RESUMEN
The sexual receptivity of female mice, shown as lordosis response, is mainly regulated by estradiol action on estrogen receptor alpha (ERα) and beta (ERß), 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 non-receptive states on the day after estrus (Day 2) are not completely understood. In the present study, we investigated the possible role of ERß, which is highly expressed in the dorsal raphe nucleus (DRN), in lordosis expression. We found that ERß-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 ERß-expressing DRN (DRN-ERß+) neuronal activity was chemogenetically suppressed. This finding suggests that excitation of DRN-ERß+ neurons is necessary for the decline of lordosis on Day 2. Fiber photometry recordings during female-male behavioral interactions revealed that DRN-ERß+ neuronal activation in response to male intromission was significantly more prolonged on Day 2 compared to Day 1. Chemogenetic over-stimulation of DRN-ERß+ 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-ERß+ cells. These findings collectively suggest that DRN-ERß+ neuronal excitation serves as an inhibitory modulator and is responsible for the decline in receptivity during non-estrus phases.Significance Statement In females, switching from a sexually receptive state to a non-receptive phase during the estrous cycle is essential for effective behavioral interactions with males and successful reproduction. Here, we delineate the possible brain regions that regulate the decline in receptive behavioral responses, such as lordosis, from those shown on the day of estrus to those on the day after estrus. We found that excitation of neurons expressing estrogen receptor (ER) ß in the midbrain dorsal raphe nucleus is crucial for the suppression of lordosis during the day after estrus. This is contrasted with the facilitatory action of ERα, another type of ER, and provides new insights for understanding the neural basis of the adaptive expression of female reproductive behavior.
RESUMEN
17ß-estradiol (E2) regulates various forms of social behavior through the activation of two types of estrogen receptors, ERα and ERß. The lateral septum (LS) is thought to be one of the potential target sites of E2, but the role played by ERα and ERß in this brain area remains largely unknown. In the present study, we first analyzed the distribution of ERα and ERß with double fluorescent immunohistochemistry in a transgenic mouse line in which red fluorescent protein (RFP) signal has been a reliable marker of ERß expression. The overall number of ERß-RFP-expressing cells was significantly higher (about 2.5 times) compared to ERα-expressing cells. The distribution of the two types of ERs was different, with co-expression only seen in about 1.2% of total ER-positive cells. Given these distinctive distribution patterns, we examined the behavioral effects of site-specific knockdown of each ER using viral vector-mediated small interference RNA (siRNA) techniques in male mice. We found ERß-specific behavioral alterations during a social interaction test, suggesting involvement of ERß-expressing LS neurons in the regulation of social anxiety and social interest. Further, we investigated the neuronal projections of ERα- and ERß-expressing LS cells by injecting an anterograde viral tracer in ERα-Cre and ERß-iCre mice. Dense expression of green fluorescence protein (GFP) in synaptic terminals was observed in ERß-iCre mice in areas known to be related to the modulation of anxiety. These findings collectively suggest that ERß expressed in the LS plays a major role in the estrogenic control of social anxiety-like behavior.