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 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 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 Lack of sex differences in gonadotropin-releasing hormone (GnRH) neuron potassium currents and excitability

2021 ◽  
Author(s):  
R Anthony DeFazio ◽  
Suzanne M Moenter
Keyword(s):  
Action Potential ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Brain Slices ◽  
Potassium Currents ◽  
Gonadotropin Releasing Hormone ◽  
Releasing Hormone ◽  
Voltage Gated ◽  
Gnrh Neurons ◽  
Gnrh Release

Gonadotropin-releasing hormone (GnRH) drives pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone, which in turn regulate gonadal functions including steroidogenesis. The pattern of GnRH release and thus fertility depend on gonadal steroid feedback. Under homeostatic (negative) feedback conditions, removal of the gonads from either females or males increases the amplitude and frequency of GnRH release and alters the long-term firing pattern of these neurons in brain slices. The neurobiological mechanisms intrinsic to GnRH neurons that are altered by homeostatic feedback are not well studied and have not been compared between sexes. During estradiol positive feedback, which is unique to females, there are correlated changes in voltage-gated potassium currents and neuronal excitability. We thus hypothesized these same mechanisms would be engaged in homeostatic negative feedback. Voltage-gated potassium channels play a direct role in setting excitability and action potential properties. Whole-cell patch-clamp recordings of GFP-identified GnRH neurons in brain slices from sham-operated and castrated adult female and male mice were made to assess fast (IA) and slow (IK) inactivating potassium currents as well as action potential properties. Surprisingly, no changes were observed in most potassium current properties, input resistance or capacitance and this was reflected in a lack of differences in excitability and specific action potential properties. These results support the concept that, in contrast to positive feedback, steroid negative feedback regulation of GnRH neurons in both sexes is likely conveyed to GnRH neurons via mechanisms that do not induce major changes in the biophysical properties of these cells.

scholarly journals Kisspeptin Acts Directly and Indirectly to Increase Gonadotropin-Releasing Hormone Neuron Activity and Its Effects Are Modulated by Estradiol

Endocrinology ◽  
2007 ◽  
Vol 149 (4) ◽  
pp. 1979-1986 ◽  
Author(s):  
Justyna Pielecka-Fortuna ◽  
Zhiguo Chu ◽  
Suzanne M. Moenter
Keyword(s):  
Brain Slices ◽  
Cell Voltage ◽  
Neuron Activity ◽  
Dependent Manner ◽  
Current Clamp ◽  
Inward Current ◽  
Neural Communication ◽  
Gnrh Neurons ◽  
Lh Release ◽  
G Protein Coupled

GnRH neurons play a pivotal role in the central regulation of fertility. Kisspeptin greatly increases GnRH/LH release and GnRH neuron firing activity and may be involved in estradiol feedback, but the neurobiological mechanisms for these actions are unknown. G protein-coupled receptor 54, the receptor for kisspeptin, is expressed by GnRH neurons as well as other hypothalamic neurons, suggesting both direct and indirect effects are possible. To investigate this and determine whether kisspeptin activation of GnRH neurons is estradiol sensitive, we recorded the firing rate of GnRH neurons in brain slices from adult female mice that were ovariectomized (OVX) and either treated with estradiol (E) capsules (OVX+E) or left without further treatment. Kisspeptin increased GnRH neuronal activity in a dose-dependent manner in cells from both OVX and OVX+E mice, and estradiol significantly potentiated the response. To begin to distinguish direct from indirect actions of kisspeptin, fast synaptic transmission mediated by ionotropic γ-aminobutyric acid and glutamate receptors was pharmacologically blocked (blockade). Blockade reduced GnRH response to kisspeptin in OVX+E but not in OVX mice. Actions of kisspeptin were also assessed using whole-cell voltage- and current-clamp recording in slices from OVX animals. Kisspeptin application depolarized GnRH neurons in current-clamp and generated inward current in voltage-clamp recordings, even after blocking action potential-dependent neural communication, consistent with a direct effect. Blockers of potassium channels abolished the inward current. Together our data indicate that kisspeptin activates GnRH neurons via both direct and transsynaptic mechanisms and that transsynaptic mechanisms are either enabled and/or potentiated by estradiol.

scholarly journals Firing patterns of gonadotropin-releasing hormone neurons are sculpted by their biologic state

