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Paul E Micevych - One of the best experts on this subject based on the ideXlab platform.
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optogenetic activation of β endorphin terminals in the medial preoptic nucleus regulates female sexual receptivity
eNeuro, 2020Co-Authors: Caroline S Johnson, Weizhe Hong, Paul E MicevychAbstract:Estrogen and progesterone (P4) act in neural circuits to elicit Lordosis, the stereotypical female sexual receptivity Behavior. Estradiol acts through membrane receptors to rapidly activate a limbic-hypothalamic circuit consisting of the arcuate (ARH), medial preoptic (MPN), and ventromedial (VMH) nuclei of the hypothalamus. This initial activation results in a transient but necessary inhibition of Lordosis, which appears to be a result of the release of β-endorphin (β-End) from proopiomelanocortin (POMC) terminals onto cells containing the µ-opioid receptor (MOR) in the MPN. To functionally examine the role of the MOR in the hypothalamic Lordosis circuit, we transfected a channelrhodopsin (ChR2) adeno-associated virus into POMC cell bodies in the ARH and photostimulated POMC/β-End axon terminals in the MPN in sexually receptive female Pomc-cre mice. Following estrogen and P4 priming, sexual receptivity was assessed by measuring the Lordosis quotient (LQ). Following an initial trial for sexual receptivity, mice were photostimulated during Behavioral testing, and brains were processed for MOR immunohistochemistry (IHC). Photostimulation decreased the LQ only in ChR2-expressing Pomc-cre mice. Furthermore, photostimulation of ChR2 in POMC/β-End axon terminals in the MPN resulted in the internalization of MOR, indicating activation of the receptor. Our results suggest that the activation of the MOR in the MPN is sufficient to attenuate Lordosis Behavior in a hormone-primed, sexually receptive female mouse. These data support a central role of MOR in female sexual Behavior, and provide further insight into the hypothalamus control of sexual receptivity.
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Integrating Neural Circuits Controlling Female Sexual Behavior
Frontiers Media S.A., 2017Co-Authors: Paul E Micevych, Robert L. MeiselAbstract:The hypothalamus is most often associated with innate Behaviors such as is hunger, thirst and sex. While the expression of these Behaviors important for survival of the individual or the species is nested within the hypothalamus, the desire (i.e., motivation) for them is centered within the mesolimbic reward circuitry. In this review, we will use female sexual Behavior as a model to examine the interaction of these circuits. We will examine the evidence for a hypothalamic circuit that regulates consummatory aspects of reproductive Behavior, i.e., Lordosis Behavior, a measure of sexual receptivity that involves estradiol membrane-initiated signaling in the arcuate nucleus (ARH), activating β-endorphin projections to the medial preoptic nucleus (MPN), which in turn modulate ventromedial hypothalamic nucleus (VMH) activity—the common output from the hypothalamus. Estradiol modulates not only a series of neuropeptides, transmitters and receptors but induces dendritic spines that are for estrogenic induction of Lordosis Behavior. Simultaneously, in the nucleus accumbens of the mesolimbic system, the mating experience produces long term changes in dopamine signaling and structure. Sexual experience sensitizes the response of nucleus accumbens neurons to dopamine signaling through the induction of a long lasting early immediate gene. While estrogen alone increases spines in the ARH, sexual experience increases dendritic spine density in the nucleus accumbens. These two circuits appear to converge onto the medial preoptic area where there is a reciprocal influence of motivational circuits on consummatory Behavior and vice versa. While it has not been formally demonstrated in the human, such circuitry is generally highly conserved and thus, understanding the anatomy, neurochemistry and physiology can provide useful insight into the motivation for sexual Behavior and other innate Behaviors in humans
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RESEARCH ARTICLE β-Arrestin Regulates Estradiol Membrane- Initiated Signaling in Hypothalamic Neurons
