Female Sexual Behavior In Rodents Research Articles

Role for the membrane estrogen receptor alpha in the sexual differentiation of the brain.

Estrogens exert pleiotropic effects on multiple physiological and behavioral responses. Male and female sexual behavior in rodents constitutes some of the best-characterized responses activated by estrogens in adulthood and largely depend on ERα. Evidence exists that nucleus- and membrane-initiated estrogen signaling cooperate to orchestrate the activation of these behaviors both in short- and long-term. However, questions remain regarding the mechanism(s) and receptor(s) involved in the early brain programming during development to organize the circuits underlying sexually differentiated responses. Taking advantage of a mouse model harboring a mutation of the ERα palmitoylation site, which prevents membrane ERα signaling (mERα; ERα-C451A), this study investigated the role of mERα on the expression of male and female sexual behavior and neuronal populations that differ between sexes. The results revealed no genotype effect on the expression of female sexual behavior, while male sexual behavior was significantly reduced, but not abolished, in males homozygous for the mutation. Similarly, the number of kisspeptin- (Kp-ir) and calbindin-immunoreactive (Cb-ir) neurons in the anteroventral periventricular nucleus (AVPv) and the sexually dimorphic nucleus of the preoptic area (SDN-POA), respectively, were not different between genotypes in females. In contrast, homozygous males showed increased numbers of Kp-ir and decreased numbers of Cb-ir neurons compared to wild-types, thus leading to an intermediate phenotype between females and wild-type males. Importantly, females neonatally treated with estrogens exhibited the same neurochemical phenotype as their corresponding genotype among males. Together, these data provide evidence that mERα is involved in the perinatal programming of the male brain.

Identification of neural cells activated by mating stimulus in the periaqueductal gray in female rats.

Induction of lordosis as typical female sexual behavior in rodents is dependent on a mount stimulus from males and blood levels of estrogen. Periaqueductal gray (PAG) efferent neurons have been suggested to be important for lordosis behavior; however, the neurochemical basis remains to be understood. In this study, we neuroanatomically examined (1) whether PAG neurons activated by mating stimulus project to the medullary reticular formation (MRF), which is also a required area for lordosis; and (2) whether these neurons are glutamatergic. Mating stimulus significantly increased the number of cFos-immunoreactive (ir) neurons in the PAG, particularly in its lateral region. Half of cFos-ir neurons in the lateral PAG were positive for a retrograde tracer (FluoroGold; FG) injected into the MRF. cFos-ir neurons also colocalized with mRNA of vesicular glutamate transporter 2 (vGLUT2), a molecular marker for glutamatergic neurons. Using retrograde tracing and in situ hybridization in conjunction with fluorescent microscopy, we also found FG and vGLUT2 mRNA double-positive neurons in the lateral PAG. These results suggest that glutamatergic neurons in the lateral PAG project to the MRF and are involved in lordosis behavior in female rats.

Neuroanatomy and sex differences of the lordosis-inhibiting system in the lateral septum.

Female sexual behavior in rodents, termed lordosis, is controlled by facilitatory and inhibitory systems in the brain. It has been well demonstrated that a neural pathway from the ventromedial hypothalamic nucleus (VMN) to the midbrain central gray (MCG) is essential for facilitatory regulation of lordosis. The neural pathway from the arcuate nucleus to the VMN, via the medial preoptic nucleus, in female rats mediates transient suppression of lordosis, until female sexual receptivity is induced. In addition to this pathway, other regions are involved in inhibitory regulation of lordosis in female rats. The lordosis-inhibiting systems exist not only in the female brain but also in the male brain. The systems contribute to suppression of heterotypical sexual behavior in male rats, although they have the potential ability to display lordosis. The lateral septum (LS) exerts an inhibitory influence on lordosis in both female and male rats. This review focuses on the neuroanatomy and sex differences of the lordosis-inhibiting system in the LS. The LS functionally and anatomically links to the MCG to exert suppression of lordosis. Neurons of the intermediate part of the LS (LSi) serve as lordosis-inhibiting neurons and project axons to the MCG. The LSi-MCG neural connection is sexually dimorphic, and formation of the male-like LSi-MCG neural connection is affected by aromatized testosterone originating from the testes in the postnatal period. The sexually dimorphic LSi-MCG neural connection may reflect the morphological basis of sex differences in the inhibitory regulation of lordosis in rats.

Estrous cycle influences the expression of neuronal nitric oxide synthase in the hypothalamus and limbic system of female mice.

BackgroundNitric oxide plays an important role in the regulation of male and female sexual behavior in rodents, and the expression of the nitric oxide synthase (NOS) is influenced by testosterone in the male rat, and by estrogens in the female. We have here quantitatively investigated the distribution of nNOS immunoreactive (ir) neurons in the limbic hypothalamic region of intact female mice sacrificed during different phases of estrous cycle.ResultsChanges were observed in the medial preoptic area (MPA) (significantly higher number in estrus) and in the arcuate nucleus (Arc) (significantly higher number in proestrus). In the ventrolateral part of the ventromedial nucleus (VMHvl) and in the bed nucleus of the stria terminalis (BST) no significant changes have been observed. In addition, by comparing males and females, we observed a stable sex dimorphism (males have a higher number of nNOS-ir cells in comparison to almost all the different phases of the estrous cycle) in the VMHvl and in the BST (when considering only the less intensely stained elements). In the MPA and in the Arc sex differences were detected only comparing some phases of the cycle.ConclusionThese data demonstrate that, in mice, the expression of nNOS in some hypothalamic regions involved in the control of reproduction and characterized by a large number of estrogen receptors is under the control of gonadal hormones and may vary according to the rapid variations of hormonal levels that take place during the estrous cycle.

