The neuropeptide S (NPS) and its receptor (NPSR1) are involved in various physiological processes, including arousal, sleep, anxiety, memory, and stress responses in rodents. Recent attention has focused on the association between the NPS/NPSR1 system and stress-related disorders, particularly involving a specific single nucleotide polymorphism (SNP) in the NPSR1 gene (rs324981). This SNP causes an amino acid change at position 107 in the protein, reducing NPSR1 signalling potency
however, its effects on behavioural, cognitive, and physiological aspects relevant to stress-related disorders remain unclear. Addressing this topic, we characterized the behavioural phenotype of a gene-editing mouse model, expressing either the murine/ancestral NPSR1-I107 variant or the human NPSR1-N107 variant. Both, male and female mice underwent a comprehensive behavioural test battery assessing arousal, exploratory and anxiety-related behaviour under varying levels of novelty stress. Moreover, cognitive functions were evaluated with a special focus on cognitive flexibility using the Attentional Set Shifting Task (ASST). Additionally, markers of behavioural and endocrine stress reactivity were assessed as well as changes in body weight and body composition. Our results showed that NPSR1-N107 mice displayed increased anxiety-related behaviour compared to NPSR1-I107 mice, with no significant differences in arousal, exploratory behaviour or hormonal stress responses. However, NPSR1-N107 mice also exhibited better rule-reversal learning in the ASST, indicating enhanced cognitive flexibility. These findings provide clear evidence for a role of the NPSR1 rs324981 SNP in regulating emotionality and cognitive flexibility, underscoring the potential of the NPSR1-I107N mouse model for further elucidating the molecular mechanisms underlying stress-related disorders.