Tph2-/- female mice restore socio-sexual recognition through upregulating ERα and OTR genes in the amygdala.

The central 5-hydroxytryptamine system impairs sociosexual behaviors and olfaction preferences in sexually naive mice. However, it remains unknown whether reproductive experiences impart an effect on the sexual olfactory preferences of female mice lacking central serotonin. Here, we aimed at examining such effects and the underlying mechanisms using Tph2 knockout female mice. Sexually naive Tph2-/- female mice failed to recognize olfactory cues regarding sex, genetic relatedness, and social hierarchy despite exhibiting normal olfactory discrimination. However, reproduction-experienced Tph2-/- female mice recovered sexual olfactory preferences, as did sexually naive Tph2+/+ females. Meanwhile, both the estrogen receptor α and oxytocin receptor in the amygdala of reproduction-experienced Tph2-/- females presented upregulated expression at the mRNA level and an upward tendency at the protein level vs. sexually naive Tph2-/- females. Intracerebroventricular administration of a combination of estrogen receptor α and oxytocin receptor agonists, but not either agent alone, could restore the sexual olfactory preferences of sexually naive Tph2-/- female mice to some degree. We speculate that estrogen receptor α and oxytocin receptor activation in the amygdala after reproductive experiences restores sexual olfactory recognition in Tph2-/- female mice.