scholarly journals Effects of Leptin and Melanocortin Signaling Interactions on Pubertal Development and Reproduction

Endocrinology ◽  
2012 ◽  
Vol 153 (5) ◽  
pp. 2408-2419 ◽  
Author(s):  
Davelene D. Israel ◽  
Sharone Sheffer-Babila ◽  
Carl de Luca ◽  
Young-Hwan Jo ◽  
Shun Mei Liu ◽  
...  
Keyword(s):  
Pubertal Development ◽  
Receptor Activation ◽  
Ingestive Behavior ◽  
Neuron Activity ◽  
Gnrh Neuron ◽  
Action Potential Firing ◽  
Related Peptide ◽  
Melanocortin 4 Receptor ◽  
Gnrh Neurons ◽  
Melanocortin Signaling

Leptin and melanocortin signaling control ingestive behavior, energy balance, and substrate utilization, but only leptin signaling defects cause hypothalamic hypogonadism and infertility. Although GnRH neurons do not express leptin receptors, leptin influences GnRH neuron activity via regulation of immediate downstream mediators including the neuropeptides neuropeptide Y and the melanocortin agonist and antagonist, α-MSH, agouti-related peptide, respectively. Here we show that modulation of melanocortin signaling in female db/db mice through ablation of agouti-related peptide, or heterozygosity of melanocortin 4 receptor, restores the timing of pubertal onset, fertility, and lactation. Additionally, melanocortin 4 receptor activation increases action potential firing and induces c-Fos expression in GnRH neurons, providing further evidence that melanocortin signaling influences GnRH neuron activity. These studies thus establish melanocortin signaling as an important component in the leptin-mediated regulation of GnRH neuron activity, initiation of puberty and fertility.

scholarly journals Projections of Arcuate Nucleus and Rostral Periventricular Kisspeptin Neurons in the Adult Female Mouse Brain

Endocrinology ◽  
2011 ◽  
Vol 152 (6) ◽  
pp. 2387-2399 ◽  
Author(s):  
Shel-Hwa Yeo ◽  
Allan E. Herbison
Keyword(s):  
Mouse Brain ◽  
Female Mouse ◽  
Arcuate Nucleus ◽  
Third Ventricle ◽  
Retrograde Tracing ◽  
Neuron Activity ◽  
Neuronal System ◽  
Gnrh Neuron ◽  
Gnrh Neurons ◽  
Tracing Techniques

The important role of kisspeptin neurons in the regulation of GnRH neuron activity is now well accepted. However, the ways in which kisspeptin neurons located in the arcuate nucleus (ARN) and rostral periventricular area of the third ventricle (RP3V) control GnRH neurons are poorly understood. The present study used anterograde and retrograde tracing techniques to establish the neuronal projection patterns of kisspeptin cell populations in the female mouse brain. Anterograde tracing studies revealed that kisspeptin neurons in the ARN innervated a wide number of hypothalamic and associated limbic region nuclei, whereas RP3V kisspeptin neurons projected to a smaller number of mostly medially located hypothalamic nuclei. Retrograde tracing confirmed a major projection of RP3V kisspeptin neurons to the ARN and showed that kisspeptin neurons located in the rostral half of the ARN projected to the rostral preoptic area. Peripheral administration of Fluorogold was found to label the majority of GnRH neurons but no kisspeptin neurons. Together, these studies highlight the complexity of the brain kisspeptin neuronal system and indicate that both ARN and RP3V kisspeptin neurons participate in a variety of limbic functions. In relation to the GnRH neuronal network, these investigations demonstrate that, alongside the RP3V kisspeptin cells, rostral ARN kisspeptin neurons may also project to GnRH neuron cell bodies. However, no kisspeptin neurons innervate GnRH nerve terminals in the external layer of the median eminence. These studies provide a neuroanatomical framework for the further elucidation of the functions of the ARN and RP3V kisspeptin neuron populations.