2016Co-Authors: Angela M. Wong, Matthew C. Abrams, Paul E MicevychAbstract:Estradiol (E2) action in the nervous system is the result of both direct nuclear and mem-brane-initiated signaling (EMS). E2 regulates membrane estrogen receptor-α (ERα) levels through opposing mechanisms of EMS-mediated trafficking and internalization. While ß-arrestin-mediated mERα internalization has been described in the cortex, a role of ß-arrestin in EMS, which underlies multiple physiological processes, remains undefined. In the arcuate nucleus of the hypothalamus (ARH), membrane-initiated E2 signaling modu-lates Lordosis Behavior, a measure of female sexually receptivity. To better understand EMS and regulation of ERαmembrane levels, we examined the role of ß-arrestin, a mole-cule associated with internalization following agonist stimulation. In the present study, we used an immortalized neuronal cell line derived from embryonic hypothalamic neurons, the N-38 line, to examine whether ß-arrestins mediate internalization of mERα. β-arrestin-1 (Arrb1) was found in the ARH and in N-38 neurons. In vitro, E2 increased trafficking and in-ternalization of full-length ERα and ERαΔ4, an alternatively spliced isoform of ERα, which predominates in the membrane. Treatment with E2 also increased phosphorylation of extra-cellular-signal regulated kinases 1/2 (ERK1/2) in N-38 neurons. Arrb1 siRNA knockdown prevented E2-induced ERαΔ4 internalization and ERK1/2 phosphorylation. In vivo, microin-fusions of Arrb1 antisense oligodeoxynucleotides (ODN) into female rat ARH knocked down Arrb1 and prevented estradiol benzoate-induced Lordosis Behavior compared with nonsense scrambled ODN (Lordosis quotient: 3 ± 2.1 vs. 85.0 ± 6.0; p< 0.0001). These re-sults indicate a role for Arrb1 in both EMS and internalization of mERα, which are required for the E2-induction of female sexual receptivity
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estradiol membrane initiated signaling and female reproduction
Comprehensive Physiology, 2015Co-Authors: Paul E Micevych, Angela May Wong, Melinda A MittelmansmithAbstract:The discoveries of rapid, membrane-initiated steroid actions and central nervous system steroidogenesis have changed our understanding of the neuroendocrinology of reproduction. Classical nuclear actions of estradiol and progesterone steroids affecting transcription are essential. However, with the discoveries of membrane-associated steroid receptors, it is becoming clear that estradiol and progesterone have neurotransmitter-like actions activating intracellular events. Ultimately, membrane-initiated actions can influence transcription. Estradiol membrane-initiated signaling (EMS) modulates female sexual receptivity and estrogen feedback regulating the luteinizing hormone (LH) surge. In the arcuate nucleus, EMS activates a Lordosis-regulating circuit that extends to the medial preoptic nucleus and subsequently to the ventromedial nucleus (VMH)—the output from the limbic and hypothalamic regions. Here, we discuss how EMS leads to an active inhibition of Lordosis Behavior. To stimulate ovulation, EMS facilitates astrocyte synthesis of progesterone (neuroP) in the hypothalamus. Regulation of GnRH release driving the LH surge is dependent on estradiol-sensitive kisspeptin (Kiss1) expression in the rostral periventricular nucleus of the third ventricle (RP3V). NeuroP activation of the LH surge depends on Kiss1, but the specifics of signaling have not been well elucidated. RP3V Kiss1 neurons appear to integrate estradiol and progesterone information which feeds back onto GnRH neurons to stimulate the LH surge. In a second population of Kiss1 neurons, estradiol suppresses the surge but maintains tonic LH release, another critical component of the estrous cycle. Together, evidence suggests that regulation of reproduction involves membrane action of steroids, some of which are synthesized in the brain.
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immediate early gene activity regulated cytoskeletal associated protein regulates estradiol induced Lordosis Behavior in female rats
Journal of Neuroscience Research, 2015Co-Authors: Amy Christensen, Phoebe Dewing, Paul E MicevychAbstract: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. Females were divided into two groups: naive, which were tested for Lordosis Behavior once, and experienced rats, which were tested for Lordosis after each EB injection. To monitor the effect of mating, the number of neurons expressing the immediate early gene activity-regulated cytoskeleton-associated protein (Arc) were counted in the mediobasal hypothalamus. Females were unreceptive following the first EB treatment, but the mating induced Arc expression. In naive rats, each subsequent EB injection increased the levels of sexual receptivity. This ramping was not observed in experienced rats, which achieved only a moderate level of sexual receptivity. However, experienced females treated with EB and progesterone were maximally receptive and did not have Arc expression. To test whether the expression of Arc attenuated Lordosis, Arc antisense oligodeoxynucleotides (asODN) were microinjected into experienced females' arcuate nuclei. Arc expression was attenuated, and the experienced EB-treated females achieved maximal sexual receptivity. These results demonstrate that Arc expression in the hypothalamus might influence future sexual receptivity and provides evidence of learning in the arcuate nucleus. The loss of Arc results in unrestrained sexual receptivity.
Amy Christensen - One of the best experts on this subject based on the ideXlab platform.
