Gonadotropin inhibitory hormone inhibits basal forebrain vGluT2‐gonadotropin‐releasing hormone neurons via a direct postsynaptic mechanism

Wu, Min; Dumalska, Iryna; Morozova, Elena; Pol, Anthony N. van den; Alreja, Meenakshi

doi:10.1113/jphysiol.2008.166447

Cited by 148 publications

(121 citation statements)

References 35 publications

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“…RFRP mRNA expression levels showed a significant negative correlation with plasma LH levels (Fig. 1F), a finding that is consistent with previous work showing that RFRP lowers circulating LH levels (13) either through reduced GnRH neuron activity or through reduced responsiveness of pituitary cells to hypophysial GnRH (22)(23)(24)(25). No effect of acute stress was found on RFRP (1.2 Ϯ 0.1-fold change, P ϭ 0.33) or OT7T022 (1.0 Ϯ 0.1-fold change, P ϭ 0.82) mRNA transcript expression immediately after stress as measured by real-time reverse transcription-polymerase chain reaction (RT-PCR) in the testes.…”

Section: Resultssupporting

confidence: 92%

Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats

Kirby

Geraghty

Ubuka

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

311

220

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The subjective experience of stress leads to reproductive dysfunction in many species, including rodents and humans. Stress effects on reproduction result from multilevel interactions between the hormonal stress response system, i.e., the hypothalamic-pituitary-adrenal (HPA) axis, and the hormonal reproductive system, i.e., the hypothalamic-pituitary-gonadal (HPG) axis. A novel negative regulator of the HPG axis known as gonadotropin-inhibitory hormone (GnIH) was recently discovered in quail, and orthologous neuropeptides known as RFamide-related peptides (RFRPs) have also been identified in rodents and primates. It is currently unknown, however, whether GnIH/RFRPs influence HPG axis activity in response to stress. We show here that both acute and chronic immobilization stress lead to an up-regulation of RFRP expression in the dorsomedial hypothalamus (DMH) of adult male rats and that this increase in RFRP is associated with inhibition of downstream HPG activity. We also show that adrenalectomy blocks the stress-induced increase in RFRP expression. Immunohistochemistry revealed that 53% of RFRP cells express receptors for glucocorticoids (GCs), indicating that adrenal GCs can mediate the stress effect through direct action on RFRP cells. It is thought that stress effects on central control of reproduction are largely mediated by direct or indirect effects on GnRH-secreting neurons. Our data show that stress-induced increases in adrenal GCs cause an increase in RFRP that contributes to hypothalamic suppression of reproductive function. This novel insight into HPA-HPG interaction provides a paradigm shift for work on stress-related reproductive dysfunction and infertility, and indicates that future work on stress and reproductive system interactions must include investigation of the role of GnIH/RFRP.GnIH ͉ reproduction ͉ RFRP S tress has acute and chronic effects on many aspects of vertebrate physiology and behavior. Reproduction is a key life-history component that is often adversely affected by physical and psychological stressors. The negative impact of stress occurs at several levels of the vertebrate hypothalamic-pituitary-gonadal (HPG) axis. Centrally, it leads to activation of the hypothalamic-pituitaryadrenal (HPA) axis, which in turn leads to suppression of HPG activity through inhibition of gonadotropin-releasing hormone (GnRH) secretion (1, 2). Downstream of GnRH, the functional effects of stress on reproduction can be seen with suppression of luteinizing hormone (LH) release from the pituitary (3, 4) and suppression of sexual behavior (5, 6). The stress effect on HPG function appears to be mediated by the adrenal stress hormones glucocorticoids (GCs). In male mammals, systemic GC administration inhibits circulating gonadotropin levels (7), decreases seminal vesicle weight, and results in fewer implantation sites and viable fetuses in female mates (8). However, hypothalamic corticotropinreleasing hormone (CRH) has also been strongly implicated in stress effects on reproduction (2, 9, 10).Gonadotropin i...

