The Neurochemistry of Limbic-Hypothalamic Circuits Regulating Sexual Receptivity

Micevych, Paul E.; Sinchak, Kevin

doi:10.1007/978-0-387-30405-2_4

Cited by 12 publications

(13 citation statements)

References 440 publications

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“…The quintessential trigger is progesterone, which augments estradiol to induce full sexual receptivity [19]. Other agents include oxytocin, vasopressin, CCK, GnRH, substance P, galanin, IGF-1, glutamate and dopamine (reviewed in [24]). Interestingly, estradiol acting through membrane ERα, can also augment a previous subthreshold priming dose [4, 5].…”

Section: Discussionmentioning

confidence: 99%

A Novel Membrane Estrogen Receptor Activated by STX Induces Female Sexual Receptivity through an Interaction with mGluR1a

Christensen¹,

Micevych²

2013

Neuroendocrinology

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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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Section: Discussionmentioning

confidence: 99%

A Novel Membrane Estrogen Receptor Activated by STX Induces Female Sexual Receptivity through an Interaction with mGluR1a

Christensen¹,

Micevych²

2013

Neuroendocrinology

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“…Of course these hypotheses were not mutually exclusive and a great deal of evidence was generated to bolster each. Over the years, investigators demonstrated the estradiol regulation of gene transcription and the expression of a cornucopia of neuropeptides, transmitters, enzymes and their cognate receptors [89]. Altered ratios of transmitters and neuropeptides modified circuits in which the flow of information was different when estradiol was present compared to when estradiol was not.…”

Section: Introductionmentioning

confidence: 99%

“…On proestrus, as systemic estradiol levels spike, β-END is released in the MPN and transiently activates/internalizes MOR, which is required for the full display of sexual behavior. Thirty to forty eight hours after the peak of estradiol, this MOR-mediated inhibition of lordosis wears off or is turned off by progesterone ([136]; Sinchak and Wagner, this volume), and estradiol activates full sexual receptivity (reviewed in [89]). The initial inhibition of lordosis through the rapid MOR activation likely allows time for the activation of transcription and translation by the nuclear ER.…”

Section: Introductionmentioning

confidence: 99%

Membrane-initiated estradiol actions mediate structural plasticity and reproduction

Micevych

Christensen

2012

Frontiers in Neuroendocrinology

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Over the years, our ideas about estrogen signaling have greatly expanded. In addition to estradiol having direct nuclear actions that mediate transcription and translation, more recent experiments have demonstrated membrane-initiated signaling. Both direct nuclear and estradiol membrane signaling can be mediated by the classical estrogen receptors, ERα and ERβ, which are two of the numerous putative membrane estrogen receptors. Thus far, however, only ERα has been shown to play a prominent role in regulating female reproduction and sexual behavior. Because ERα is a ligand-gated transcription factor and not a typical membrane receptor, trafficking to the cell membrane requires post-translational modifications. Two necessary modifications are palmitoylation and association with caveolins, a family of scaffolding proteins. In addition to their role in trafficking, caveolin proteins also serve to determine ERα interactions with metabotropic glutamate receptors (mGluRs). It is through these complexes that ERα, which cannot by itself activate G proteins, is able to initiate intracellular signaling. Various combinations of ERα-mGluR interactions have been demonstrated throughout the nervous system from hippocampus to striatum to hypothalamus to dorsal root ganglion (DRG) in both neurons and astrocytes. These combinations of ER and mGluR allow estradiol to have both facilitative and inhibitory actions in neurons. In hypothalamic astrocytes, the estradiol-mediated release of intracellular calcium stores regulating neurosteroid synthesis requires ERα-mGluR1a interaction. In terms of estradiol regulation of female sexual receptivity, activation of ERα-mGluR1a signaling complex leads to the release of neurotransmitters and alteration of neuronal morphology. This review will examine estradiol membrane signaling (EMS) activating a limbic-hypothalamic lordosis regulating circuit, which involves ERα trafficking, internalization, and modifications of neuronal morphology in a circuit that underlies female sexual receptivity.

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“…For example, the expression of a large number of neuropeptides and receptors implicated in reproductive function are regulated by estradiol [reviewed in (119)]. However, in some cases, colocalization of nuclear ER and estrogen-sensitive neuropeptides could not be demonstrated (5), suggesting that other mechanisms were involved.…”

Section: Introductionmentioning

confidence: 99%

Estradiol Membrane‐Initiated Signaling and Female Reproduction

Micevych

Wong

Mittelman-Smith

2015

Comprehensive Physiology

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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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The Neurochemistry of Limbic-Hypothalamic Circuits Regulating Sexual Receptivity

Cited by 12 publications

References 440 publications

A Novel Membrane Estrogen Receptor Activated by STX Induces Female Sexual Receptivity through an Interaction with mGluR1a

A Novel Membrane Estrogen Receptor Activated by STX Induces Female Sexual Receptivity through an Interaction with mGluR1a

Membrane-initiated estradiol actions mediate structural plasticity and reproduction

Estradiol Membrane‐Initiated Signaling and Female Reproduction

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