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 A role for glial fibrillary acidic protein (GFAP)-expressing cells in the regulation of gonadotropin-releasing hormone (GnRH) but not arcuate kisspeptin neuron output

2021 ◽  
Author(s):  
Charlotte Vanacker ◽  
R. Anthony DeFazio ◽  
Charlene M. Sykes ◽  
Suzanne M. Moenter
Keyword(s):  
Arcuate Nucleus ◽  
Designer Drugs ◽  
Neuron Activity ◽  
Gnrh Neurons ◽  
Hypothalamic Arcuate Nucleus ◽  
Lh Release ◽  
Main Regulator ◽  
Kndy Neurons

AbstractGnRH neurons are the final central neural output regulating fertility. Kisspeptin neurons in the hypothalamic arcuate nucleus (KNDy neurons) are considered the main regulator of GnRH output. GnRH and KNDy neurons are surrounded by astrocytes, which can modulate neuronal activity and communicate over distances. Prostaglandin E2 (PGE2), synthesized primarily by astrocytes, increases GnRH neuron activity and downstream pituitary release of luteinizing hormone (LH). We hypothesized GFAP-expressing astrocytes play a role regulating GnRH and/or KNDy neuron activity and LH release. We used adenoassociated viruses to target designer receptor exclusively activated by designer drugs (DREADDs) to GFAP-expressing cells to activate Gq or Gi-mediated signaling. Activating Gq signaling in the preoptic area, near GnRH neurons, but not in the arcuate, increases LH release in vivo and GnRH firing in vitro via a mechanism in part dependent upon PGE2. These data suggest astrocytes can activate GnRH/LH release in a manner independent of KNDy neurons.

scholarly journals Evidence That Dynorphin Acts Upon KNDy and GnRH Neurons During GnRH Pulse Termination in the Ewe

Endocrinology ◽  
2018 ◽  
Vol 159 (9) ◽  
pp. 3187-3199 ◽  
Author(s):  
Peyton W Weems ◽  
Lique M Coolen ◽  
Stanley M Hileman ◽  
Steven Hardy ◽  
Rick B McCosh ◽  
...  
Keyword(s):  
Arcuate Nucleus ◽  
Third Ventricle ◽  
Pulse Generation ◽  
G Protein Coupled Receptors ◽  
Neurokinin B ◽  
Gnrh Secretion ◽  
Pulsatile Gnrh ◽  
Gnrh Neurons ◽  
Kndy Neurons ◽  
G Protein Coupled

Abstract A subpopulation of neurons located within the arcuate nucleus, colocalizing kisspeptin, neurokinin B, and dynorphin (Dyn; termed KNDy neurons), represents key mediators of pulsatile GnRH secretion. The KNDy model of GnRH pulse generation proposes that Dyn terminates each pulse. However, it is unknown where and when during a pulse that Dyn is released to inhibit GnRH secretion. Dyn acts via the κ opioid receptor (KOR), and KOR is present in KNDy and GnRH neurons in sheep. KOR, similar to other G protein–coupled receptors, are internalized after exposure to ligand, and thus internalization can be used as a marker of endogenous Dyn release. Thus, we hypothesized that KOR will be internalized at pulse termination in both KNDy and GnRH neurons. To test this hypothesis, GnRH pulses were induced in gonad-intact anestrous ewes by injection of neurokinin B (NKB) into the third ventricle and animals were euthanized at times of either pulse onset or termination. NKB injections produced increased internalization of KOR within KNDy neurons during both pulse onset and termination. In contrast, KOR internalization into GnRH neurons was seen only during pulse termination, and only in GnRH neurons within the mediobasal hypothalamus (MBH). Overall, our results indicate that Dyn is released onto KNDy cells at the time of pulse onset, and continues to be released during the duration of the pulse. In contrast, Dyn is released onto MBH GnRH neurons only at pulse termination and thus actions of Dyn upon KNDy and GnRH cell bodies may be critical for pulse termination.