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Section: Resultssupporting

confidence: 92%

Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats

Kirby

Geraghty

Ubuka

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

311

220

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“…Indirect support for such hypothesis comes from our pharmacological testing of the antagonist of RFRP receptors, RF9, in vivo that revealed potent gonadotropin-releasing effects of the antagonist (19). From a mechanistic standpoint, previous data on the ability of RFRP3 to inhibit electrical activity and c-fos expression in GnRH neurons in mice and rats strongly suggest that the inhibitory responses detected in our in vivo experiments in male and GNX female rats are caused, at least partially, by direct inhibition of this neuronal population (5,31). Notably, a recent report in mice suggests that the effects of RFRP3 on GnRH neuronal firing may not be homogeneous, since only ϳ40% of these neurons responded to RFRP3 with rapid and repeatable inhibition in that particular study, whereas even excitatory responses were detected in as much as 12% of this population (5).…”

Section: ϫ8mentioning

confidence: 82%

Characterization of the inhibitory roles of RFRP3, the mammalian ortholog of GnIH, in the control of gonadotropin secretion in the rat: in vivo and in vitro studies

Pineda

García-Galiano

Sánchez-Garrido

et al. 2010

American Journal of Physiology-Endocrinology and Metabolism

133

103

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van Noort PI, Tena-Sempere M. Characterization of the inhibitory roles of RFRP3, the mammalian ortholog of GnIH, in the control of gonadotropin secretion in the rat: in vivo and in vitro studies. Am J Physiol Endocrinol Metab 299: E39 -E46, 2010. First published April 27, 2010; doi:10.1152/ajpendo.00108.2010.-RF-amide related peptides (RFRP), as putative mammalian orthologs of the avian gonadotropin-inhibitory hormone (GnIH), have been proposed as key regulators of gonadotropin secretion in higher vertebrates. Yet considerable debate has arisen recently on their physiological relevance and potential mechanisms and sites of action. Present studies were undertaken to further characterize the effects of RFRP on LH and FSH secretion by a combination of in vivo and in vitro approaches in male and female rats. Initial screening via intracerebroventricular (icv) administration of different analogs of RFRP1 (RFRP1-12 and RFRP1-20) and RFRP3 (RFRP3-8 and RFRP3-17), as well as the related neuropeptide FF (NPFF8), to gonadectomized (GNX) female rats evidenced significant, albeit modest, inhibitory effects on LH secretion only for RFRP3-8 and RFRP3-17, which were detectable at the high dose rage (1 nmol for RFRP3-8, 5 nmol for RFRP3-17). This moderate inhibitory action was also documented after icv administration of RFRP3-8 to intact and GNX male rats. In addition, systemic (intravenous) administration of RFRP3-8 decreased the circulating levels of both gonadotropins in GNX male rats. Likewise, RFRP3-8 inhibited basal and GnRH-stimulated LH secretion by pituitaries from GNX males in vitro. This inhibitory effect was blocked by the antagonist of RFRP receptors, RF9. In summary, our results support a putative inhibitory role of RFRP3 as ortholog of GnIH in the regulation of gonadotropin secretion in mammals, which appears to involve direct pituitary actions as well as potential central (hypothalamic) effects.RF-amide related peptide; gonadotropin-inhibitory hormone; gonadotropin-releasing hormone; neuropeptide FF; receptor; RF9 THE NEUROENDOCRINE CONTROL of the gonadotropic axis relies on a complex array of stimulatory and inhibitory signals that primarily, but not exclusively, impinge onto a subset of hypothalamic neurons producing the decapeptide gonadotropinreleasing hormone (GnRH) (7, 15). Our knowledge on the nature and mechanisms of action of these neuroendocrine regulators has enlarged considerably recently, with the identification of novel factors (e.g., kisspeptins) and unsuspected biological effects of classical signals (e.g., excitatory actions of putative inhibitory neurotransmitters such as GABA) (7,22). In this context, a 12-amino acid neuropeptide, with a distinctive RF-amide (RFa) motif at its COOH terminus, was isolated from the avian brain in 2000 and termed gonadotropin-inhibitory hormone (GnIH) due to its capacity to suppress gonadotropin release by quail pituitaries (30). This finding boosted a considerable interest in the field, as this was thought to represent the physiological counterpart of GnRH or on...