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immediate early gene activity regulated cytoskeletal associated protein regulates estradiol induced Lordosis Behavior in female rats
Journal of Neuroscience Research, 2015Co-Authors: Amy Christensen, Phoebe Dewing, Paul E MicevychAbstract: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. Females were divided into two groups: naive, which were tested for Lordosis Behavior once, and experienced rats, which were tested for Lordosis after each EB injection. To monitor the effect of mating, the number of neurons expressing the immediate early gene activity-regulated cytoskeleton-associated protein (Arc) were counted in the mediobasal hypothalamus. Females were unreceptive following the first EB treatment, but the mating induced Arc expression. In naive rats, each subsequent EB injection increased the levels of sexual receptivity. This ramping was not observed in experienced rats, which achieved only a moderate level of sexual receptivity. However, experienced females treated with EB and progesterone were maximally receptive and did not have Arc expression. To test whether the expression of Arc attenuated Lordosis, Arc antisense oligodeoxynucleotides (asODN) were microinjected into experienced females' arcuate nuclei. Arc expression was attenuated, and the experienced EB-treated females achieved maximal sexual receptivity. These results demonstrate that Arc expression in the hypothalamus might influence future sexual receptivity and provides evidence of learning in the arcuate nucleus. The loss of Arc results in unrestrained sexual receptivity.
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modulation of the arcuate nucleus medial preoptic nucleus Lordosis regulating circuit a role for gabab receptors
Hormones and Behavior, 2013Co-Authors: Kevin Sinchak, Amy Christensen, Phoebe Dewing, Laura Ponce, Liliana Gomez, Max Berger, Paul E MicevychAbstract: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. Estradiol treatment induces activation/internalization of MPN μ-opioid receptors (MOR) to inhibit Lordosis. Estradiol membrane action modulates ARH gamma-aminobutyric acid receptor-B (GABAB) activity. We tested the hypothesis that ARH GABAB receptors mediate estradiol-induced MOR activation and facilitation of sexual receptivity. Double-label immunohistochemistry revealed expression of GABAB receptors in NPY, ERα and POMC expressing ARH neurons. Approximately 70% of POMC neurons expressed GABAB receptors. Because estradiol initially activates an inhibitory circuit and maintains activation of this circuit, the effects of blocking GABAB receptors were evaluated before estradiol benzoate (EB) treatment and after at the time of Lordosis testing. Bilateral infusions of the GABAB receptor antagonist, CGP52432, into the ARH prior to EB treatment of ovariectomized rats prevented estradiol-induced activation/internalization of MPN MOR, and the rats remained unreceptive. However, in EB-treated rats, bilateral CGP52432 infusions 30 min before Behavior testing attenuated MOR internalization and facilitated Lordosis. These results indicated that GABAB receptors were located within the Lordosis-regulating ARH microcircuit and are necessary for activation and maintenance of the estradiol inhibition of Lordosis Behavior. Although GABAB receptors positively influence estradiol signaling, they negatively regulate Lordosis Behavior since GABAB activity maintains the estradiol-induced inhibition.
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A Novel Membrane Estrogen Receptor Activated by STX Induces Female Sexual Receptivity through an Interaction with mGluR1a.
Neuroendocrinology, 2013Co-Authors: Amy Christensen, Paul E MicevychAbstract:Membrane initiated estradiol signaling has been shown to be vital for multiple physiological processes. Several receptors have been proposed to mediate the actions of estradiol at the membrane. Here, we examined the ability of STX, an agonist of a novel putative membrane estrogen receptor, to activate sexually receptive Behavior in the female rat. Infusions of STX into the arcuate nucleus of the hypothalamus resulted in the activation and internalization of μ-opioid receptors in the medial preoptic nucleus, an action that is required for Lordosis Behavior. Indeed, STX was able to augment sexual receptivity in female rats given a sub-Behavioral dose of estradiol. However, if the mGluR1a antagonist, LY367,385, was administered prior to STX, its circuit-activating effects, the internalization of μ-opioid receptors, were lost. This suggests that the receptor stimulated by STX activates rapid membrane-initiated signaling through an interaction with mGluR1a – an effect previously described for estrogen receptor-α at the membrane.
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cav1 sirna reduces membrane estrogen receptor α levels and attenuates sexual receptivity
Endocrinology, 2012Co-Authors: Amy Christensen, Paul E MicevychAbstract:Although classic estrogen receptors (ER) have been proposed to mediate estradiol signaling, it has been relatively recently that mechanisms of trafficking these receptors have been elucidated. ERα is palmitoylated and associates with caveolin proteins to be targeted to the cell membrane. Caveolins are scaffold proteins that not only traffic ERα to the membrane but also are involved in establishing metabotropic glutamate receptor interactions that are necessary for activating G protein signaling. To demonstrate the role of caveolin proteins in regulating an estradiol-dependent Behavior, sexual receptivity, we used small interfering RNA to knock down caveolin-1 (CAV1) expression in the arcuate nucleus of the hypothalamus. In CAV1 knockdown rats, membrane, but not intracellular levels of ERα, were significantly reduced. As expected, estrogenic stimulation of the arcuate nucleus of the hypothalamus to medial preoptic nucleus projection was abrogated in CAV1 knockdown rats, indicating that the membrane-initiated activation of this circuit was compromised. Moreover, estradiol-induced Lordosis Behavior that is dependent on activation of μ-opioid receptors in the medial preoptic nucleus was also significantly reduced. Thus, CAV1-mediated ERα trafficking to the cell membrane is required for estradiol activation of circuits underlying female sexual receptivity.
