[Oxytocin regulates social familiarity-dependent mate choice in medaka]

Some social animals have evolved the ability to distinguish between familiar and unfamiliar individuals and to flexibly modify their behavior according to social context. Disruption of this system has been implicated in neurodevelopmental disorders such as autism, motivating efforts to elucidate its molecular basis. Among the factors involved in social behavior, oxytocin has attracted considerable attention; however, its actions are not uniform and may vary across species and between sexes. Here, we investigated how oxytocin regulates familiarity-dependent mate choice using medaka, a model organism that relies primarily on visual cues for social recognition. In female medaka, wild-type individuals preferentially accepted familiar males, whereas oxytocin-deficient females rapidly accepted even unfamiliar males, resulting in a loss of familiarity-dependent preference. In contrast, oxytocin-deficient males showed reduced courtship toward unfamiliar females, but their courtship frequency increased with cohabitation. Furthermore, in triadic social interactions, oxytocin-deficient males displayed enhanced mate-guarding behavior toward familiar females, indicating exaggerated preference. These results demonstrate that oxytocin deficiency produces sex-dependent effects on mate choice. Whole-brain transcriptome analyses revealed a consistent reduction in the expression of complement component C1q genes in both sexes, suggesting abnormalities in neurodevelopmental processes. In addition, genes related to GABA metabolism were selectively altered in females, indicating sex-specific molecular pathways downstream of oxytocin signaling. Finally, we introduce UPA-seq, a method to evaluate RNA-protein interactions genome-wide. Integrating UPA-seq into future studies is expected to enable efficient identification of previously uncharacterized genes downstream of the pathways identified here, providing new insights into the molecular mechanisms underlying oxytocin-dependent mate choice.