Oxytocin is a central neuromodulator required for facilitating mate preferences 
for familiar individuals in a monogamous rodent (prairie vole), irrespective of 
sex. While the role of oxytocin in mate choice is only understood in a few 
monogamous species, its function in nonmonogamous species, comprising the vast 
majority of vertebrate species, remains unclear. To address this issue, we 
evaluated the involvement of an oxytocin homolog (isotocin, referred herein as 
oxt) in mate choice in medaka fish (Oryzias latipes). Female medaka prefer to 
choose familiar mates, whereas male medaka court indiscriminately, irrespective 
of familiarity. We generated mutants of the oxt ligand (oxt) and receptor genes 
(oxtr1 and oxtr2) and revealed that the oxt-oxtr1 signaling pathway was 
essential for eliciting female mate preference for familiar males. This pathway 
was also required for unrestricted and indiscriminate mating strategy in males. 
That is, either oxt or oxtr1 mutation in males decreased the number of courtship 
displays toward novel females, but not toward familiar females. Further, males 
with these mutations exhibited enhanced mate-guarding behaviors toward familiar 
females, but not toward novel females. In addition, RNA-sequencing (seq) 
analysis revealed that the transcription of genes involved in gamma-amino 
butyric acid metabolism as well as those encoding ion-transport ATPase are 
up-regulated in both oxt and oxtr1 mutants only in female medaka, potentially 
explaining the sex difference of the mutant phenotype. Our findings provide 
genetic evidence that oxt-oxtr1 signaling plays a role in the mate choice for 
familiar individuals in a sex-specific manner in medaka fish.