A hypothalamic node for the cyclical control of female sexual rejection

Internal state-dependent behavioral flexibility, such as the ability to switch between rejecting and accepting sexual advances based on a female's reproductive capacity, is crucial for maintaining meaningful social interactions. While the role of the ventrolateral ventromedial hypothalamus (VMHvl) in sexual acceptance is well established, the neural mechanisms underlying sexual rejection remain unexplored. In this study, we identify progesterone receptor-expressing neurons in the anterior VMHvl (aVMHvl^PR+) as key regulators of cyclical female sexual rejection behavior. In vivo recordings reveal that these neurons are active during sexual rejection but inactive during sexual acceptance. Slice electrophysiology demonstrates that aVMHvl^PR+ neurons receive a reduced excitatory-to-inhibitory synaptic input balance in receptive females. Furthermore, activating and inhibiting aVMHvl^PR+ neurons increases rejection in receptive females and reduces rejection in non-receptive females, respectively. Thus, aVMHvl^PR+ neurons constitute a critical neural substrate controlling female sexual behavior, providing an additional barrier to mating when fertilization is not possible.