Hypothalamic circuits for the flexible control of female sexual behavior

Cyclic fluctuations in the levels of sex hormones coordinate sexual receptivity with reproductive capacity across the female’s reproductive cycle. In mice, only females in the fertile phase engage in sexual behavior, whereas outside this period they actively reject males by escaping, adopting defensive postures or even punching and kicking the male. While receptivity has been extensively studied and primarily linked to the posterior ventrolateral ventromedial hypothalamus (pVMHvl), sexual rejection has been largely overlooked and often considered as the passive absence of receptivity.
Our recent work identified a hypothalamic node for the control of active sexual rejection. Progesterone receptor-expressing neurons in the anterior VMHvl (aVMHvlPR+) bidirectionally regulate sexual rejection and undergo inhibitory synaptic remodeling across the estrous cycle. Thus, anteroposteriorly segregated VMHvl populations independently govern rejection and receptivity, enabling flexible control of sexual interactions.
To uncover the basis of these anteroposterior functional differences, we mapped whole-brain inputs and outputs of aVMHvlPR+ and pVMHvlPR+ neurons. aVMHvlPR+ neurons exhibit distinct connectivity from their posterior counterparts, showing strong connectivity to regions involved in arousal and defense. Notably, they project strongly to the dorsomedial periaqueductal gray (PAGdm), and optogenetic stimulation of these terminals partially recapitulates rejection behavior in receptive females.
A striking aspect of sexual rejection is its marked reduction upon the first penile insertion, which can occur even under optogenetic stimulation of aVMHvl PR+ neurons. In the final part of my talk, I will present our latest findings on how the first penile insertion, which marks the transition from appetitive to consummatory behavior, is encoded in a hypothalamic population interconnected with the VMHvl. I will show how this representation may not only inhibit the expression of sexual rejection but also initiate preparatory neural processes for motherhood.