Post-ejaculatory inhibition of female sexual drive via heterogeneous neuronal ensembles in the medial preoptic area

Male ejaculation acutely suppresses sexual motivation in male mice. In contrast, relatively little is known about how male ejaculation affects sexual motivation and sexual behavior in female mice. How the brain responds to the completion of mating is also unclear. Here, by using a self-paced mating assay, we first demonstrate that female mice show decreased sexual motivation acutely after experiencing male ejaculation. By using brain-wide analysis of activity-dependent labeling, we next pin-pointed the medial preoptic area as a brain region strongly activated during the post-ejaculatory period. Furthermore, using freely moving in vivo calcium imaging to compare the neural activity of inhibitory and excitatory neurons in the medial preoptic area, we revealed that a subset of the neurons in this region responds significantly and specifically to male ejaculation but not to female-to-male sniffing or to male mounting. While there were excitatory and inhibitory neurons that showed increased response to male ejaculation, the response magnitude as well as the proportion of neurons responding to the event was significantly larger in the inhibitory neuron population. Next, by unbiased classification of their responses, we also found a subpopulation of neurons that increase their activity late after the onset of male ejaculation. These neurons were all inhibitory indicating that male ejaculation induces a prolonged inhibitory activity in the medial preoptic area. Lastly, we found that chemogenetic activation of medial preoptic area neurons that were active during the post-ejaculatory period, but not during appetitive or consummatory periods, were sufficient to suppress female sexual motivation. Together, our data illuminate the importance of the medial preoptic area as a brain node which encodes a negative signal that sustains a low sexual motivation state after the female mice experience ejaculation.