scholarly journals Prenatal Androgenization of Female Mice Programs an Increase in Firing Activity of Gonadotropin-Releasing Hormone (GnRH) Neurons That Is Reversed by Metformin Treatment in Adulthood

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 618-628 ◽  
Author(s):  
Alison V. Roland ◽  
Suzanne M. Moenter
Keyword(s):  
Polycystic Ovary ◽  
Neuron Activity ◽  
Metformin Treatment ◽  
Ampk Activation ◽  
Gnrh Neuron ◽  
Firing Activity ◽  
Ovary Syndrome ◽  
Estrous Cycles ◽  
Compound C ◽  
Gnrh Neurons

Abstract Prenatal androgenization (PNA) of female mice with dihydrotestosterone programs reproductive dysfunction in adulthood, characterized by elevated luteinizing hormone levels, irregular estrous cycles, and central abnormalities. Here, we evaluated activity of GnRH neurons from PNA mice and the effects of in vivo treatment with metformin, an activator of AMP-activated protein kinase (AMPK) that is commonly used to treat the fertility disorder polycystic ovary syndrome. Estrous cycles were monitored in PNA and control mice before and after metformin administration. Before metformin, cycles were longer in PNA mice and percent time in estrus lower; metformin normalized cycles in PNA mice. Extracellular recordings were used to monitor GnRH neuron firing activity in brain slices from diestrous mice. Firing rate was higher and quiescence lower in GnRH neurons from PNA mice, demonstrating increased GnRH neuron activity. Metformin treatment of PNA mice restored firing activity and LH to control levels. To assess whether AMPK activation contributed to the metformin-induced reduction in GnRH neuron activity, the AMPK antagonist compound C was acutely applied to cells. Compound C stimulated cells from metformin-treated, but not untreated, mice, suggesting that AMPK was activated in GnRH neurons, or afferent neurons, in the former group. GnRH neurons from metformin-treated mice also showed a reduced inhibitory response to low glucose. These studies indicate that PNA causes enhanced firing activity of GnRH neurons and elevated LH that are reversible by metformin, raising the possibility that central AMPK activation by metformin may play a role in its restoration of reproductive cycles in polycystic ovary syndrome.

scholarly journals Orexin A Suppresses Gonadotropin-Releasing Hormone (GnRH) Neuron Activity in the Mouse

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 3850-3860 ◽  
Author(s):  
Garrett T. Gaskins ◽  
Suzanne M. Moenter
Keyword(s):  
Negative Feedback ◽  
Time Of Day ◽  
Neuron Activity ◽  
Gnrh Neuron ◽  
Orexin A ◽  
Electrophysiological Response ◽  
Firing Rates ◽  
Gnrh Neurons ◽  
Spike Initiation ◽  
Interevent Interval

GnRH neurons are critical for the central regulation of fertility, integrating steroidal, metabolic and other cues. GnRH neurons appear to lack receptors for many of these cues, suggesting involvement of afferent systems to convey information. Orexin A (orexin) is of interest in this regard as a neuromodulator that up-regulates metabolic activity, increases wakefulness, and affects GnRH/LH release. We examined the electrophysiological response of GnRH neurons to orexin application and how this response changes with estradiol and time of day in a defined animal model. Mice were either ovariectomized (OVX) or OVX and implanted with estradiol capsules (OVX+E). GnRH neurons from OVX+E mice exhibit low firing rates in the morning, due to estradiol-negative feedback, and high firing rates in the evening, due to positive feedback. Orexin inhibited activity of GnRH neurons from OVX mice independent of time of day. In GnRH neurons from OVX+E mice, orexin was inhibitory during the evening, suggesting orexin inhibition is not altered by estradiol. No effect of orexin was observed in OVX+E morning recordings, due to low basal GnRH activity. Inhibitory effects of orexin were mediated by the type 1 orexin receptor, but antagonism of this receptor did not increase GnRH neuron activity during estradiol-negative feedback. Spike pattern analysis revealed orexin increases interevent interval by reducing the number of single spikes and bursts. Orexin reduced spikes/burst and burst duration but did not affect intraburst interval. This suggests orexin may reduce overall firing rate by suppressing spike initiation and burst maintenance in GnRH neurons.