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membrane initiated estradiol signaling induces spinogenesis required for female sexual receptivity
The Journal of Neuroscience, 2011Co-Authors: Amy Christensen, Phoebe Dewing, Paul E MicevychAbstract: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. In the hypothalamus, estradiol increases spine density in mediobasal hypothalamic nuclei that regulate reproduction. The hypothalamic arcuate nucleus (ARH), an important site for modulation of female sexual receptivity, has a sexual dimorphism in dendritic spine density that favors females. In the present study, we used both β-actin immunostaining and Golgi staining to visualize estradiol-induced changes in spine density in Long–Evans rats. Golgi impregnation was used to visualize spine shape, and then β-actin immunoreactivity was used as a semiquantitative measure of spine plasticity since actin forms the core of dendritic spines. At 4 h after estradiol treatment, both β-actin immunofluorescence and filopodial spines were increased (from 70.57 ± 1.09% to 78.01 ± 1.05%, p < 0.05). Disruption of estradiol-induced β-actin polymerization with cytochalasin D attenuated Lordosis Behavior, indicating the importance of estradiol-mediated spinogenesis for female sexual receptivity (81.43 ± 7.05 to 35.00 ± 11.76, p < 0.05). Deactivation of cofilin, an actin depolymerizing factor is required for spinogenesis. Membrane-initiated estradiol signaling involving the metabotropic glutamate receptor 1a was responsible for the phosphorylation and thereby deactivation of cofilin. These data demonstrate that estradiol-induced spinogenesis in the ARH is an important cellular mechanism for the regulation of female sexual Behavior.
Donald W. Pfaff - One of the best experts on this subject based on the ideXlab platform.
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histaminergic responses by hypothalamic neurons that regulate Lordosis and their modulation by estradiol
Proceedings of the National Academy of Sciences of the United States of America, 2010Co-Authors: Christophe Dupre, Matthew Lovettbarron, Donald W. PfaffAbstract:How do fluctuations in the level of generalized arousal of the brain affect the performance of specific motivated Behaviors, such as sexual Behaviors that depend on sexual arousal? A great deal of previous work has provided us with two important starting points in answering this question: (i) that histamine (HA) serves generalized CNS arousal and (ii) that heightened electrical activity of neurons in the ventromedial nucleus of the hypothalamus (VMN) is necessary and sufficient for facilitating the primary female sex Behavior in laboratory animals, Lordosis Behavior. Here we used patch clamp recording technology to analyze HA effects on VMN neuronal activity. The results show that HA acting through H1 receptors (H1R) depolarizes these neurons. Further, acute administration of estradiol, an estrogen necessary for Lordosis Behavior to occur, heightens this effect. Hyperpolarization, which tends to decrease excitability and enhance inhibition, was not affected by acute estradiol or mediated by H1R but was mediated by other HA receptor subtypes, H2 and H3. Sampling of mRNA from individual VMN neurons showed colocalization of expression of H1 receptor mRNA with estrogen receptor (ER)-α mRNA but also revealed ER colocalization with the other HA receptor subtypes and colocalization of different subtypes with each other. The latter finding provides the molecular basis for complex “push-pull” regulation of VMN neuronal excitability by HA. Thus, in the simplest causal route, HA, acting on VMN neurons through H1R provides a mechanism by which elevated states of generalized CNS arousal can foster a specific estrogen-dependent, aroused Behavior, sexual Behavior.
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reverse engineering the Lordosis Behavior circuit
Hormones and Behavior, 2008Co-Authors: Donald W. Pfaff, Michael D Loose, Loretta M FlanagancatoAbstract:Abstract Reverse engineering takes the facts we know about a device or a process and reasons backwards to infer the principles underlying the structure–function relations. The goal of this review is to apply this approach to a well-studied hormone-controlled Behavior, namely the reproductive stance of female rodents, Lordosis. We first provide a brief overview on the considerable amount of progress in the analysis of female reproductive Behavior. Then, we propose an analysis of the mechanisms of this Behavior from a reverse-engineering perspective with the goal of generating novel hypotheses about the properties of the circuitry elements. In particular, the previously proposed neuronal circuit modules, feedback signals, and genomic mechanisms are considered to make predictions in this manner. The Lordosis Behavior itself appears to proceed ballistically once initiated, but negative and positive hormonal feedback relations are evident in its endocrine controls. Both rapid membrane-initiated and slow genomic hormone effects contribute to the Behavior's control. We propose that the value of the reverse-engineering approach is based on its ability to provide testable, mechanistic hypotheses that do not emerge from either traditional evolutionary or simple reductionistic perspectives, and several are proposed in this review. These novel hypotheses may generalize to brain functions beyond female reproductive Behavior. In this way, the reverse-engineering perspective can further develop our conceptual frameworks for Behavioral and systems neuroscience.