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 New Perspectives for Anatomical and Molecular Studies of Kisspeptin Neurons in the Aging Human Brain

2019 ◽  
Vol 109 (3) ◽  
pp. 230-241 ◽  
Author(s):  
Erik Hrabovszky ◽  
Szabolcs Takács ◽  
Balázs Göcz ◽  
Katalin Skrapits
Keyword(s):  
Arcuate Nucleus ◽  
Anatomical Site ◽  
Neuronal System ◽  
Hormone Signaling ◽  
Neurokinin B ◽  
Molecular Approaches ◽  
Endocrine Organs ◽  
Aging Men ◽  
Gnrh Neurons

The human infundibular nucleus (corresponding to the rodent arcuate nucleus) serves as an important integration center for neuronal signals and hormones released by peripheral endocrine organs. Kisspeptin (KP)-producing neurons of this anatomical site, many of which also synthesize neurokinin B (NKB), are critically involved in sex hormone signaling to gonadotropin-releasing hormone (GnRH) neurons. In recent years, the basic topography, morphology, neuropeptide content, and connectivity of human KP neurons have been investigated with in situ hybridization and immunohistochemistry on postmortem tissues. These studies revealed that human KP neurons differ neurochemically from their rodent counterparts and show robust aging-related plasticity. Earlier immunohistochemical experiments also provided evidence for temporal changes in the hypothalamus of aging men whose NKB and KP neurons undergo hypertrophy, increase in number, exhibit increased neuropeptide mRNA expression and immunoreactivity and give rise to higher numbers of immunoreactive fibers and afferent contacts onto GnRH neurons. Increasing percentages of KP-expressing NKB perikarya, NKB axons, and NKB inputs to GnRH neurons raise the intriguing possibility that a significant subset of NKB neurons begins to cosynthesize KP as aging advances. Although use of postmortem tissues is technically challenging, recently available single-cell anatomical and molecular approaches discussed in this review provide promising new tools to investigate the aging-related anatomical and functional plasticity of the human KP neuronal system.

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 The Differential Roles for Neurodevelopmental and Neuroendocrine Genes in Shaping GnRH Neuron Physiology and Deficiency

2021 ◽  
Vol 22 (17) ◽  
pp. 9425
Author(s):  
Roberto Oleari ◽  
Valentina Massa ◽  
Anna Cariboni ◽  
Antonella Lettieri
Keyword(s):  
Phenotypic Variability ◽  
Hypogonadotropic Hypogonadism ◽  
Neuroendocrine Cells ◽  
Delayed Puberty ◽  
Neuronal System ◽  
Gnrh Neuron ◽  
Neuron Development ◽  
Gnrh Neurons ◽  
Genes Encoding ◽  
Functional Relevance

Gonadotropin releasing hormone (GnRH) neurons are hypothalamic neuroendocrine cells that control sexual reproduction. During embryonic development, GnRH neurons migrate from the nose to the hypothalamus, where they receive inputs from several afferent neurons, following the axonal scaffold patterned by nasal nerves. Each step of GnRH neuron development depends on the orchestrated action of several molecules exerting specific biological functions. Mutations in genes encoding for these essential molecules may cause Congenital Hypogonadotropic Hypogonadism (CHH), a rare disorder characterized by GnRH deficiency, delayed puberty and infertility. Depending on their action in the GnRH neuronal system, CHH causative genes can be divided into neurodevelopmental and neuroendocrine genes. The CHH genetic complexity, combined with multiple inheritance patterns, results in an extreme phenotypic variability of CHH patients. In this review, we aim at providing a comprehensive and updated description of the genes thus far associated with CHH, by dissecting their biological relevance in the GnRH system and their functional relevance underlying CHH pathogenesis.

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 Single-cell morphological characterization of CRH neurons throughout the whole mouse brain

BMC Biology ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Yu Wang ◽  
Pu Hu ◽  
Qinghong Shan ◽  
Chuan Huang ◽  
Zhaohuan Huang ◽  
...  
Keyword(s):  
Single Cell ◽  
Mouse Brain ◽  
Stress Responses ◽  
Third Ventricle ◽  
Brain Regions ◽  
Morphological Characterization ◽  
Neuronal System ◽  
Mouse Line ◽  
Layer 4 ◽  
Local Circuits

