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![Evidence of gap junctions between glial cells through TEM A: mosaic image of three cells (C1, C2, C3). C1 shows characteristics of neuronal cytoplasm enriched in RER and ribosomes (n nucleus). C2 and C3 show characteristics of glial cytoplasm containing glycogen particles ([GRAPHIC]). A': enlarged view of black square in A showing the presence of a LDCV, membrane specialization ([GRAPHIC]) and an amorphous structure ([GRAPHIC]) that could correspond to LDCV content release (GnRH) (bar 2 m). B: close apposition of glial cell processes characterized by the presence of glycogen particles ([GRAPHIC]). Black arrow heads delineate a gap junction between two processes. Note the thinness of some processes ( 500nm). Bar 1 m. B': enlarged view of white rectangle in B. Bar 200nm.](profile/Anne-Duittoz/publication/283729024/figure/fig3/AS:365553102409730@1464166059592/Evidence-of-gap-junctions-between-glial-cells-through-TEM-A-mosaic-image-of-three-cells.png)
Evidence of gap junctions between glial cells through TEM A: mosaic image of three cells (C1, C2, C3). C1 shows characteristics of neuronal cytoplasm enriched in RER and ribosomes (n nucleus). C2 and C3 show characteristics of glial cytoplasm containing glycogen particles ([GRAPHIC]). A': enlarged view of black square in A showing the presence of a LDCV, membrane specialization ([GRAPHIC]) and an amorphous structure ([GRAPHIC]) that could correspond to LDCV content release (GnRH) (bar 2 m). B: close apposition of glial cell processes characterized by the presence of glycogen particles ([GRAPHIC]). Black arrow heads delineate a gap junction between two processes. Note the thinness of some processes ( 500nm). Bar 1 m. B': enlarged view of white rectangle in B. Bar 200nm.
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Episodic release of gonadotropin hormone (GnRH) is essential for reproductive function. In vitro studies have established that this episodic release is an endogenous property of GnRH neurons, and that GnRH secretory pulses are associated with synchronization of GnRH neuron activity. The cellular mechanisms by which GnRH neurons synchronize remain l...
Citations
... Finally, another type of cell-cell communication has also been suggested to modulate GnRH secretion. Astrocyte-astrocyte communication through connexin 43, a gap junction expressed predominantly in astrocytes, has been shown to regulate GnRH secretion in ex vivo GnRH neurons from embryonic mouse nasal explants in culture.52 Indeed, treatment with a pharmacological blocker of connexin 43 led to a decrease in GnRH activity and pulsatile secretion. ...
GnRH neurons (GnRH neurons) sitting within the hypothalamus control the production of gametes and sex steroids by the gonads, therefore ensuring survival of species. As orchestrators of reproductive function, GnRH neurons integrate information from external and internal cues. This occurs through an extensively studied neuronal network known as the “GnRH neuronal network”. However, the brain is not only composed of neurons. Evidence suggests a role for glial cells in controlling GnRH neuron activity, secretion and fertility outcomes, however, numerous questions remain. Glial cells have historically been seen as support cells for neurons. This idea has been challenged by the discovery that some neurological diseases originate from glial dysfunction. The prevalence of infertility disorders is increasing worldwide, with 1 in 4 couples affected, therefore it remains essential to understand the mechanisms by which the brain controls fertility. The “GnRH glial network” could be a major player in infertility disorders and represent a potential therapeutic target. In polycystic ovary syndrome (PCOS), the most common infertility disorder of reproductive aged women worldwide, the brain is considered a prime suspect. Recent studies have demonstrated pathological neuronal wiring of the “GnRH neuronal network” in PCOS‐like animal models. However, the role of the “GnRH glial network” remains to be elucidated. In this review, I aim to propose glial cells as unusual suspects in infertility disorders such as PCOS. In the first part, I will state our current knowledge about the role of glia in the regulation of GnRH neurons and fertility. In the second part, based on our recent findings, I will discuss how glial cells could be implicated in PCOS pathology. This article is protected by copyright. All rights reserved.
... The distal GnRH dendrites are interconnected and share input from ARC kisspeptin neurons as well as from glia and other neurons (Fig. 2). These connections help to synchronize the activity of GnRH neurons so that GnRH is released in pulses Han et al., 2015;Campbell et al., 2009;Pinet-Charvet et al., 2016;Moore et al., 2015Moore et al., , 2018a). The GnRH system is responsive to changes in physiological state and external circumstances of relevance to fertility. ...