2020 ◽  
Vol 7 (8) ◽  
pp. 201040
Author(s):  
Jonathon Penix ◽  
R. Anthony DeFazio ◽  
Eden A. Dulka ◽  
Santiago Schnell ◽  
Suzanne M. Moenter
Keyword(s):  
Action Potential ◽  
Polycystic Ovary ◽  
Brain Slices ◽  
Gonadotropin Releasing Hormone ◽  
Neuron Activity ◽  
Interval Order ◽  
Short Term ◽  
Firing Patterns ◽  
Releasing Hormone ◽  
Gnrh Neurons

Gonadotropin-releasing hormone (GnRH) neurons form the final pathway for the central neuronal control of fertility. GnRH is released in pulses that vary in frequency in females, helping drive hormonal changes of the reproductive cycle. In the common fertility disorder polycystic ovary syndrome (PCOS), persistent high-frequency hormone release is associated with disrupted cycles. We investigated long- and short-term action potential patterns of GnRH neurons in brain slices before and after puberty in female control and prenatally androgenized (PNA) mice, which mimic aspects of PCOS. A Monte Carlo (MC) approach was used to randomize action potential interval order. Dataset distributions were analysed to assess (i) if organization persists in GnRH neuron activity in vitro , and (ii) to determine if any organization changes with development and/or PNA treatment. GnRH neurons in adult control, but not PNA, mice produce long-term patterns different from MC distributions. Short-term patterns differ from MC distributions before puberty but become absorbed into the distributions with maturation, and the distributions narrow. These maturational changes are blunted by PNA treatment. Firing patterns of GnRH neurons in brain slices thus maintain organization dictated at least in part by the biologic status of the source and are disrupted in models of disease.

scholarly journals Dose-Dependent Switch in Response of Gonadotropin-Releasing Hormone (GnRH) Neurons to GnRH Mediated through the Type I GnRH Receptor

Endocrinology ◽  
2004 ◽  
Vol 145 (2) ◽  
pp. 728-735 ◽  
Author(s):  
Chun Xu ◽  
Xu-Zhi Xu ◽  
Craig S. Nunemaker ◽  
Suzanne M. Moenter
Keyword(s):  
Firing Rate ◽  
Fluorescent Protein ◽  
Brain Slices ◽  
Dose Dependence ◽  
Gnrh Receptor ◽  
Neuron Activity ◽  
Type I ◽  
Pulsatile Release ◽  
Gnrh Neurons ◽  
Green Fluorescent

Abstract Pulsatile release of GnRH provides central control of reproduction. GnRH neuron activity is likely synchronized to produce hormone pulses, but the mechanisms are largely unknown. One candidate for communication among these neurons is GnRH itself. Cultured embryonic and immortalized GnRH neurons express GnRH receptor type I (GnRHR-1), but expression has not been shown in adult GnRH neurons. Using mice that express green fluorescent protein (GFP) in GnRH neurons, we tested whether adult GnRH neurons express GnRHR-1. GFP-positive (n = 42) and -negative neurons (n = 22) were harvested from brain slices, and single-cell RT-PCR was performed with cell contents. Fifty-two percent of the GnRH neurons tested expressed GnRHR-1, but only 9% of non-GnRH hypothalamic neurons expressed GnRHR-1; no false harvest controls (n = 13) were positive. GnRHR-1 expression within GnRH neurons suggested a physiological ultrashort loop feedback role for GnRH. Thus, we examined the effect of GnRH on the firing rate of GnRH neurons. Low-dose GnRH (20 nm) significantly decreased firing rate in 12 of 22 neurons (by 42 ± 4%, P < 0.05), whereas higher doses increased firing rate (200 nm, five of 10 neurons, 72 ± 26%; 2000 nm, nine of 13 neurons, 53 ± 8%). Interestingly, the fraction of GnRH neurons responding was similar to the fraction in which GnRHR-1 was detected. Together, these data demonstrate that a subpopulation of GnRH neurons express GnRHR-1 and respond to GnRH with altered firing. The dose dependence suggests that this autocrine control of GnRH neurons may be not only a mechanism for generating and modulating pulsatile release, but it may also be involved in the switch between pulse and surge modes of release.

scholarly journals Kisspeptin Increases γ-Aminobutyric Acidergic and Glutamatergic Transmission Directly to Gonadotropin-Releasing Hormone Neurons in an Estradiol-Dependent Manner

