Impact of the Neuropeptide S system and NPS-receptor polymorphisms on fear and anxiety
The objective of project A08 is the functional characterization of a single-nucleotide polymorphism (SNP) in the neuropeptide S receptor (NPSR1) gene that has been linked to panic disorders and increased stress levels in a novel genetically engineered mouse model. Based on the findings from the last funding period, a novel mouse model was generated by the use of CRISPR/Cas9 mediated gene editing inducing an amino acid substitution of isoleucine (I) by arginine (N) at position 107 in the NPSR1 protein. Our hypothesis is that the introduced single-nucleotide polymorphism (SNP), analogue to the SNP described in humans, will alter NPSR1 functionality, NPSR1-modulated circuits and behavior in mice. The differential function of the NPS system in the two interconnected brain regions (anxiolytic in BLA vs. anxiogenic in PVT) will be analyzed in wild-type and mutant mice of the NPSR1-I107N mouse line. In vitro electrophysiological recordings and behavioral experiments, using well established paradigms, combined with pharmacological manipulations, will be performed to functional characterize the NPSR1 I107N polymorphism in terms of anxiety-like behavior, fear extinction and generalization, and the underlying neuronal correlates. Finally, in vitro and in vivo optogenetic techniques will be used to determine the impact the PVT-BA circuit on fear- and anxiety-like behavior and the effect of the two different NPSR1 variants on this circuit. This translation of the human cohort research into an animal model and the translation of expected results of the detailed functional and behavioral characterization of the novel animal model back to human oriented research will help to improve the treatment of anxiety disorders.