Abstract Background Corticotropin-releasing hormone (CRH) is an important neuromodulator that is widely distributed in the brain and plays a key role in mediating stress responses and autonomic functions. While the distribution pattern of fluorescently labeled CRH-expressing neurons has been studied in different transgenic mouse lines, a full appreciation of the broad diversity of this population and local neural connectivity can only come from integration of single-cell morphological information as a defining feature. However, the morphologies of single CRH neurons and the local circuits formed by these neurons have not been acquired at brain-wide and dendritic-scale levels. Results We screened the EYFP-expressing CRH-IRES-Cre;Ai32 mouse line to reveal the morphologies of individual CRH neurons throughout the whole mouse brain by using a fluorescence micro-optical sectioning tomography (fMOST) system. Diverse dendritic morphologies and projection fibers of CRH neurons were found in various brain regions. Follow-up reconstructions showed that hypothalamic CRH neurons had the smallest somatic volumes and simplest dendritic branches and that CRH neurons in several brain regions shared a common bipolar morphology. Further investigations of local CRH neurons in the medial prefrontal cortex unveiled somatic depth-dependent morphologies of CRH neurons that exhibited three types of mutual connections: basal dendrites (upper layer) with apical dendrites (layer 3); dendritic-somatic connections (in layer 2/3); and dendritic-dendritic connections (in layer 4). Moreover, hypothalamic CRH neurons were classified into two types according to their somatic locations and characteristics of dendritic varicosities. Rostral-projecting CRH neurons in the anterior parvicellular area had fewer and smaller dendritic varicosities, whereas CRH neurons in the periventricular area had more and larger varicosities that were present within dendrites projecting to the third ventricle. Arborization-dependent dendritic spines of CRH neurons were detected, among which the most sophisticated types were found in the amygdala and the simplest types were found in the hypothalamus. Conclusions By using the CRH-IRES-Cre;Ai32 mouse line and fMOST imaging, we obtained region-specific morphological distributions of CRH neurons at the dendrite level in the whole mouse brain. Taken together, our findings provide comprehensive brain-wide morphological information of stress-related CRH neurons and may facilitate further studies of the CRH neuronal system.

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 Identification of Prolactin-Sensitive GABA and Kisspeptin Neurons in Regions of the Rat Hypothalamus Involved in the Control of Fertility

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 526-535 ◽  
Author(s):  
Ilona C. Kokay ◽  
Sandra L. Petersen ◽  
David R. Grattan
Keyword(s):  
Arcuate Nucleus ◽  
Direct Action ◽  
Third Ventricle ◽  
Prolactin Receptor ◽  
Afferent Pathways ◽  
Ovx Rats ◽  
Gnrh Neurons ◽  
Rostral Hypothalamus ◽  
Neuroendocrine Axis ◽  
Labeled Rna

Abstract High levels of circulating prolactin are known to cause infertility, but the precise mechanisms by which prolactin influences the neuroendocrine axis are yet to be determined. We used dual-label in situ hybridization to investigate whether prolactin-receptor (PRLR) mRNA is expressed in GnRH neurons. In addition, because γ-aminobutyric acidergic and kisspeptin neurons in the rostral hypothalamus are known to regulate GnRH neurons and, hence, might mediate the actions of prolactin, we investigated whether these neurons coexpress PRLR mRNA. 35S-labeled RNA probes to detect PRLR mRNA were hybridized together with digoxigenin-labeled probes to detect either GnRH, Gad1/Gad2, or Kiss1 mRNA in the rostral hypothalamus of ovariectomized (OVX), estradiol-treated rats. Additional sets of serial sections were cut through the arcuate nucleus of OVX rats, without estradiol replacement, to examine coexpression of PRLR mRNA in the arcuate population of kisspeptin neurons. PRLR mRNA was highly expressed throughout the rostral preoptic area, particularly in periventricular regions surrounding the third ventricle, and there was a high degree of colocalization of PRLR mRNA in both Gad1/Gad2 and Kiss1 mRNA-containing cells (86 and 85.5%, respectively). In contrast, only a small number of GnRH neurons (<5%) was found to coexpress PRLR mRNA. In the arcuate nucleus of OVX rats, the majority of Kiss1 mRNA-containing cells also coexpressed PRLR mRNA. These data are consistent with the hypothesis that, in addition to a direct action on a small subpopulation of GnRH neurons, prolactin actions on GnRH neurons are predominantly mediated indirectly, through known afferent pathways.

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