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“…The above-described effects of MCH occurred in a very unique population of neurons within the MSDB. The MCH-inhibited vGluT2-GnRH neurons could be distinguished from other major neuronal populations within the MSDB by their lack of excitatory response to the Group I glutamate metabotropic-receptor agonist DHPG and by their strong and persistent activation by the neuropeptide, kisspeptin, the natural ligand of GPR54 (19,52). Although DHPGsensitivity was examined in every neuron tested, because of the strong and prolonged nature of the kisspeptin response, kisspeptin agonist was applied only at the end of the experiment.…”

Section: Mch Selectively Inhibits a Subpopulation Of Kisspeptin-activmentioning

confidence: 99%

“…MCH inhibited a unique subpopulation of vGluT2-GnRH neurons in the MSDB that can be identified in slices prepared from either vGluT2-GFP or GnRH-GFP mice (19,52). MCH (1 M) produced a 3-to 20-mV hyperpolarization (mean: 8.1 Ϯ 1.5 mV; n ϭ 15) in 59% of vGluT2-GnRH neurons recorded in brain slices prepared from 17 postpubertal mice (n ϭ 22 cells; 35-160 days of age).…”

Section: Mch Inhibits Vglut2-gnrh Neurons Via a Mchr1-transduced Directmentioning

confidence: 99%

Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction

Dumalska²,

Morozova³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

104

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A link between energy balance and reproduction is critical for the survival of all species. Energy-consuming reproductive processes need to be aborted in the face of a negative energy balance, yet knowledge of the pathways mediating this link remains limited. Fasting and food restriction that inhibit fertility also upregulate the hypothalamic melanin-concentrating hormone (MCH) system that promotes feeding and decreases energy expenditure; MCH knockout mice are lean and have a higher metabolism but remain fertile. MCH also modulates sleep, drug abuse behavior, and mood, and MCH receptor antagonists are currently being developed as antiobesity and antidepressant drugs. Despite the clinical implications of MCH, the direct postsynaptic effects of MCH have never been reported in CNS neurons. Using patch-clamp recordings in brain slices from multiple lines of transgenic GFP mice, we demonstrate a strong inhibitory effect of MCH on an exclusive population of septal vGluT2-GnRH neurons that is activated by the puberty-triggering and preovulatory luteinizing hormone surge-mediating peptide, kisspeptin. MCH has no effect on kisspeptin-insensitive GnRH, vGluT2, cholinergic, or GABAergic neurons located within the same nucleus. The inhibitory effects of MCH are reproducible and nondesensitizing and are mediated via a direct postsynaptic Ba 2؉ -sensitive K ؉ channel mechanism involving the MCHR1 receptor. MCH immunoreactive fibers are in close proximity to vGluT2-GFP and GnRH-GFP neurons. Importantly, MCH blocks the excitatory effect of kisspeptin on vGluT2-GnRH neurons. Considering the role of MCH in regulating energy balance and of GnRH and kisspeptin in triggering puberty and maintaining fertility, MCH may provide a critical link between energy balance and reproduction directly at the level of the kisspeptin-activated vGluT2-GnRH neuron.fertility ͉ gonadotropins ͉ HPG axis ͉ obesity ͉ starvation N utritional status and availability of energy stores exert a profound impact on reproductive function (1-3). Reproduction is an expensive energy-consuming process, and thus it is important that puberty, pregnancy, and lactation occur only when metabolic fuel is available (4). Availability of metabolic fuel is conveyed to the brain by peripherally generated signals, such as leptin, insulin, and ghrelin, as well as by centrally released peptides such as neuropeptide Y, melanocortins, and melanin-concentrating hormone (MCH). One or more of these signals can directly or indirectly link energy balance with reproduction at one or more levels of the hypothalamic-pituitary-gonadal (HPG) axis. Thus, insulin and leptin may indirectly influence GnRH neurons (2, 5-7); leptin could regulate the HPG axis via kisspeptin-containing hypothalamic neurons (8, 9). Kisspeptin and its receptor are critical for reproduction (10-12); both kisspeptin and kisspeptin receptor knockout mice fail to enter puberty, and humans with loss of function mutations in the kisspeptin receptor exhibit hypogonadotropic hypogonadism and are infertile (13-15). Mechanisti...

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Gonadotropin inhibitory hormone inhibits basal forebrain vGluT2‐gonadotropin‐releasing hormone neurons via a direct postsynaptic mechanism

Cited by 148 publications

References 35 publications

Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats

Stress increases putative gonadotropin inhibitory hormone and decreases luteinizing hormone in male rats

Characterization of the inhibitory roles of RFRP3, the mammalian ortholog of GnIH, in the control of gonadotropin secretion in the rat: in vivo and in vitro studies

Melanin-concentrating hormone directly inhibits GnRH neurons and blocks kisspeptin activation, linking energy balance to reproduction

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