scholarly journals The Gonadotropin-Releasing Hormone (GnRH) Neuronal Population Is Normal in Size and Distribution in GnRH-Deficient and GnRH Receptor-Mutant Hypogonadal Mice

Endocrinology ◽  
2008 ◽  
Vol 149 (9) ◽  
pp. 4596-4604 ◽  
Author(s):  
John C. Gill ◽  
Brandon Wadas ◽  
Peilin Chen ◽  
Wendy Portillo ◽  
Andrea Reyna ◽  
...  
Keyword(s):  
Fluorescent Protein ◽  
Gene Dosage ◽  
Normal Population ◽  
Reproductive Function ◽  
Neuronal Population ◽  
Mouse Strains ◽  
Gnrh Neuron ◽  
Action Potential Firing ◽  
Adult Mice ◽  
Gnrh Neurons

Hypothalamic GnRH neurons are essential for initiation and regulation of reproductive function. In addition to pituitary gonadotrope stimulation, activity of GnRH through its receptor (GnRHR) has been suggested to include autocrine regulation of the GnRH neuron. Two hypogonadal mouse strains, the Gnrh1 mutant (hpg) mice and Gnrhr mutant mice were used to investigate the potential role of GnRH signaling in the proper development and maintenance of GnRH neurons. Immunocytochemical analysis of heterozygous hpg mice revealed a GnRH neuron population that was normal in size and distribution, indicating no effect from reduced Gnrh1 gene dosage on the neurons themselves. To visualize GnRH neurons in homozygous GnRH-deficient hpg mice, heterozygous hpg mice were crossed with GnRH-green fluorescent protein (GFP) transgenic mice with targeted expression of the GFP reporter gene in GnRH neurons. Analysis of forebrains of homozygous hpg/GFP-positive mice immunostained for GFP revealed a normal population size and appropriate distribution of GnRH neurons in hpg mice, with immunoreactive neuronal processes present at the median eminence. Similarly, adult mice deficient in functional GnRHR possessed a full complement of GnRH neurons in the basal forebrain that was indistinguishable from the distribution of GnRH neurons in their wild-type counterparts. Moreover, hpg/GFP neurons retained the ability to generate spontaneous bursts of action potential firing activity, suggesting that GnRH peptide is not required for this function. These data establish that autocrine-paracrine GnRH-signaling is not a prerequisite for the developmental migration of GnRH neurons into the brain or for the projection of GnRH neurosecretory axons.

scholarly journals Androgens Increase Gonadotropin-Releasing Hormone Neuron Firing Activity in Females and Interfere with Progesterone Negative Feedback

Endocrinology ◽  
2006 ◽  
Vol 147 (3) ◽  
pp. 1474-1479 ◽  
Author(s):  
Justyna Pielecka ◽  
Samuel D. Quaynor ◽  
Suzanne M. Moenter
Keyword(s):  
Animal Models ◽  
Firing Rate ◽  
Negative Feedback ◽  
Brain Slices ◽  
Neuron Activity ◽  
Gnrh Neuron ◽  
Firing Activity ◽  
Neuron Firing ◽  
Gnrh Neurons ◽  
Gaba Transmission

GnRH neurons are the central regulators of fertility, and their activity is modulated by steroid feedback. In women with hyperandrogenemic infertility and in animal models of these disorders, elevated androgen levels interfere with progesterone (P) negative feedback. Our previous work showed that steroids altered the frequency and amplitude of γ-aminobutyric acid (GABA) transmission to GnRH neurons. Specifically, P inhibited GABA transmission, which can excite GnRH neurons, whereas dihydrotestosterone (DHT) increased GABA transmission. In this study the GnRH neuron firing rate was examined in the same animal models. Adult (>2 months) female mice were ovariectomized and treated for 8–12 d with implants containing estradiol (E), E and P, E and DHT, or E, P, and DHT. Targeted extracellular recordings were used to examine the long-term firing activity of green fluorescent protein-identified GnRH neurons in brain slices from these mice. In comparing E alone to E plus P animals, P increased the percentage of time that GnRH neurons were quiescent and reduced the area under the curve of the firing rate and the instantaneous firing frequency, suggesting that P provides additional negative feedback over E alone. The addition of DHT markedly increased GnRH neuron activity in both the presence and absence of P. DHT also altered the firing pattern of GnRH neurons, such that peaks in the firing rate detected by the Cluster8 algorithm were approximately doubled in frequency and amplitude. These data support and extend our previous findings and are consistent with the hypothesis that the changes in GABAergic transmission observed in these animal models impact upon the activity of GnRH neurons, and central androgen action probably stimulates GnRH release.