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acute estrogen potentiates excitatory responses of neurons in rat hypothalamic ventromedial nucleus
Brain Research, 2005Co-Authors: Lee-ming Kow, A Easton, Donald W. PfaffAbstract:In a previous Behavioral study, brief application of a membrane-limited estrogen to neurons in rat hypothalamic ventromedial nucleus (VMN) facilitated Lordosis Behavior-inducing genomic actions of estrogen. Here, electrophysiological recordings from single neurons were employed to characterize these membrane-initiated actions. From rat hypothalamic slices, electrical activity was recorded from neurons in the ventrolateral VMN, the cell group crucial for estrogen induction of Lordosis. In addition to the resting activity, neuronal responses to histamine (HA) and N-methyl-d-aspartate (NMDA) were also recorded before, during, and after a brief (10–15 min) application of estradiol (E, 10 nM). These two transmitters were chosen because their actions are mediated by different mechanisms: HA through G protein-coupled receptors and NMDA by ligand-activated ion channels. Vehicle applications did not affect either resting activity or neuronal responses. In contrast, acute E exposure modulated neuronal responses to transmitters, with no significant effect on the resting activity. It potentiated excitatory responses to HAs (20 out of 48 cells tested) and to NMDA (10 out of 19 cells), but attenuated inhibitory responses to HA (3 out of 6 units). Both of these hormonal actions would increase VMN neuronal excitation. In separate experiments, neuronal excitation was found to be suppressed by anesthetics, which would block E's induction of Lordosis when administered at the time of estrogen application. These data are consistent with the notion that increasing electrical excitation of VMN neurons can be a mechanism by which acute E exposure facilitates the Lordosis-inducing genomic actions of estrogens.
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the membrane actions of estrogens can potentiate their Lordosis Behavior facilitating genomic actions
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Lee-ming Kow, Donald W. PfaffAbstract:The membrane actions of estrogens can facilitate their genomic actions. To determine whether this facilitation bears on CNS mechanisms for estrogen-dependent Behaviors, ovariectomized rats were subjected to a two-pulse treatment of estrogen directly in the hypothalamic ventromedial nucleus. Two days later, each rat was given progesterone and then tested for Lordosis Behavior, the induction of which requires the genomic actions of estrogen. When estrogen was given in both pulses (15 min to 2 h duration, and 5 h apart) Lordosis was induced. Based on results from studies on neuroblastoma cells, we hypothesized that the membrane actions of estrogen in the first pulse would potentiate the genomic actions of estrogen in the second. This hypothesis was confirmed with the use of a membrane-impermeable estrogen. However, surprisingly, the order of the pulses could be reversed and still achieve Lordosis Behavior induction. Finally, activators of protein kinase A or PKC were effective substitutes for the membrane-limited pulse of estrogen. Thus, estrogen-induced membrane actions in the hypothalamus can potentiate its Lordosis-inducing genomic actions on Behavior and may be mediated by signaling pathways involving the activation of protein kinase A and PKC.
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differential interaction of estrogen receptor and thyroid hormone receptor isoforms on the rat oxytocin receptor promoter leads to differences in transcriptional regulation
Neuroendocrinology, 2001Co-Authors: Nandini Vasudevan, Yuanshan Zhu, William W Chin, Genoveva Davidkova, Noriyuki Koibuchi, Donald W. PfaffAbstract:Both the estrogen receptor (ER) and thyroid hormone receptor (TR) are members of the nuclear receptor superfamily. Two isoforms of the ER, alpha and beta, exist. The TRalpha and beta isoforms are products of two distinct genes that are further differentially spliced to give TRalpha1 and alpha2, TRbeta1 and beta2. The TRs have been shown to interfere with ER-mediated transcription from both the consensus estrogen response element (ERE) and the rat preproenkephalin (PPE) promoter, possibly by competing with ER binding to the ERE or by squelching coactivators essential for ER-mediated transcription. The rat oxytocin receptor (OTR) gene is thought to be involved in several facets of reproductive and affiliative Behaviors. 17beta-Estradiol-bound ERs upregulate the OTR gene in the ventromedial hypothalamus, a region critical for the induction of Lordosis Behavior in several species. We investigated the effects of the ligand-binding TR isoforms on the ER-mediated transcription from a physiological promoter of a Behaviorally relevant gene such as the OTR. Only ERalpha could induce the OTR gene in two cell lines tested, the CV-1 and the SK-N-BE2C neuroblastoma cell lines. ERbeta was incapable of inducing the gene in either cell line. ERalpha is therefore not equivalent to ERbeta on this physiological promoter. Indeed, in the neural cell line, ERbeta can inhibit ERalpha-mediated induction from the OTR promoter. While the TRalpha1 isoform inhibited ERalpha-mediated induction in the neural cell line, the TRbeta1 isoform stimulated induction, thus demonstrating isoform specificity in the interaction. The use of a DNA-binding mutant, the TR P box mutant, showed that inhibition of ERalpha-mediated induction of the rat OTR gene promoter by the TRalpha1 isoform does not require DNA-binding ability. SRC-1 overexpression relieved TRalpha1-mediated inhibition in both cell lines, suggesting that squelching for coactivators is an important molecular mechanism in TRalpha-mediated inhibition. Such interactions between TR and ER isoforms on the rat OTR promoter provide a mechanism to achieve neuroendocrine integration.
