Social interactions can take different courses depending on the internal state of the participants. For instance, a sexually receptive female mouse will allow a male’s attempt to mount her, but a non-receptive female will fight or flee the same male. Here, we propose to determine how neuronal circuits in the female mouse brain support flexible, state-dependent interactions with male conspecifics. It is known that female receptivity depends on the ventrolateral region of the ventromedial hypothalamus. Within this region there is a population of neurons that expresses receptors for the sex hormone progesterone (PR+ neurons), whose levels cycle with reproductive state. In pilot experiments, we found that PR+ neurons are not homogeneous: some respond during receptive behaviors but others respond during defensive or aggressive behaviors. Our main objective is to determine how female hypothalamic PR+ neurons participate in state-dependent behavioral responses to males. Our hypothesis is that two subpopulations of PR+ neurons are differentially modulated by the reproductive cycle and that each sub-population activates a different downstream circuit, one specialized for receptive and the other for defensive behaviors. Our specific aims are to: (1) characterize the functional selectivity of individual female PR+ neurons across the reproductive cycle; (2) map the connectivity of PR+ neurons to their output targets; (3) test the impact of different PR+ output pathways by genetically activating and silencing them; and (4) determine how reproductive hormones modulate the synaptic and intrinsic functional properties of PR+ neurons. These studies will elucidate the neuronal circuit mechanisms of a biologically essential female behavior. More broadly, this work will reveal mechanisms by which neuronal circuits can support flexible state-dependent adaptive behaviors.
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