scholarly journals A CRH Receptor Type 1 Agonist Increases GABA Transmission to GnRH Neurons in a Circulating-Estradiol-Dependent Manner

Endocrinology ◽  
2020 ◽  
Vol 161 (11) ◽  
Author(s):  
Chayarndorn Phumsatitpong ◽  
Rose M De Guzman ◽  
Damian G Zuloaga ◽  
Suzanne M Moenter
Keyword(s):  
Brain Slices ◽  
Potassium Currents ◽  
Neuron Activity ◽  
Dependent Manner ◽  
Gnrh Neuron ◽  
Factors Affecting ◽  
Voltage Gated ◽  
Gnrh Neurons ◽  
As Stress ◽  
Gaba Transmission

Abstract GnRH neurons are central regulators of reproduction and respond to factors affecting fertility, such as stress. Corticotropin-releasing hormone (CRH) is released during stress response. In brain slices from unstressed controls, CRH has opposite, estradiol-dependent effects on GnRH neuron firing depending on the CRH receptor activated; activating CRHR-1 stimulates whereas activating CRHR-2 suppresses activity. We investigated possible direct and indirect mechanisms. Mice were ovariectomized and either not treated further (OVX) or given a capsule producing high positive feedback (OVX + E) or low negative feedback (OVX + low E) physiologic circulating estradiol levels. We tested possible direct effects on GnRH neurons by altering voltage-gated potassium currents. Two types of voltage-gated potassium currents (transient IA and sustained IK) were measured; neither CRHR-1 nor CRHR-2 agonists altered potassium current density in GnRH neurons from OVX + E mice. Further, neither CRH nor receptor-specific agonists altered action potential generation in response to current injection in GnRH neurons from OVX + E mice. To test the possible indirect actions, GABAergic postsynaptic currents were monitored. A CRHR-1 agonist increased GABAergic transmission frequency to GnRH neurons from OVX + E, but not OVX, mice, whereas a CRHR-2 agonist had no effect. Finally, we tested if CRH alters the firing rate of arcuate kisspeptin neurons, which provide an important excitatory neuromodulatory input to GnRH neurons. CRH did not acutely alter firing activity of these neurons from OVX, OVX + E or OVX + low E mice. These results suggest CRH increases GnRH neuron activity in an estradiol-dependent manner in part by activating GABAergic afferents. Mechanisms underlying inhibitory effects of CRH remain unknown.

scholarly journals Vasoactive Intestinal Peptide Excites GnRH Neurons in Male and Female Mice

Endocrinology ◽  
2016 ◽  
Vol 157 (9) ◽  
pp. 3621-3630 ◽  
Author(s):  
Richard Piet ◽  
Henry Dunckley ◽  
Kiho Lee ◽  
Allan E. Herbison
Keyword(s):  
Vasoactive Intestinal Peptide ◽  
Estrous Cycle ◽  
Suprachiasmatic Nucleus ◽  
Fluorescent Protein ◽  
Neuron Activity ◽  
Gnrh Neuron ◽  
Male And Female ◽  
Vip Receptors ◽  
Female Mice ◽  
Gnrh Neurons

