Hypothalamic and Extrahypothalamic Mediation of Pulsatile Discharges of Luteinizing Hormone in the Ovariectomized Rat*

Soper, B. D.; Weick, Richard F.

doi:10.1210/endo-106-1-348

Cited by 92 publications

(61 citation statements)

References 30 publications

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“…We have now identified a P4-sensitive GABAergic network residing specifically within the ARN potentially mediating these disruptions. In rodent species, the ARN has been demonstrated to be essential for pulsatile LH release (40), estrous cyclicity (24), and estradiol negative feedback regulation of GnRH neurons (41). Likewise, in the ewe, the ARN plays a major role in mediating P4 negative feedback to GnRH neurons (42), predominantly through dynorphin and kappa opioid receptor actions (43).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome

Moore

Prescott

Marshall

et al. 2014

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

180

254

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Polycystic ovarian syndrome (PCOS), the leading cause of female infertility, is associated with an increase in luteinizing hormone (LH) pulse frequency, implicating abnormal steroid hormone feedback to gonadotropin-releasing hormone (GnRH) neurons. This study investigated whether modifications in the synaptically connected neuronal network of GnRH neurons could account for this pathology. The PCOS phenotype was induced in mice following prenatal androgen (PNA) exposure. Serial blood sampling confirmed that PNA elicits increased LH pulse frequency and impaired progesterone negative feedback in adult females, mimicking the neuroendocrine abnormalities of the clinical syndrome. Imaging of GnRH neurons revealed greater dendritic spine density that correlated with increased putative GABAergic but not glutamatergic inputs in PNA mice. Mapping of steroid hormone receptor expression revealed that PNA mice had 59% fewer progesterone receptor-expressing cells in the arcuate nucleus of the hypothalamus (ARN). To address whether increased GABA innervation to GnRH neurons originates in the ARN, a viral-mediated Cre-lox approach was taken to trace the projections of ARN GABA neurons in vivo. Remarkably, projections from ARN GABAergic neurons heavily contacted and even bundled with GnRH neuron dendrites, and the density of fibers apposing GnRH neurons was even greater in PNA mice (56%). Additionally, this ARN GABA population showed significantly less colocalization with progesterone receptor in PNA animals compared with controls. Together, these data describe a robust GABAergic circuit originating in the ARN that is enhanced in a model of PCOS and may underpin the neuroendocrine pathophysiology of the syndrome.GnRH | PCOS | GABA | progesterone receptor | luteinizing hormone G onadotropin-releasing hormone (GnRH) neurons, located in the hypothalamus, control fertility by driving the secretion of the gonadotrophins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) from the pituitary gland. The pulse amplitude and frequency of LH and FSH shape the sequence of events that occur at the ovary, including follicular development, gonadal steroid synthesis, and ovulation.

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Section: Discussionmentioning

confidence: 99%

Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome

Moore

Prescott

Marshall

et al. 2014

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

180

254

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“…The GnRH pulse generator, the neuronal machinery that governs the pulsatile GnRH secretion, resides in the medial basal hypothalamus in rats [2, 3, 4]as well as in monkeys [5]. There is evidence to suggest that the networks of GnRH neurons constitute the GnRH pulse generator.…”

Section: Introductionmentioning

confidence: 99%

Pulsatile Gonadotropin-Releasing Hormone (GnRH) Secretion Is an Inherent Function of GnRH Neurons, as Revealed by the Culture of Medial Olfactory Placode Obtained from Embryonic Rats

Funabashi

Daikoku²,

Shinohara³

et al. 2000

Neuroendocrinology

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To determine whether gonadotropin-releasing hormone (GnRH) neurons in culture without the hypothalamus secrete GnRH in a pulsatile fashion, the nasal placode (NAP) was obtained at day 13.5 of gestation and cultured by a roller tube method. If the GnRH release occurs in a pulsatile fashion, it can be said that the pulse generator of GnRH exists inherently in each cell or community of cells in the culture. The concentration of GnRH in the NAP culture medium collected at 8-min intervals for 160 min after 2- to 4-week cultures showed that GnRH release occurred in a pulsatile fashion with a mean interpulse interval of 29.8 ± 2.3 min (n = 9). When the NAP was cultured with tissues of the forebrain vesicle (n = 3) or the hypothalamus (n = 4), GnRH was also released in a pulsatile fashion with similar intervals (27.3 ± 1.0 min for the NAP+forebrain vesicle culture and 36.0 ± 6.3 min for the NAP+hypothalamus culture) as those in cultures without brain tissues. It is concluded that pulsatile GnRH release is an inherent function of GnRH neurons.

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“…Within this region, particular attention has been focused on the arcuate nucleus (ARN) (13,14), where studies have also recorded multiunit activity that correlates with pulsatile LH secretion in a variety of mammals (15)(16)(17)(18). Although the identity of the neural elements giving rise to multiunit activity are unknown, it has been suggested that they may represent the activity of kisspeptin neurons within the ARN (19).…”

mentioning

confidence: 99%

Selective optogenetic activation of arcuate kisspeptin neurons generates pulsatile luteinizing hormone secretion

Han

McLennan

Czieselsky

et al. 2015

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

160

111

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Normal reproductive functioning in mammals depends upon gonadotropin-releasing hormone (GnRH) neurons generating a pulsatile pattern of gonadotropin secretion. The neural mechanism underlying the episodic release of GnRH is not known, although recent studies have suggested that the kisspeptin neurons located in the arcuate nucleus (ARN) may be involved. In the present experiments we expressed channelrhodopsin (ChR2) in the ARN kisspeptin population to test directly whether synchronous activation of these neurons would generate pulsatile luteinizing hormone (LH) secretion in vivo. Characterization studies showed that this strategy targeted ChR2 to 70% of all ARN kisspeptin neurons and that, in vitro, these neurons were activated by 473-nm blue light with high fidelity up to 30 Hz. In vivo, the optogenetic activation of ARN kisspeptin neurons at 10 and 20 Hz evoked high amplitude, pulse-like increments in LH secretion in anesthetized male mice. Stimulation at 10 Hz for 2 min was sufficient to generate repetitive LH pulses. In diestrous female mice, only 20-Hz activation generated significant increments in LH secretion. In ovariectomized mice, 5-, 10-, and 20-Hz activation of ARN kisspeptin neurons were all found to evoke LH pulses. Part of the sex difference, but not the gonadal steroid dependence, resulted from differential pituitary sensitivity to GnRH. Experiments in kisspeptin receptor-null mice, showed that kisspeptin was the critical neuropeptide underlying the ability of ARN kisspeptin neurons to generate LH pulses. Together these data demonstrate that synchronized activation of the ARN kisspeptin neuronal population generates pulses of LH.GnRH | kisspeptin | optogenetics | arcuate nucleus | gonadal steroids

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Hypothalamic and Extrahypothalamic Mediation of Pulsatile Discharges of Luteinizing Hormone in the Ovariectomized Rat*

Cited by 92 publications

References 30 publications

Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome

Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome

Pulsatile Gonadotropin-Releasing Hormone (GnRH) Secretion Is an Inherent Function of GnRH Neurons, as Revealed by the Culture of Medial Olfactory Placode Obtained from Embryonic Rats

Selective optogenetic activation of arcuate kisspeptin neurons generates pulsatile luteinizing hormone secretion

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