Immediate early gene activity-regulated cytoskeletal-associated protein regulates estradiol-induced lordosis behavior in female rats.

Sensory feedback is an important component of any behavior, with each instance influencing subsequent activity. Female sexual receptivity is mediated both by the steroid hormone milieu and interaction with the male. We tested the influence of repeated mating on the level of sexual receptivity in ovariectomized rats treated with estradiol benzoate (EB) once every fourth day to mimic the normal phasic changes of circulating estradiol.

Modulation of the arcuate nucleus-medial preoptic nucleus lordosis regulating circuit: a role for GABAB receptors.

Estradiol rapidly activates a microcircuit in the arcuate nucleus of the hypothalamus (ARH) that is needed for maximal female sexual receptivity. Membrane estrogen receptor-α complexes with and signals through the metabotropic glutamate receptor-1a stimulating NPY release within the ARH activating proopiomelanocortin (POMC) neurons. These POMC neurons project to the medial preoptic nucleus (MPN) and release β-endorphin.

Membrane-initiated estradiol signaling in immortalized hypothalamic N-38 neurons.

Regulation of sexual reproduction by estradiol involves the activation of estrogen receptors (ERs) in the hypothalamus. Of the two classical ERs involved in reproduction, ERα appears to be the critical isoform. The role of ERα in reproduction has been found to involve a nuclear ERα that induces a genomic mechanism of action.

Membrane-initiated estradiol signaling induces spinogenesis required for female sexual receptivity.

Estrogens have profound actions on the structure of the nervous system during development and in adulthood. One of the signature actions of estradiol is to alter the morphology of neural processes. In the hippocampus, estradiol modulates spines and cellular excitability that affect cognitive behaviors.

Sex differences in hypothalamic astrocyte response to estradiol stimulation.

Background: Reproductive functions controlled by the hypothalamus are highly sexually differentiated. One of the most dramatic differences involves estrogen positive feedback, which leads to ovulation. A crucial feature of this positive feedback is the ability of estradiol to facilitate progesterone synthesis in female hypothalamic astrocytes.

Membrane-initiated estradiol signaling regulating sexual receptivity.

Estradiol has profound actions on the structure and function of the nervous system. In addition to nuclear actions that directly modulate gene expression, the idea that estradiol can rapidly activate cell signaling by binding to membrane estrogen receptors (mERs) has emerged. Even the regulation of sexual receptivity, an action previously thought to be completely regulated by nuclear ERs, has been shown to have a membrane-initiated estradiol signaling (MIES) component.

Protein kinase C signaling in the hypothalamic arcuate nucleus regulates sexual receptivity in female rats.

Rapid membrane-mediated estradiol signaling regulating sexual receptivity requires the interaction of the estrogen receptor (ER)-alpha and the metabotropic glutamate receptor 1a (mGluR1a). A cell signaling antibody microarray revealed that estradiol activated 42 proteins in the arcuate nucleus of the hypothalamus (ARH). To begin an analysis of various signaling pathways, protein kinase A and protein kinase C (PKC)-theta, whose signaling pathways have been implicated in the estradiol regulation of sexual receptivity, were examined.

Membrane estrogen receptor-alpha interactions with metabotropic glutamate receptor 1a modulate female sexual receptivity in rats.

In rats, female sexual behavior is regulated by a well defined limbic-hypothalamic circuit that integrates sensory and hormonal information. Estradiol activation of this circuit results in mu-opioid receptor (MOR) internalization in the medial preoptic nucleus, an important step for full expression of sexual receptivity. Estradiol acts through both membrane and intracellular receptors to influence neuronal activity and behavior, yet the mechanism(s) and physiological significance of estradiol-mediated membrane responses in vivo have remained elusive.

Release of orphanin FQ/nociceptin in the medial preoptic nucleus and ventromedial nucleus of the hypothalamus facilitates lordosis.

Opioid regulation of reproduction has been widely studied. However, the role of opioid receptor-like 1 receptor (NOP; also referred to as ORL-1 and OP4) and its endogenous ligand orphanin FQ/nociceptin (OFQ/N) have received less attention despite their extensive distribution throughout nuclei of the limbic-hypothalamic system, a circuit that regulates reproductive behavior in the female rat. Significantly, the expression of both receptor and ligand is regulated in a number of these nuclei by estradiol and progesterone.

Estradiol stimulates progesterone synthesis in hypothalamic astrocyte cultures.

The brain synthesizes steroids de novo, especially progesterone. Recently estradiol has been shown to stimulate progesterone synthesis in the hypothalamus and enriched astrocyte cultures derived from neonatal cortex. Estradiol-induced hypothalamic progesterone has been implicated in the control of the LH surge.

Direct regulation of adult brain function by the male-specific factor SRY.

The central dogma of mammalian brain sexual differentiation has contended that sex steroids of gonadal origin organize the neural circuits of the developing brain. Recent evidence has begun to challenge this idea and has suggested that, independent of the masculinizing effects of gonadal secretions, XY and XX brain cells have different patterns of gene expression that influence their differentiation and function. We have previously shown that specific differences in gene expression exist between male and female developing brains and that these differences precede the influences of gonadal hormones.

Sexual receptivity is reduced in the female mu-opioid receptor knockout mouse.

Activation of mu-opioid receptors is critical to steroid regulation of female sexual behavior, lordosis, in rodents. Estrogen treatment activates mu-opioid receptors in the medial preoptic area inhibiting lordosis, but ultimately appears important for progesterone facilitation of lordosis. We investigated the role of mu-opioid receptors in the expression of sexual receptivity in mice lacking mu-opioid receptors.

Sexually dimorphic gene expression in mouse brain precedes gonadal differentiation.

The classic view of brain sexual differentiation and behavior is that gonadal steroid hormones act directly to promote sex differences in neural and behavioral development. In particular, the actions of testosterone and its metabolites induce a masculine pattern of brain development, while inhibiting feminine neural and behavioral patterns of differentiation. However, recent evidence indicates that gonadal hormones may not solely be responsible for sex differences in brain development and behavior between males and females.

Dimerization of SOX9 is required for chondrogenesis, but not for sex determination.

The SRY-related SOX9 gene is involved in both chondrogenesis and the early steps of mammalian sex determination. Mutations in the human SOX9 gene cause campomelic dysplasia, a severe skeletal malformation syndrome associated with male-to-female sex reversal in most, but not all, XY individuals. Here we show that SOX9 contains a dimerization domain, and binds co-operatively as a dimer in the presence of the DNA enhancer element in genes involved in chondrocyte differentiation, such as Col11a2 and Col9a2, but binds as a monomer to the regulatory region of the sex-determining gene SF1.

Disorders of gonadal development.

The molecular mechanisms of gonadal development are a complex process, which involves the tightly regulated differentiation of a bipotential embryonic gonad into either testes or ovary. Once this has occurred, the phenotypic and gonadal sex of an individual has been genetically determined. This process, however, may not always be so straightforward.