Neural substrates of female sexual rejection: hypothalamic pathways to the periaqueductal gray

Abstract Selecting an appropriate behavioral response according to one’s internal state is essential for well-being. Across the reproductive cycle, fluctuating levels of sex hormones align female behavior with reproductive capacity by modulating neuronal circuits that express hormone receptors. Sex hormone receptor-expressing neurons present along the anterior-posterior axis of the ventrolateral region of the ventromedial hypothalamus (VMHvl) are key regulators of female sexual behavior. While posterior progesterone receptor-expressing neurons of the VMHvl (pVMHvl PR+ ) are fundamental for female sexual receptivity during the receptive phase of the reproductive cycle, we have recently shown that anterior VMHvl PR+ (aVMHvl PR+ ) neurons are involved in rejection behavior when non-receptive. Here, we mapped the connectional architecture of aVMHvl PR+ neurons using viral tracing approaches. As expected, these neurons strongly project to several hypothalamic areas. Furthermore, consistent with previous reports, we show that aVMHvl PR+ neurons robustly project to several columns of the periaqueductal gray (PAG) along its anterior-posterior axis. Artificial activation of aVMHvl PR+ somas selectively recruits the dorsomedial PAG (dmPAG). Optogenetic activation of aVMHvl PR+ axons in the dmPAG partially recapitulates the rejection phenotype observed upon activation of aVMHvl PR+ somas, increasing the rate of rejections in receptive females. These findings reveal a putative pathway regulating female rejection behavior within a more complex circuit, ensuring that mating does not occur during non fertile periods.