The hypothalamic-pituitary-gonadal axis is controlled by gonadotropin-releasing hormone (GnRH) released by the hypothalamus. Disruption of this system leads to impaired reproductive maturation and function, a condition known as hypogonadotropic hypogonadism (HH). Most studies to date have focused on genetic causes of HH that impact neuronal development and function. However, variants may also impact the functioning of non-neuronal cells known as glia. Glial cells make up 50% of brain cells of humans, primates, and rodents. They include radial glial cells, microglia, astrocytes, tanycytes, oligodendrocytes, and oligodendrocyte precursor cells. Many of these cells influence the hypothalamic neuroendocrine system controlling fertility. Indeed, glia regulate GnRH neuronal activity and secretion, acting both at their cell bodies and their nerve endings. Recent work has also made clear that these interactions are an essential aspect of how the HPG axis integrates endocrine, metabolic, and environmental signals to control fertility. Recognition of the clinical importance of interactions between glia and the GnRH network may pave the way for the development of new treatment strategies for dysfunctions of puberty and adult fertility.
... vivo p75, GnRH, GFAP-GFP immunohitochemistry (IHC). Nonspecific binding sites were blocked as previously described and incubated overnight at + 4 °C with polyclonal chicken anti-GFP (1:10000, Aves Lab), polyclonal rabbit anti-p75 (1:1000, promega ref G3231), polyclonal sheep anti-GnRH (1:5000, gift from Dr Alain Caraty)37,63 . Sections were then rinsed in PBS and incubated for two hours at room temperature in secondary antibodies Alexa 488 donkey anti-chicken IgY (1:500), Alexa 633 donkey anti rabbit IgG (1:500) and Alexa 546 donkey anti sheep IgG (1:500). ...
The control of ovulation helps guarantee the success of reproduction and as such, contributes to the fitness of a species. In mammals, two types of ovulation are observed: induced and spontaneous ovulation. Recent work on camelids, that are induced ovulators, highlighted the role of a factor present in seminal plasma, beta Nerve Growth Factor (β-NGF), as the factor that triggers ovulation in a GnRH dependent manner. In the present work, we characterized alpaca β-NGF (aβ-NGF) and its 3D structure and compared it with human recombinant β-NGF (hβ-NGF). We showed that the β-NGF enriched fraction of alpaca semen and the human recombinant protein, both stimulated spontaneous electrical activity of primary GnRH neurons derived from mouse embryonic olfactory placodes. This effect was dose-dependent and mediated by p75 receptor signaling. P75 receptors were found expressed in vitro by olfactory ensheathing cells (OEC) in close association with GnRH neurons and in vivo by tanycytes in close vicinity to GnRH fibers in adult mouse. Altogether, these results suggested that β-NGF induced ovulation through an increase in GnRH secretion provoked by a glial dependent P75 mediated mechanism.
... Le blocage de la communication par les jonctions gap entre cellules gliales provoque une importante diminution de la sécrétion pulsatile de la GnRH suggérant qu'à l'état basal la communication via des jonctions gap des cellules gliales est indispensable pour une sécrétion adéquate de GnRH. (Pinet-Charvet et al., 2016). ...
Le déclenchement de l’ovulation peut se faire selon deux modes chez les mammifères : spontané et provoqué. L’ovulation spontanée intervient au cours du cycle œstral sous l’effet de facteurs internes hormonaux. L’ovulation provoquée est déclenchée par l’accouplement avec un mâle. Dans les deux cas, c’est une augmentation de la sécrétion de GnRH qui conduit à l’augmentation de LH qui provoque l’ovulation. Les facteurs qui conduisent à l’augmentation de sécrétion de GnRH sont différents selon les deux modalités : principalement la kisspeptine (ovulation spontanée) et le b-NGF (ovulation provoquée). Les protocoles d’induction de l’ovulation actuels reposent sur une action directe sur l’ovaire, grâce à l’utilisation de gonadotropines hétérologues, ou bien par une action sur l’hypophyse grâce aux agonistes du GnRH. Ces protocoles présentent différents inconvénients : perte d’efficacité dans le temps, stimulation supra-physiologique qui peut être délétère, problème éthique posé par l’obtention de certaines molécules. De nouveaux paradigmes d’induction de l’ovulation ciblant l’hypothalamus, et favorisant un déclenchement physiologique de l’ovulation sans supplémentation en hormones sont en cours de développement. Cette revue a pour objectif de présenter au lecteur les mécanismes intimes impliqués dans la régulation et le déclenchement de l’ovulation ainsi que deux approches nouvelles respectueuses de la physiologie de l’animal et de l’environnement.
