Neural control of female sexual behaviors

Abstract

Reproduction is the biological process by which new individuals are produced by their parents. It is the fundamental feature of all known life and is required for the existence of all species. All mammals reproduce sexually, a process that involves the union of two reproductive cells, one from a male and one from a female. Sexual behaviors are a series of actions leading to reproduction. They are composed of appetitive, action, and refractory phases, each supported by dedicated developmentally-wired neural circuits to ensure high reproduction success. In rodents, successful reproduction can only occur during female ovulation. Thus, female sexual behavior is tightly coupled with ovarian activity, namely the estrous cycle. This is achieved through the close interaction between the female sexual behavior circuit and the hypothalamic-pituitary-gonadal (HPG) axis. In this review, we will summarize our current understanding, learned mainly in rodents, regarding the neural circuits underlying each phase of the female sexual behaviors and their interaction with the HPG axis, highlighting the gaps in our knowledge that require future investigation.

Keywords: Female sexual behaviors; HPG axis; Neural circuits; Rodents; Sex hormones.

Figure 1.

Three phases of female sexual behaviors in rodents. (A) The appetitive phase includes detection, approach, and investigation. These three actions occur in loops until the consummatory phase begins. (B) During the consummatory phase, the male initiates mounting, positioning itself on top of the female while holding the female’s flanks with its front paws. If the female is receptive, it stays stationary with its back arching downward, a posture known as lordosis. (C) After the male ejaculates, both males and females show reduced sexual interest and spend most time grooming and licking themselves. Dark gray: male; light gray: female.

Figure 2.

Behavioral paradigms to assess social odor detection and sexual interest. (A) Habituation-dishabituation test to measure social odor detection and discrimination. The test animals are presented with urine from a conspecific 3–4 times, followed by urine from a different conspecific. (B, C) Three-chamber (B) and Y-Maze (C) social preference tests to assess animals’ social interest. Each end chamber/arm contains one type of odor source or a conspecific. (D) Nose entry test to examine females’ interest in a specific odor. Each tube attached to the nose port contains an odor source, e.g., urine. (E) Paced mating test to measure females’ sexual motivation. (Left) For rats, the test arena is divided into a ‘male’ chamber and an ‘escape’ chamber by a barrier with a small hole that females, but not males, can fit through. (Right) For mice, the male is tethered to the “male” chamber while the female could easily jump through the barrier to enter the escape the “male chamber”.

Figure 3.

A hypothesized model describing the neural circuits underlying various aspects of female sexual behaviors. During the appetitive phase of female sexual behaviors, male-related volatiles are detected by the MOE-MOB-CoApl circuit and converge with the non-volatile cues detected via VNO-AOB at the MeA. These chemosensory cues then evoke dopamine release at the NAc through the MPOA-VTA-NAc pathway to mediate the female’s high interest in the male. During the consummatory phase, male mounting associated somatosensory inputs activate the PAG to evoke the lordosis reflex. PAG is gated by the VMHvl, which is under the strong influence of sex hormones and male chemosensory inputs. PMv facilitates lordosis and MPOA inhibits lordosis by providing excitatory and inhibitory inputs to the VMHvl, respectively. When the male ejaculates, responses of the VMHvl and MPOA trigger prolactin surges essential for uterus development via ARCDA cells. Meanwhile, ejaculation causes a strong activation of BNSTpr cells, inhibiting the VMHvl and reducing the sexual interest. The mating circuit also interacts with the HPG axis extensively. VMHvl and PMv provide excitatory inputs to AVPVKiss cells to facilitate GnRH surge during proestrus. In turn, sex hormones released from the HPG axis modulate the overall state of the mating circuit. MOE: main olfactory epithelium; MOB: main olfactory bulb; OT: olfactory tubercle; Pir: piriform cortex; EC: entorhinal cortex; CoApl: posterolateral part of cortical amygdala; VNO: vomeronasal organ; AOB: accessory olfactory bulb; MeA: medial amygdala; PMCo: posteromedial cortical amygdala; BNSTpr: principal nucleus of bed nucleus of the stria terminalis; MPOA: medial preoptic area; VMHvl: ventrolateral part of the ventromedial hypothalamus; PMv: ventral part of premammillary nucleus; VTADA: ventral tegmental area dopaminergic cells; NAc: nucleus accumbens; PAG: periaqueductal gray; ARCDA: arcuate nucleus dopaminergic cells; AVPVKiss: anteroventral periventricular nucleus kisspeptin cells; GnRH: gonadotropin-releasing hormone.

Figure 4.

The role of VMHvllCckar cells in female sexual behaviors. (A) Diagram showing the location of VMH in the hypothalamus and its functionally and molecularly distinct subdivisions. Mating-related VMHvll cells may project to PAG and AVPV to control female lordosis and the HPG axis, respectively. (B) A summary of the in vivo and in vitro activity patterns of VMHvllCckar cells during estrus and diestrus and the behavior changes induced by VMHvllCckar manipulation (Yin et al., 2022). LQ: Lordosis quotient.

Figure 5.

A model of the lordosis reflex circuit. During diestrus, VMHvl is in a low activity state and consequently PAG is far from its activation threshold. When the somatosensory input related to male mounting reaches PAG, it fails to push the PAG pass its activation threshold to drive lordosis. In contrast, during estrus, VMHvl Cckar cells are in a high activity state, moving PAG closer to its activation threshold. Therefore, the same male mounting-associated somatosensory input now can drive the PAG pass the threshold to induce lordosis. PAG cells relevant for female sexual behaviors could be Esr1+

Figure 6.

Schematic illustration of the hormonal, neural, and behavioral changes during pregnancy and lactation in rodents. In rodents, after the female receives ejaculation, serum progesterone (black) increases with the progress of pregnancy, reaches its peak value at gestation day 16, and rapidly decreases before parturition. Serum estradiol (purple) increases from mid-pregnancy to term and declines rapidly before parturition. Prolactin (orange) transiently increases right after ejaculation and then surges twice daily for the first half of pregnancy. Prolactin surges again the night before parturition and maintains a high level during lactation. The activity of VMHvllCckar cells is highly correlated with female sexual receptivity: both are high during estrus and low during pregnancy and lactation. During postpartum day 1, female sexual receptivity is high, a phenomenon known as postpartum heat, and VMHvllCckar cell activity is possibly also high, although no recording data is currently available. Light gray bar: daytime; dark gray bar: nighttime.

Figure 7.

Neural control of the HPG axis (A) A model showing the hypothalamic regions/populations controlling the cascade of hormone release along the HPG axis. Specifically, ARCKiss controls the pulsatile release of GnRH and AVPVKiss controls GnRH surge. VMHvl and PMv facilitate GnRH surge through their inputs to ARCKiss, AVPVKiss and GnRH cells. GnRH stimulates the biosynthesis and the release of LH and FSH from the anterior pituitary gland, which promotes the release of sex hormones (estradiol and progesterone) from ovaries. (B) Schematics showing the putative activity patterns of AVPVKiss and ARCKiss cells (Herbison, 2020) and the release patterns of GnRH, LH, FSH, progesterone, and estradiol across the estrus cycle. ARCKiss: arcuate nucleus kisspeptin cells; AVPVKiss: anteroventral periventricular nucleus kisspeptin cells; GnRH, gonadotropin-releasing hormone; FSH, folliclestimulating hormone; LH, luteinizing hormone.