Lynda Uphouse - One of the best experts on this subject based on the ideXlab platform.
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repeated estradiol benzoate treatment protects against the Lordosis inhibitory effects of restraint and prevents effects of the antiprogestin ru486
Pharmacology Biochemistry and Behavior, 2015Co-Authors: Lynda Uphouse, Cindy Hiegel, Giovanny Martinez, Christian Solano, William GusickAbstract:Abstract The following experiment was designed to test two specific questions: (1) Does the antiprogestin, RU486, reduce emergence of Lordosis Behavior and/or proceptivity in rats given repeated treatment with 10 μg estradiol benzoate (EB) and/or a single high dose (40 μg) of EB? (2) Does RU486 accentuate the effects of a 5 min restraint experience on sexual Behaviors in rats given repeated treatment with estradiol benzoate (EB) and/or a high dose of EB? RU486 was used to determine if a high dose and/or repeated treatment with EB enhanced proceptivity and reduced the response to mild stress through an intracellular progesterone receptor-mediated process. Ovariectomized Fischer rats were injected with a single dose of 10 or 40 μg estradiol benzoate (EB) or received 4 consecutive weeks of treatment with 10 μg EB. Forty-eight hours after the last treatment with EB, rats were injected with 5 mg/kg of the antiprogestin, RU486, or the RU486 vehicle. That afternoon, rats were monitored for sexual Behaviors. Sexually-receptive rats were then restrained for 5 min and again tested for sexual Behaviors. A separate set of rats received 4 consecutive weeks of 10 μg EB treatment before treatment with a higher (5 mg/rat) dose of RU486. Lordosis to mount ratios, Lordosis quality, proceptivity, and resistance were monitored. RU486 had no effect on the emergence of sexual Behaviors but did accentuate the Lordosis-inhibitory effect of restraint in rats given a single treatment with EB. Rats treated for 4 consecutive weeks with EB showed no effect of restraint and were unaffected by RU486. These findings lead to the suggestion that repeated EB initiates select Behavioral effects that are not mimicked by acute EB treatment and that the intracellular progesterone receptor may not be involved.
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dose dependent effects of the antiprogestin ru486 on sexual Behavior of naturally cycling fischer rats
Behavioural Brain Research, 2015Co-Authors: Lynda UphouseAbstract:Abstract Regularly cycling Fischer female rats were treated with either a low (5 mg/kg) or high (5 mg/RAT; approximately 30 mg/kg) dose of the antiprogestin, RU486, before the morning of proestrus or on the morning of proestrus. The emergence of sexual Behavior after treatment with RU486 was examined in a mating test with a sexually active male rat. Lordosis Behavior was remarkably resistant to the effects of RU486. Only the high dose of RU486 given the evening before proestrus, approximately 22 h before mating, reduced Lordosis Behavior. Independent of dose or time of treatment, proceptivity was reduced and resistance to the male's attempts to mount was increased by RU486 treatment. In addition, the effect of a 5 min restraint stress on sexual Behavior was examined. In contrast to the relative resistance of Lordosis Behavior of unrestrained rats to RU486 treatment, RU486 treated rats showed a significant decline in Lordosis Behavior after restraint. These findings allow the suggestion that the emergence of Lordosis Behavior is relatively resistant to the antiprogestin while the maintenance of Lordosis Behavior after restraint may require participation of intracellular progesterone receptors.