... GnRH neurons receive their highest density of synaptic innervation along their proximal dendrons (up to ∼500 µm from the cell body), which contain the action potential initiation site (30,31). At their distal dendrons (∼500 µm from the cell body), GnRH neurons appear to be interconnected through dendro-dendritic bundling and associated shared inputs from ARC KP neurons and possibly other neurons and glial cells, which may provide a mechanism for the synchronization of GnRH neuron activity necessary for pulsatile GnRH secretion, as well as an additional mechanism for its direct modulation (4,(32)(33)(34)(35)(36). ...
Gonadotropin-releasing hormone (GnRH) neuron activity and GnRH secretion are essential for fertility in mammals. Here, I review findings from mouse studies on the direct modulation of GnRH neuron activity and GnRH secretion by non-peptide neurotransmitters (GABA, glutamate, dopamine, serotonin, norepinephrine, epinephrine, histamine, ATP, adenosine, and acetylcholine), gasotransmitters (nitric oxide and carbon monoxide), and gliotransmitters (prostaglandin E2 and possibly GABA, glutamate, and ATP). These neurotransmitters, gasotransmitters, and gliotransmitters have been shown to directly modulate activity and/or GnRH secretion in GnRH neurons in vivo or ex vivo (brain slices), from postnatal through adult mice, or in embryonic or immortalized mouse GnRH neurons. However, except for GABA, nitric oxide, and prostaglandin E2, which appear to be essential for normal GnRH neuron activity, GnRH secretion, and fertility in males and/or females, the biological significance of their direct modulation of GnRH neuron activity and/or GnRH secretion in the central regulation of reproduction remains largely unknown and requires further exploration.
... supported by recent data indicating that GFAP, Cx43 and GnRH closely associate in the mouse median eminence. In addition, in cultured embryonic mouse nasal placode explants, pharmacological Cx43 gap junction blockade reduces both GnRH neuron synchronicity and GnRH secretion(88). Furthermore, female Cx43+/-mice show altered reproductive behaviour and disrupted oestrus cycles, providing indirect in vivo evidence for a potential role of astrocyte-neuronal communication in the regulation of reproductive function(87).In addition to connexins, other mediators of neural cell interaction have been implicated in regulating activity of GnRH neurons. ...
A class of glial cell, astrocytes are highly abundant in the CNS. In addition to maintaining tissue homeostasis, astrocytes regulate neuronal communication and synaptic plasticity. There is an ever‐increasing appreciation that astrocytes are involved in the regulation of physiology and behaviour in normal and pathological states, including within neuroendocrine systems. Indeed, astrocytes are direct targets of hormone action in the CNS, via receptors expressed on their surface, and are also a source of regulatory neuropeptides, neurotransmitters, and gliotransmitters. Furthermore, as part of the neurovascular unit, astrocytes can regulate hormone entry into the CNS. This review is intended to provide an overview of how astrocytes are impacted by and contribute to the regulation of a diverse range of neuroendocrine systems: energy homeostasis and metabolism, reproduction, fluid homeostasis, the stress response, and circadian rhythms.
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... Важную роль играет их синхронная активность, которая осуществляется благодаря взаимодействию через щелевые межнейрональные контакты. Доказательством этого служит то, что мутация в гене коннексина-36, участвующего в образовании щелевого контакта между нейронами, приводит к гипогонадотропному гипогонадизму у людей [15,16]. ...
... More broadly, electrical coupling is a feature of neuroendocrine secretion patterns in many species. Neuronal synchronization is dependent on functional gap junctions for the pulsatile release of GnRH in the hypothalamus (Pinet-Charvet et al., 2016), for reproductive neurohormone release in aplysia (Dargaei et al., 2014), and for coordinated neurosecretion in the supraoptic nucleus (Yang and Hatton, 1988) and suprachiasmatic nucleus (Colwell, 2000;Long et al., 2005). ...
