Estrous Cycle-Dependent Modulation of Sexual Receptivity in Female Mice by Estrogen Receptor Beta-Expressing Cells in the Dorsal Raphe Nucleus

The sexual receptivity of female mice, shown as lordosis response, is mainly regulated by estradiol action on estrogen receptor alpha (ERα) and beta (ERβ), depending on the day of the estrous cycle. Previous studies revealed that ERα in the ventromedial nucleus of the hypothalamus (VMH) plays an essential role in the induction of lordosis on the day of estrus (Day 1). However, the mechanisms of the transition to nonreceptive states on the day after estrus (Day 2) are not completely understood. In the present study, we investigated the possible role of ERβ, which is highly expressed in the dorsal raphe nucleus (DRN), in lordosis expression. We found that ERβ-Cre female mice, which were ovariectomized and primed with estradiol and progesterone to mimic the estrous cycle, showed high levels of lordosis on Day 2 when ERβ-expressing DRN (DRN-ERβ⁺) neuronal activity was chemogenetically suppressed. This finding suggests that excitation of DRN-ERβ⁺ neurons is necessary for the decline of lordosis on Day 2. Fiber photometry recordings during female-male behavioral interactions revealed that DRN-ERβ⁺ neuronal activation in response to male intromission was significantly more prolonged on Day 2 compared with Day 1. Chemogenetic overstimulation of DRN-ERβ⁺ neurons induced c-Fos expression in brain areas known to be inhibitory for lordosis expression, even though they did not express anterogradely labeled fibers of DRN-ERβ⁺ cells. These findings collectively suggest that DRN-ERβ⁺ neuronal excitation serves as an inhibitory modulator and is responsible for the decline in receptivity during nonestrus phases.