes with the expression of contextual, but not auditory cued fear memory. Together, these data suggest the existence of a specific NPS-responsive circuitry between EPN and BLA, likely involved in contextual aspects of fear memory.

Intranasally Administered Neuropeptide S (NPS) Exerts Anxiolytic Effects Following Internalization Into NPS Receptor-Expressing Neurons

“…This may result in a shorter depolarization period of the postsynaptic membrane and thus in a decreased magnitude of LTP, which might causally contribute to the reported NPS-mediated reduction of fear memory retrieval after extinction training (Jüngling et al, 2008). Here, we propose an involvement of the ventral hippocampus in the mechanistic model of NPS-mediated regulation of anxiety demonstrated by others who identified the amygdala as a major player in mediating the anxiolytic effects of NPS (Meis et al, 2008;Fendt et al, 2010;Jüngling et al, 2008). As the ventral hippocampus and especially the ventral CA1 region are known to be closely connected to the amygdaloid nuclei by extensive bidirectional connections (Fanselow and Dong, 2010), our results suggest that the ventral hippocampus may, in addition to the well-described direct effects of NPS in the amygdala, modulate the activity of amygdaloid nuclei with a view toward reducing anxiety.…”

A neuropeptide S receptor variant associated with overinterpretation of fear reactions: a potential neurogenetic basis for catastrophizing

“…1,2 Recent evidence from rodent models indicates that the NPS system is critically involved in the regulation of unconditioned and conditioned fear behaviors. 1,[3][4][5][6][7] In humans, the locus for the NPS receptor gene NPSR1 maps to a chromosomal region that has reproducibly been linked to PD, with those markers creating the highest lod scores lying in close vicinity to he NPSR1 locus. [8][9][10] NPSR1 contains a frequent A>T polymorphism (rs324981) that codes for an Asn/Ile change at position 107.…”

Neuropeptide S receptor gene — converging evidence for a role in panic disorder

“…7 On an anatomical level, NPS has been shown to be expressed in the amygdaloid complex 8 and exert a modulatory effect on both afferent and intrinsic transmission in amygdala networks in rodent models. [9][10][11] On a cellular level, NPS increases glutamatergic transmission to intercalated GABAergic neurons in the amygdala conferring an inhibitory influence on the central amygdaloid nucleus and thereby attenuating anxiety-like responses. 9 Given the crucial role of the amygdala in the elicitation and regulation of anxiety-related responses [12][13][14] and increased amygdala activity in patients with anxiety disorders, [15][16][17][18] this finding underlines the importance of NPS in the processing of acute fear.…”