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an antiprogestin cdb4124 blocks progesterone s attenuation of the negative effects of a mild stress on sexual Behavior
Behavioural Brain Research, 2013Co-Authors: Lynda Uphouse, Cindy HiegelAbstract:These experiments were designed to test the hypothesis that a progesterone receptor antagonist would block progesterone's ability to reduce the negative effects of a 5 min restraint on female rat sexual Behavior. Ovariectomized Fischer rats were injected with 10 μg estradiol benzoate. Two days later, rats were injected subcutaneously (sc) with the progesterone receptor antagonist, CDB4124 (17α-acetoxy-21-methoxy-11β-[4-N,N-dimethyaminopheny]-19-norpregna-4,9-dione-3,20-dione) (60 mg/kg), or vehicle (20% DMSO+propylene glycol). One hour later, rats were injected sc with 500 μg progesterone or vehicle (sesame seed oil). Rats were assigned to one of three different treatment conditions: (1) (ECV) estradiol benzoate, CDB4124, sesame seed oil vehicle, (2) (ECP) estradiol benzoate, CDB4124, progesterone, and (3) (EVP) estradiol benzoate, DMSO/propylene glycol vehicle, progesterone. That afternoon sexual Behavior was examined before and after a 5 min restraint experience. Before restraint, Lordosis Behavior was comparable across treatment conditions but only progesterone-treated rats exhibited proceptive Behavior. CDB4124 did not block progesterone's induction of proceptivity. However, after restraint, CDB4124 attenuated the positive effects of progesterone on all sexual Behaviors examined. The restraint experience inhibited sexual Behavior in rats treated with estradiol benzoate and CDB4124 and in rats treated with estradiol benzoate, CDB4124, and progesterone but not in rats given estradiol benzoate and progesterone without CDB4124. These findings are consistent with the hypothesis that progesterone receptors mediate progesterone's ability to reduce the negative sexual Behavioral effects of a mild stressor.
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progesterone reduces the inhibitory effect of a serotonin 1b receptor agonist on Lordosis Behavior
Pharmacology Biochemistry and Behavior, 2010Co-Authors: Lynda Uphouse, Jutatip Guptarak, Cindy HiegelAbstract:Abstract Ovariectomized Fischer inbred rats were hormonally primed with 10 μg estradiol benzoate and sesame seed oil (EO rats) or with estradiol benzoate and 500 μg progesterone (EP rats). Four to six hours after progesterone or oil, rats were pretested for sexual Behavior and then infused bilaterally into the ventromedial nucleus of the hypothalamus with 0, 50, 100 or 200 ng of the 5-HT1B receptor agonist, 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrol[3,2-bi]pyridin-5-one-dihydrochloride (CP 93129). Sexual receptivity was monitored by the Lordosis to mount (L/M) ratio. EO rats showed a transient decline in Lordosis Behavior following infusion with the saline vehicle and this was amplified by CP 93129. There were no effects of any infusion in EP rats. These findings are discussed in terms of the possible stress effect of the intracranial infusion in EO rats and their implications for a role of 5-HT1B receptors in the response to a mild stress.
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progesterone reduces the effect of the serotonin 1b 1d receptor antagonist gr 127935 on Lordosis Behavior
Hormones and Behavior, 2009Co-Authors: Lynda Uphouse, Jutatip Guptarak, Cindy Hiegel, Navin MaswoodAbstract:Ovariectomized rats were hormonally primed with 10 μg estradiol benzoate or with estradiol benzoate plus 500 μg progesterone. Rats received a bilateral infusion with 200 ng of the 5-HT1B/1D receptor antagonist, N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)-1-1′-biphenyl-4-carboxamide hydrochloride (GR 127935), into the ventromedial nucleus of the hypothalamus (VMN), followed by a 5 min restraint or home cage experience. In estrogen-primed females that had experienced minimal handling between ovariectomy and use in the experiment, infusion with the water vehicle transiently inhibited Lordosis Behavior, and the 5-HT1B/1D receptor antagonist amplified this inhibition. There were no effects in rats hormonally primed with estrogen and progesterone. Handling for two days before the experiment reduced the effects of the infusions in estrogen-primed rats. However, when a 5 min restraint experience followed infusion with GR 127935, there was a significant decline in Lordosis Behavior that persisted for 10 to 15 min after the experience. Regardless of the prior experience or type of infusion, the addition of progesterone to the hormonal priming completely prevented the Lordosis inhibition. These findings are consistent with prior evidence that progesterone protects against the inhibitory effects of a 5 min restraint experience on Lordosis Behavior. Moreover, these are the first experiments to demonstrate an inhibitory effect of a selective 5-HT1B/1D receptor antagonist in the VMN on Lordosis Behavior of estrogen primed, but not estrogen and progesterone primed, ovariectomized rats.
Sonoko Ogawa - One of the best experts on this subject based on the ideXlab platform.