Effects of manipulating progesterone and NMDA receptors in the ventral tegmental area for lordosis of hamsters and rats

Progesterone (P4) has actions in the ventral tegmental area (VTA) to regulate female sexual behavior in rodents. However, there are few intracellular progestin receptors (PRs) that have been identified in the VTA through which P4 may have its actions to facilitate lordosis. There are N-methyl-D: -aspartate receptors (NMDARs) in the VTA that may be a substrate for P4's effects. We investigated the effects of pharmacologically manipulating NMDARs in the VTA for E2- and P4-facilitated lordosis of hamsters and rats. We examined the effect of systemic injections (intraperitoneal; IP) and bilateral infusions to the VTA of the highly specific, competitive NMDAR antagonist, 9-0-6-phosphonomethyl-deca-hydroisoquinoline-3-carboxylic acid (LY235959); 0, 0.3, and 1 mg/kg IP and 0, 1.0, and 10 ng/mul intra-VTA), on lordosis of estradiol-primed (E2; 10 microg) and P4-primed (0, 50, 250, or 500 microg) ovariectomized hamsters and rats. Intra-VTA administration of the NMDAR antagonist, LY235959, produced similar effects as systemic administration to enhance lordosis, particularly in E2-primed rats or hamsters administered moderate P4 levels (less than 500 microg). Administration of LY235959 to the substantia nigra did not produce similar effects as intra-VTA infusions for lordosis. Together, these data suggest that blocking NMDARs in the VTA enhances lordosis of hamsters and rats.

The Role of Neurosteroids and Nongenomic Effects of Progestins in the Ventral Tegmental Area in Mediating Sexual Receptivity of Rodents

Progesterone (P4) in the ventromedial hypothalamus (VMH) and ventral tegmental (VTA) is important for facilitation of lordosis; however, P4's actions in these brain areas are different. Using lordosis in rodents as in vivo experimental models, we have examined the effects progestins exert in the midbrain and hypothalamus. Localization and blocker studies indicate that P4's actions in the VMH require intracellular progestin receptors (PRs) but in the VTA they do not. Progestins that have rapid, membrane effects, and/or are devoid of affinity for PRs, facilitate lordosis when applied to the VTA. Manipulation of GABA and/or GABAA/benzodiazepine receptor complexes (GBRs) in the VTA alter lordosis, which suggests that progestins may interact with GBRs to facilitate receptivity by enhancing the function of GABAergic neurons. Interfering with P4's metabolism to 5α-pregnan-3α-ol-20-one (3α,5α-THP), the most effective endogenous positive modulator of GBRs, or the biosynthesis of the neurosteroid 3α,5α-THP in the VTA attenuates female sexual behavior in rodents. Stimulation of mitochondrial benzodiazepine receptors (MBRs), which enhance neurosteroid production, by infusions of a MBR agonist to the VTA enhances lordosis. 3α,5α-THP is increased in the midbrain of mated > proestrous > diestrous rodents. These data suggest that 3α,5α-THP has a proximate modulatory role on lordosis. In summary, the actions of P4 in the VTA are different from those in the VMH that involve PRs. In the VTA, P4 may facilitate lordosis following metabolism to and/or biosynthesis of 3α,5α-THP, which may have subsequent actions at GBRs and/or MBRs to acutely modulate female sexual behavior in rodents.

Interruption of the lordosis reflex of female rats by ventral midbrain stimulation

The lordosis reflex, dorsiflexion of the vertebral column, is an estrogen-dependent, essential element of female sexual behavior in rodents. Unilateral electrical stimulation of the midbrain ventral tegmental area through a chronically implanted electrode in freely moving, estrogen-primed ovariectomized female rats caused a rapid and strong suppression of the lordosis reflex in response to either male mounts or manual cutaneous stimuli. The interruption occurred in a graded manner to increased stimulus intensity, with a threshold at 30 μA. The optimal frequency was at 75–125 Hz. After the termination of electrical stimulation, lordosis performance returned promptly to the prestimulation level. No aversive response accompanied the blockade of lordosis. Electrical stimulation specifically blocked lordosis, without disrupting the proceptive components of female sexual behavior. In 10 animals tested, concomitant injection of dopamine receptor blocker pimozide tended to offset the effects of electrical stimulation in 2 cases. Interruption of the lordosis reflex might be mediated by projections from the ventral tegmental area, which activate a descending pathway inhibitory to the lordosis reflex arc at or below the lower brain stem.

Lordosis: Inhibiting effects of progesterone in the female rat

Progesterone has two types of inhibitory effects on female sexual behavior that have been well-documented in the guinea pig. The first occurs when high levels of progesterone are present around the start of the estrogen-priming process (“concurrent inhibition”). The second occurs immediately after the display of an estrogen-progesterone-induced period of estrous behavior (“sequential inhibition”). In the present set of experiments, we show that the rat, like the guinea pig, is capable of exhibiting both of these inhibitory effects of progesterone. However, rats require higher doses of progesterone than guinea pigs, at least for concurrent inhibition to be evident. In addition, we show that the dose of progesterone required in a single injection to produce concurrent inhibition is higher than the dose required to produce sequential inhibition in rats. A theory of how progesterone may be accomplishing its inhibitory effects on female sexual behavior in rodents is presented.