Reproductive state switches the valence of male urinary pheromones in female mice

Internal states shape responses to sensory stimuli. Mammalian female reproductive states are understudied considering they are one of the most regular state changes in the animal kingdom. Here we examine female house mouse preferences toward male odors across the reproductive states of estrus and late-stage pregnancy. In house mice, urine scent marks are salient social odors that convey information about the sex and identity of individuals by major urinary proteins (MUPs). Males secrete a sex-specific pheromonal protein called darcin (MUP20). Additionally, genetically diverse mice secrete unique combinations of MUPs used in individual recognition. Prior work has revealed that male odors are powerful social stimuli for female mice, yet we have a limited understanding of how the valence of such odors change across reproductive states. We discovered a valence shift among estrus and pregnant females toward novel male urine, in which estrus females exhibit preference and pregnant females show strong avoidance. This valence switch also occurs toward darcin alone, providing further support for darcin as a strong sexual signal. However, when presented with familiar male urine, the approach-avoidance response disappears, even when additional darcin is added. In contrast, when an existing identity protein (MUP11) is added to familiar male urine the approach-avoidance response is recovered. This indicates that darcin in the absence of other identity information denotes a novel male and that familiar identity information present in male urine is sufficient to modify responses to darcin. Our findings suggest that the sex and identity information encoded by MUPs are likely processed via distinct, and potentially opposing pathways, that modulate responses toward complex social odor blends. Furthermore, we identify a state-modulated shift in decision-making toward social odors and propose a neural circuit model for this flow of information. These data underscore the importance of physiological state and signal context for interpreting the meaning and importance of social odors.