A variety of external and internal factors modulate the activity of GnRH neurons to control fertility in mammals. A direct, vasoactive intestinal peptide (VIP)-mediated input to GnRH neurons originating from the suprachiasmatic nucleus is thought to relay circadian information within this network. In the present study, we examined the effects of VIP on GnRH neuron activity in male and female mice at different stages of the estrous cycle. We carried out cell-attached recordings in slices from GnRH-green fluorescent protein mice and calcium imaging in slices from a mouse line expressing the genetically encoded calcium indicator GCaMP3 selectively in GnRH neurons. We show that 50%–80% of GnRH neurons increase their firing rate in response to bath-applied VIP (1nM–1000nM) in both male and female mice and that this is accompanied by a robust increase in intracellular calcium concentrations. This effect is mediated directly at the GnRH neuron likely through activation of high-affinity VIP receptors. Because suprachiasmatic nucleus-derived timing cues trigger the preovulatory surge only on the afternoon of proestrus in female mice, we examined the effects of VIP during the estrous cycle at different times of day. VIP responsiveness in GnRH neurons did not vary significantly in diestrous and proestrous mice before or around the time of the expected preovulatory surge. These results indicate that the majority of GnRH neurons in male and female mice express functional VIP receptors and that the effects of VIP on GnRH neurons do not alter across the estrous cycle.

scholarly journals Progesterone Treatment Inhibits and Dihydrotestosterone (DHT) Treatment Potentiates Voltage-Gated Calcium Currents in Gonadotropin-Releasing Hormone (GnRH) Neurons

Endocrinology ◽  
2010 ◽  
Vol 151 (11) ◽  
pp. 5349-5358 ◽  
Author(s):  
Jianli Sun ◽  
Suzanne M. Moenter
Keyword(s):  
Cell Voltage ◽  
Time Of Day ◽  
Calcium Currents ◽  
Neuron Activity ◽  
Dependent Manner ◽  
Gnrh Neuron ◽  
Ovarian Steroid ◽  
Voltage Gated ◽  
Gnrh Neurons ◽  
In Cells

GnRH neurons are central regulators of fertility, and their activity is modulated by steroid feedback. In normal females, GnRH secretion is regulated by estradiol and progesterone (P). Excess androgens present in hyperandrogenemic fertility disorders may disrupt communication of negative feedback signals from P and/or independently stimulate GnRH release. Voltage-gated calcium channels (VGCCs) are important in regulating excitability and hormone release. Estradiol alters VGCCs in a time-of-day-dependent manner. To further elucidate ovarian steroid modulation of GnRH neuron VGCCs, we studied the effects of dihydrotestosterone (DHT) and P. Adult mice were ovariectomized (OVX) or OVX and treated with implants containing DHT (OVXD), estradiol (OVXE), estradiol and DHT (OVXED), estradiol and P (OVXEP), or estradiol, DHT, and P (OVXEDP). Macroscopic calcium current (ICa) was recorded in the morning or afternoon 8–12 d after surgery using whole-cell voltage-clamp. ICa was increased in afternoon vs. morning in GnRH neurons from OVXE mice but this increase was abolished in cells from OVXEP mice. ICa in cells from OVXD mice was increased regardless of time of day; there was no additional effect in OVXED mice. P reduced N-type and DHT potentiated N- and R-type VGCCs; P blocked the DHT potentiation of N-type-mediated current. These data suggest P and DHT have opposing actions on VGCCs in GnRH neurons, but in the presence of both steroids, P dominates. VGCCs are targets of ovarian steroid feedback modulation of GnRH neuron activity and, more specifically, a potential mechanism whereby androgens could activate GnRH neuronal function.

scholarly journals RFamide-related Peptide-3 and the Trade-off between Reproductive and Ingestive Behavior

2017 ◽  
Vol 57 (6) ◽  
pp. 1225-1239 ◽  
Author(s):  
Jill E Schneider ◽  
Noah A Benton ◽  
Kim A Russo ◽  
Candice M Klingerman ◽  
Wilbur P Williams ◽  
...  
Keyword(s):  
Ingestive Behavior ◽  
Trade Off ◽  
Related Peptide
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