Endocrinology ◽  
2010 ◽  
Vol 151 (1) ◽  
pp. 291-300 ◽  
Author(s):  
Justyna Pielecka-Fortuna ◽  
Suzanne M. Moenter
Keyword(s):  
Negative Feedback ◽  
Positive Feedback ◽  
Brain Slices ◽  
Cell Voltage ◽  
Dependent Manner ◽  
Glutamatergic Transmission ◽  
Neuron Response ◽  
Gnrh Neurons ◽  
Gnrh Release ◽  
In Cells

Abstract GnRH neurons are the final central pathway controlling fertility. Kisspeptin potently activates GnRH release via G protein-coupled receptor 54 (GPR54). GnRH neurons express GPR54, and kisspeptin can act directly; however, GPR54 is broadly expressed, suggesting indirect actions are possible. Transsynaptic mechanisms are involved in estradiol-induced potentiation of GnRH neuron response to kisspeptin. To investigate these mechanisms, separate whole-cell voltage-clamp recordings were performed of γ-aminobutyric acid (GABA)-ergic and glutamatergic transmission to GnRH neurons in brain slices before and during kisspeptin treatment. To determine whether estradiol alters the effect of kisspeptin on synaptic transmission, mice were ovariectomized and either left with no further treatment (OVX) or treated with estradiol implants (OVX+E). Cells were first studied in the morning when estradiol exerts negative feedback. Kisspeptin increased frequency and amplitude of GABAergic postsynaptic currents (PSCs) in GnRH neurons from OVX+E mice. Blocking action potentials eliminated the effect on frequency, indicating presynaptic actions. Amplitude changes were due to postsynaptic actions. Kisspeptin also increased frequency of glutamatergic excitatory PSCs in cells from OVX+E animals. Kisspeptin did not affect either GABAergic or glutamatergic transmission to GnRH neurons in cells from OVX mice, indicating effects on transmission are estradiol dependent. In contrast to stimulatory effects on GABAergic PSC frequency during negative feedback, kisspeptin had no effect during positive feedback. These data suggest estradiol enables kisspeptin-mediated increases in GABA and glutamate transmission to GnRH neurons. Furthermore, the occlusion of the response during positive feedback implies one consequence of estradiol positive feedback is an increase in transmission to GnRH neurons mediated by endogenous kisspeptin.

scholarly journals Morphological Characterization of the Action Potential Initiation Segment in GnRH Neuron Dendrites and Axons of Male Mice

Endocrinology ◽  
2015 ◽  
Vol 156 (11) ◽  
pp. 4174-4186 ◽  
Author(s):  
Michel K. Herde ◽  
Allan E. Herbison
Keyword(s):  
Action Potential ◽  
Cell Body ◽  
Brain Slices ◽  
Gnrh Neuron ◽  
Male Mice ◽  
Single Action ◽  
Ankyrin G ◽  
Gnrh Neurons ◽  
Action Potential Initiation ◽  
Potential Initiation

GnRH neurons are the final output neurons of the hypothalamic network controlling fertility in mammals. In the present study, we used ankyrin G immunohistochemistry and neurobiotin filling of live GnRH neurons in brain slices from GnRH-green fluorescent protein transgenic male mice to examine in detail the location of action potential initiation in GnRH neurons with somata residing at different locations in the basal forebrain. We found that the vast majority of GnRH neurons are bipolar in morphology, elaborating a thick (primary) and thinner (secondary) dendrite from opposite poles of the soma. In addition, an axon-like process arising predominantly from a proximal dendrite was observed in a subpopulation of GnRH neurons. Ankyrin G immunohistochemistry revealed the presence of a single action potential initiation zone ∼27 μm in length primarily in the secondary dendrite of GnRH neurons and located 30 to 140 μm distant from the cell soma, depending on the type of process and location of the cell body. In addition to dendrites, the GnRH neurons with cell bodies located close to hypothalamic circumventricular organs often elaborated ankyrin G–positive axon-like structures. Almost all GnRH neurons (>90%) had their action potential initiation site in a process that initially, or ultimately after a hairpin loop, was coursing in the direction of the median eminence. These studies indicate that action potentials are initiated in different dendritic and axonal compartments of the GnRH neuron in a manner that is dependent partly on the neuroanatomical location of the cell body.

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 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.

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