We thank the Lima Laboratory and Champalimaud Research members for helpful comments on the manuscript, Gil Costa for the graphical abstract design and the Champalimaud Foundation Advanced Bio-optics and Bio-imaging platform for the microscopy technical assistance. This work was supported by the Champalimaud Foundation, Portuguese national funds, through FCT -Fundação para a Ciência e a Tecnologia -in the context of the project UIDB/04443/2020, by the research infrastructure CONGENTO, co-financed by Lisboa Regional Operational Programme (Lisboa2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF) and Fundação para a Ciência e Tecnologia (Portugal) under the project LISBOA-01-0145-FEDER-022170, the imagin platform under the project LISBOA-01-0145-FEDER-022122, the project BioData.Pt -LISBOA-01-0145-FEDER-022231 and an ERC Consolidator Grant (772827, SQL).

No abstract

Selecting an appropriate behavioral response in a context and internal state dependent manner is fundamental to maintain social interactions and wellbeing. Thus, the existence of robust organizing mechanisms such as the one coordinating sexual receptivity and reproductive capacity should come as no surprise, with females cyclically switching between rejecting sexual advances to accepting them depending on their fertility state. Whereas sexual acceptance has been the focus of extensive investigation, rejection behavior has been largely ignored and falls short of a neural substrate. Here we characterize a dedicated circuit for the cyclical control of rejection behavior located in the anterior portion of the ventrolateral part of the ventromedial hypothalamus (aVMHvl) in naturally cycling females. In vivo recordings reveal that progesterone receptor expressing neurons in the aVMHvl (aVMHvlPr+) are active during the expression of sexual rejection but silent when females accept to engage in sexual behavior. Moreover, aVMHvlPr+ neurons undergo a significant reduction in their excitatory to inhibitory synaptic input balance during the receptive phase of the reproductive cycle. Finally, optogenetic activation of aVMHvlPr+ neurons in receptive females is sufficient to increase the expression of rejection behavior, significantly disrupting the willingness of receptive females to engage in sexual behavior without compromising other male-directed interactions. Altogether, the population of aVMHvlPr+ neurons and its dynamic control of rejection behavior represents a key neural substrate for the internal state regulation of female sexual behavior, providing an additional barrier that prevents mating when fertilization is not possible.

Sex hormone levels continuously fluctuate across the reproductive cycle, changing the activity of neuronal circuits to coordinate female behavior and reproductive capacity. The ventrolateral division of the ventromedial hypothalamus (VMHvl) contains neurons expressing receptors for sex hormones and its function is intimately linked to female sexual receptivity. However, recent findings suggest that the VMHvl is functionally heterogeneous. Here, we used whole cell recordings and intracellular labeling to characterize the electrophysiological and morphological properties of individual VMHvl neurons in naturally cycling females. We found that the properties of progesterone receptor expressing (PR+) neurons, but not PR- neurons, depended systematically on the neuron's location along the anterior-posterior axis of the VMHvl and the phase within the reproductive cycle. Prominent amongst this, the resting membrane potential of anterior PR+ neurons decreased during the receptive phase, while the excitability of medial PR+ neurons increased during the non-receptive phase. During the receptive phase of the cycle, posterior PR+ neurons simultaneously showed an increase in dendritic complexity and a decrease in spine density. These findings reveal an extensive diversity of local rules driving structural and physiological changes in response to fluctuating levels of sex hormones, supporting the anatomical and functional subdivision of the VMHvl and its possible role in the orchestration of different aspects of female socio-sexual behavior.