Neuropeptide S (NPS) is a recently discovered G protein-coupled receptor ligand that modulates fear-like behaviors in rodents. A frequent A>T single-nucleotide polymorphism in the human NPS receptor gene NPSR1 confers a 10-fold higher efficacy of NPS signaling in vitro and has been linked with panic disorder (PD). We here report data from a classical fear-conditioning paradigm in healthy normal volunteers, in which carriers of the NPSR1 T allele evaluated their fear reactions to conditioned stimuli (CSs) as more pronounced than AA homozygous participants, although they did not show elevated peripheral-physiological conditioned responses (skin conductance responses-SCRs). T carriers also exhibited stronger CS-evoked brain activity in the rostral dorsomedial prefrontal cortex (dmPFC), an area that supports the explicit, conscious appraisal of threat stimuli. By contrast, more caudally situated mid-dmPFC, which has previously been associated with the generation of SCRs, showed no elevated response. Moreover, rostral dmPFC activation was correlated with participants' fear evaluations, further strengthening the link of this activation to increased individual fear appraisal. Our data suggest a genetic and neuroanatomical substrate for catastrophizing overinterpretations of fear reactions and provide a mechanistic explanation for the association between the NPSR1 T allele and PD.