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the role of estrogen receptor β in the dorsal raphe nucleus on the expression of female sexual Behavior in c57bl 6j mice
Frontiers in Endocrinology, 2018Co-Authors: Kazuhiro Sano, Chihiro Morimoto, Mariko Nataka, Sergei Musatov, Mumeko C Tsuda, Naoko Yamaguchi, Toshiro Sakamoto, Sonoko OgawaAbstract:17-Estradiol (E2) regulates the expression of female sexual Behavior by acting through estrogen receptor (ER) and . Previously, we have shown that ER knockout female mice maintain high level of Lordosis expression on the day after Behavioral estrus when wild-type mice show a clear decline of the Behavior, suggesting ER may be involved in inhibitory regulation of Lordosis. However, it is not identified yet in which brain region(s) ER may mediate an inhibitory action of E2. In this study, we have focused on the dorsal raphe nucleus (DRN) that expresses ER in higher density than ER. We site specifically knocked down ER in the DRN in ovariectomized mice with virally mediated RNA interference method. All mice were tested weekly for a total of three weeks for their Lordosis expression against a stud male in two consecutive days: Day 1 with the hormonal condition mimicking the day of Behavioral estrus, and Day 2 under the hormonal condition mimicking the day after Behavioral estrus. We found that the level of Lordosis expression in ER knockdown (ERKD) mice was not different from that of control mice on Day 1. However, βERKD mice continuously showed elevated levels of Lordosis Behavior on Day 2 tests, whereas control mice showed a clear decline of the Behavior on Day 2. These results suggest that the expression of ERβ in the DRN may be involved in the inhibitory regulation of sexual Behavior on the day after Behavioral estrus in cycling female mice.
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The Role of Estrogen Receptor β in the Dorsal Raphe Nucleus on the Expression of Female Sexual Behavior in C57BL/6J Mice
Frontiers Media S.A., 2018Co-Authors: Kazuhiro Sano, Chihiro Morimoto, Mariko Nataka, Sergei Musatov, Mumeko C Tsuda, Naoko Yamaguchi, Toshiro Sakamoto, Sonoko OgawaAbstract:17β-Estradiol (E2) regulates the expression of female sexual Behavior by acting through estrogen receptor (ER) α and β. Previously, we have shown that ERβ knockout female mice maintain high level of Lordosis expression on the day after Behavioral estrus when wild-type mice show a clear decline of the Behavior, suggesting ERβ may be involved in inhibitory regulation of Lordosis. However, it is not identified yet in which brain region(s) ERβ may mediate an inhibitory action of E2. In this study, we have focused on the dorsal raphe nucleus (DRN) that expresses ERβ in higher density than ERα. We site specifically knocked down ERβ in the DRN in ovariectomized mice with virally mediated RNA interference method. All mice were tested weekly for a total of 3 weeks for their Lordosis expression against a stud male in two consecutive days: day 1 with the hormonal condition mimicking the day of Behavioral estrus, and day 2 under the hormonal condition mimicking the day after Behavioral estrus. We found that the level of Lordosis expression in ERβ knockdown (βERKD) mice was not different from that of control mice on day 1. However, βERKD mice continuously showed elevated levels of Lordosis Behavior on day 2 tests, whereas control mice showed a clear decline of the Behavior on day 2. These results suggest that the expression of ERβ in the DRN may be involved in the inhibitory regulation of sexual Behavior on the day after Behavioral estrus in cycling female mice
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effects of an intrahypothalamic injection of antisense oligonucleotides for preproenkephalin mrna in female rats evidence for opioid involvement in Lordosis reflex
Brain Research, 1997Co-Authors: Arnaud Nicot, Sonoko Ogawa, Yemiliya Berman, Kenneth D Carr, Donald W. PfaffAbstract:Previous studies in female rats have shown that estrogen increases preproenkephalin (PPE) mRNA levels in the ventrolateral part of the ventromedial nucleus of the hypothalamus (VMHVL), an area implicated in the modulation of sexual Behavior. In order to assess the physiological role of hypothalamic opioid expression in Lordosis reflex 16-mer oligodeoxynucleotide (ODN) directed towards the PPE mRNA were acutely microinjected above the VMH of estradiol-primed ovariectomized rats. Estradiol-induced Lordosis Behavior was observed in response to a stud male 2 days thereafter. Antisense (without or with 4 mismatches) ODN injections near the VMHVL resulted in a significant reduction in Lordosis quotient compared to control (reverse sense) ODN treatment or to antisense ODN injections targeted anterior or posterior to the VMHVL. In contrast, locomotor activity of these animals in the open-field test was not affected by ODN treatments. Enkephalin immunoreactive levels were determined by radioimmunoassay in the preoptic area, a major terminal field of the VMHVL. Estradiol-induced enkephalin levels were greatly reduced in antisense-treated groups. Using the in situ hybridization technique, PPE mRNA levels in the VMHVL were also determined. A 1.5-2-fold increase in PPE mRNA levels was observed in estradiol-treated rats compared to ovariectomized rats as previously described. This increase in PPE mRNA levels was not affected by ODN treatment, suggesting that the reduction of enkephalin expression was mainly due to physical blockade of PPE mRNA translation and not to its degradation. Taken together, these data further support the Behavioral role of PPE expressing VMHVL neurons. They also highlight the in vivo potency of acute administration of antisense phosphorothioate ODNs in blocking neuronal target gene expression.