A fast, neuromodulatory role for estrogen signaling has been reported in many regions of the vertebrate brain. Regional differences in the cellular distribution of aromatase (estrogen synthase) in several species suggest that mechanisms for neuroestrogen signaling differ between and within brain regions. A more comprehensive understanding of neuroestrogen signaling depends on characterizing the cellular identities of neurons that express aromatase. Calcium-binding proteins such as parvalbumin and calbindin are molecular markers for interneuron subtypes, and are co-expressed with aromatase in human temporal cortex. Songbirds like the zebra finch have become important models to understand the brain synthesis of steroids like estrogens and the implications for neurobiology and behavior. Here, we investigated the regional differences in cytoarchitecture and cellular identities of aromatase-expressing neurons in the auditory and sensorimotor forebrain of zebra finches. Aromatase was co-expressed with parvalbumin in the caudomedial nidopallium (NCM) and HVC shelf (proper name) but not in the caudolateral nidopallium (NCL) or hippocampus. By contrast, calbindin was not co-expressed with aromatase in any region investigated. Notably, aromatase-expressing neurons were found in dense somato-somatic clusters, suggesting a coordinated release of local neuroestrogens from clustered neurons. Aromatase clusters were also more abundant and tightly packed in the NCM of males as compared to females. Overall, this study provides new insights into neuroestrogen regulation at the network level, and extend previous findings from human cortex by identifying a subset of aromatase neurons as putative inhibitory interneurons. This article is protected by copyright. All rights reserved.
... However, gap junctions between GnRH neurons (84) and surrounding cells (86) could allow signal propagation from one GnRH neuron to another and contribute to the synchronicity. In nasal explants, non-neuronal cells exhibit [Ca 2+ ]i oscillations (87) and blocking gap junctions impairs GnRH secretion (86). Hypothetically, if GnRH neurons were electrically connected in vivo, electrical activation of a subpopulation of GnRH neurons should propagate through the entire population and evoke an all-or-none GnRH/LH secretory response. ...
Fertility relies on the proper functioning of the hypothalamic–pituitary–gonadal axis. The hormonal cascade begins with hypothalamic neurons secreting gonadotropin-releasing hormone (GnRH) into the hypophyseal portal system. In turn, the GnRH-activated gonadotrophs in the anterior pituitary release gonadotropins, which then act on the gonads to regulate gametogenesis and sex steroidogenesis. Finally, sex steroids close this axis by feeding back to the hypothalamus. Despite this seeming straightforwardness, the axis is orchestrated by a complex neuronal network in the central nervous system. For reproductive success, GnRH neurons, the final output of this network, must integrate and translate a wide range of cues, both environmental and physiological, to the gonadotrophs via pulsatile GnRH secretion. This secretory profile is critical for gonadotropic function, yet the mechanisms underlying these pulses remain unknown. Literature supports both intrinsically and extrinsically driven GnRH neuronal activity. However, the caveat of the techniques supporting either one of the two hypotheses is the gap between events recorded at a single-cell level and GnRH secretion measured at the population level. This review aims to compile data about GnRH neuronal activity focusing on the physiological output, GnRH secretion.
... These cellto-cell interactions can trigger intracellular signaling cascades that can affect both glial and neuronal activities (Viguie et al., 2001;Parkash and Kaur, 2007;Sharif et al., 2013). Altering cell-to-cell communication through glial gap junctions or hemichannels decreases dramatically GnRH neuronal activity and GnRH secretion in vitro (Pinet-Charvet et al., 2015). Gapjunctions have previously been reported in the hypothalamus, particularly in the ArcN of female rats, where they are regulated by estrogen (Perez et al., 1990). ...
This review aims at giving an overview on the physiological events leading to puberty onset in mammals and more specifically in cattle. Puberty is an important developmental milestone in mammals involving numerous changes in various physiological regulations and behaviors. It is a physiological unique event integrating several important central regulations at the crossroad of adaptation to environment: reproductive axis, feeding behavior and nutritional controls, growth, seasonal rhythm and stress. Puberty onset is also an important economic parameter in replacement heifer program and in genomic selection (genomic bulls). The quest for advanced puberty onset should be carefully balanced by its impact on physiological parameters of the animal and its offspring. Thus one has to carefully consider each step leading to puberty onset and set up a strategy that will lead to early puberty without being detrimental in the long term. In this review, major contributions in the understanding of puberty process obtained in rodents, primates and farm animals such as sheep and cattle are discussed. In the first part we will detail the endocrine events leading to puberty onset with a special focus on the regulation of GnRH secretion. In the second part we will describe the neural mechanisms involved in silencing and reactivating the GnRH neuronal network. These central mechanisms are at the crossroad of the integration of environmental factors such as the nutritional status, the stress and the photoperiod that will be discussed in the third part. In the fourth part, we will discuss the genetic determinants of puberty onset and more particularly in humans, where several pathologies are associated with puberty delay or advance and in cattle where several groups have now identified genomic regions or gene networks associated with puberty traits. Last but not least, in the last part we will focus on the embryologist point of view, how to get good oocytes for in vitro fertilization and embryo development from younger animals.
