Mammalian reproduction is a resource-intensive undertaking, particularly when you consider the significant energy expense required of females during mating, gestation and raising offspring. From an evolutionary point of view, it would seem plausible that female mammals would be selective about their mates to ensure their energy investment allows successful transmission of their genes to the next generation. “Female selectivity” implies that a female decides to mate or not mate with a particular male, and that this information is integrated at higher levels in the brain. However, from a recent issue of Cell, we learn that the brain may not be involved and certain environmental cues are effectively ignored at the level of the sensory neuron (Dey et al 2015). In this study, an interdisciplinary team of researchers from several institutes investigated how hormonal fluctuations in the murine estrous cycle influence female sensory perception of male pheromonal cues.
Female behavior to emitted male pheromones varies throughout the estrous cycle. During estrus, female mice are receptive to mating; in diestrus, females may be neutral or aggressively opposed to mating. Dey et al. investigated the neurological basis through which this difference in behavior to a common stimulus manifests itself. Using behavioral assays, the researchers confirmed that female C57BL/6J (000664) mice in estrus preferred purified recombinant male urinary proteins (rMUPs), while those in diestrus were indifferent to them.
In order to understand the circuitry for rMUP attraction during estrus, vomeronasal sensory neurons (VSNs) were dissociated from the olfactory centers and subjected to in vitro fluorescent calcium imaging. Total VSNs from estrus-staged females were more sensitive to rMUPs than VSNs from diestrus-stage females. Interestingly, VSNs from ovariectomized females responded similarly to females in estrus, suggesting that a hormone present during diestrus, namely progesterone, is responsible for inhibiting rMUP sensation. Importantly, progesterone did not inhibit activation of VSNs that detect compounds from predatory animals, indicating that females can respond appropriately to dangerous environmental cues irrespective of estrous stage.
The role of progesterone was investigated further. For example, RNA-sequencing of rMUP responsive VSNs implicated a specific progesterone receptor-phospholipase C family member (PLCβ2) signaling pathway important to this sensory transmission. PLCβ2 was expressed at high levels in rMUP-responsive neurons but was not expressed in all VSN neurons, indicating the presence of a specialized set of neurons involved in the responses being observed. Dey et al. examined VSNs from PLCβ2-deficient female mice (B6.129S1-Plcb2tm1Dwu/J (018064)) and found they failed to respond to rMUP stimulation. Finally, when these researchers administered progesterone to VSNs dissociated from normal mice, PLCβ2 became phosphorylated and inactivated. These results indicate that specific VSNs important for mating are inhibited by progesterone.
Taken together, these data suggest that females in diestrus cannot sense male pheromones at the level of the olfactory organs, thereby preventing further transmission of these sensory cues to higher centers in the brain. The findings in this study have stark evolutionary implications – females are blocked early in their sensory infrastructure during a period in which mating would be unsuccessful and thus, unnecessarily costly to survival.