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Neurons that produce gonadotropin-releasing hormone (GnRH), which control fertility, complete their nose-to-brain migration by birth. However, their function depends on integration within a complex neuroglial network during postnatal development. Here, we show that rodent GnRH neurons use a prostaglandin D2 receptor DP1 signaling mechanism during infancy to recruit newborn astrocytes that ‘escort’ them into adulthood, and that the impairment of postnatal hypothalamic gliogenesis markedly alters sexual maturation by preventing this recruitment, a process mimicked by the endocrine disruptor bisphenol A. Inhibition of DP1 signaling in the infantile preoptic region, where GnRH cell bodies reside, disrupts the correct wiring and firing of GnRH neurons, alters minipuberty or the first activation of the hypothalamic–pituitary–gonadal axis during infancy, and delays the timely acquisition of reproductive capacity. These findings uncover a previously unknown neuron-to-neural-progenitor communication pathway and demonstrate that postnatal astrogenesis is a basic component of a complex set of mechanisms used by the neuroendocrine brain to control sexual maturation. GnRH neurons control their own connectivity and function as well as the sexual maturation of the individual by using prostaglandin D2 DP1 signaling to recruit and stably associate with newborn astrocytes in the preoptic region during infancy in rodents.

Neurons that produce gonadotropin-releasing hormone (GnRH), which control fertility, complete their nose-to-brain migration by birth. However, their function depends on integration within a complex neuroglial network during postnatal development. Here, we show that rodent GnRH neurons use a prostaglandin D

Introduction L’hormone anti-Mullerienne (AMH) dont les taux sont plus eleves dans le syndrome des ovaires polykystiques est connue pour augmenter la secretion de LH/GnRH [1] , [2] . Par ailleurs, les tanycytes, qui enchâssent les terminaisons des neurones a GnRH [3] , [4] , expriment le recepteur a l’AMH [2] . Ainsi, notre objectif est de tester les deux hypotheses suivantes dans un modele animal et chez la femme. La physiopathologie du SOPK : – est-elle liee a une retraction des tanycytes provoquee par l’AMH, entrainant l’augmentation de la secretion de LH/GnRH ? Et/ou – est-elle liee a une augmentation de l’activite des neurones a GnRH AMH-dependante ? Methode Nous avons etudie la modification de la plasticite neuro-structurale de l’hypothalamus en microscopie electronique chez des rats traites par de l’AMH et des controles. Puis, nous avons etudie de la meme facon un modele de souris SOPK en comparaison a des controles. Enfin, nous avons conduit une etude clinique par spectroscopie par resonance magnetique comparant les ratios de metabolites cerebraux entre des femmes SOPK et des temoins. Resultats Nous avons observe une augmentation significative du nombre de terminaisons de neurones a GnRH situees a proximite de l’espace peri-capillaire dans le groupe traite par l’AMH par rapport aux controles et nous avons fait les memes observations chez les souris SOPK comparees aux controles. Nos recents resultats chez les rongeurs SOPK, ont mis en evidence une augmentation des afferences excitatrices sur les neurones a GnRH [5] . Notre etude par IRM, chez les femmes SOPK et controles, vient conforter cette precedente etude, en montrant une augmentation de la viabilite/activite neuronale. Conclusion Cette etude translationelle suggere que l’augmentation des secretions de LH/GnRH retrouvee dans le SOPK serait dependante, d’une part, d’un rapprochement des terminaisons a GnRH vers l’espace peri-capillaire, et d’autre part, a une augmentation de l’activite neuronal hypothalamique.

Remerciements :Inra, UMR PRC 0085, Plateforme PIC, Centre Tours Val de Loire; Neurogenesis is the process by which new neurons are generated. This process, well established during development, persists in adulthood owing to the presence of neural stem cells (NSCs) localized in specific brain areas called neurogenic niches. Adult neurogenesis has recently been shown to occur in the hypothalamus, a structure involved in the neuroendocrine regulation of reproduction and metabolism, among others. In the adult sheep—a long-lived mammalian model—we have previously reported the existence of such a neurogenic niche located in the hypothalamic arcuate nucleus and the median eminence. In addition, in this seasonal species, the proliferation as well as neuroblasts production varies depending on the time of the year. In the present study, we provide a better characterization of the hypothalamic neurogenic niche by identifying the main components (NSCs, migrating cells, glial cells and blood vessels) using immunohistochemistry for validated markers. Then, we demonstrate the strong sensitivity of these various neurogenic niche components to the season, particularly in the arcuate nucleus. Further, using an electron microscopic approach, we reveal the cellular and cytoarchitectural reorganization of the arcuate nucleus niche following exposure to contrasting seasons. This study provides evidence that the arcuate nucleus and the median eminence contain two independent niches that react differently to the season. In addition, our results support the view that the cytoarchitectural organization of the sheep arcuate nucleus share comparable features with the structure of the subventricular zone in humans and non-human primates.

International audience; The delivery of blood-borne molecules conveying metabolic information to neural networks that regulate energy homeostasis is restricted by brain barriers. The fenestrated endothelium of median eminence microvessels and tight junctions between tanycytes together compose one of these. Here, we show that the decrease in blood glucose levels during fasting alters the structural organization of this blood-hypothalamus barrier, resulting in the improved access of metabolic substrates to the arcuate nucleus. These changes are mimicked by 2-deoxyglucose-induced glucoprivation and reversed by raising blood glucose levels after fasting. Furthermore, we show that VEGF-A expression in tanycytes modulates these barrier properties. The neutralization of VEGF signaling blocks fasting-induced barrier remodeling and significantly impairs the physiological response to refeeding. These results implicate glucose in the control of blood-hypothalamus exchanges through a VEGF-dependent mechanism and demonstrate a hitherto unappreciated role for tanycytes and the permeable microvessels associated with them in the adaptive metabolic response to fasting.

Introduction/objectifs Dans le syndrome des ovaires polykystiques (SOPK), les taux d’hormone anti-Mullerienne (AMH) sont 2 a 3 fois plus eleves [1] . Or, l’AMH augmente la secretion de LH via une hyper-activation des neurones a GnRH [2] . Par ailleurs, les tanycytes, qui enchâssent les terminaisons des neurones a GnRH [3] , [4] , [5] , expriment l’AMH et son recepteur [2] . Notre objectif est de determiner si l’AMH pourrait conduire a la retraction des tanycytes, entrainant l’augmentation de la secretion de GnRH/LH dans le SOPK. Materiels/Patients et methodes Nous avons realise des cultures cellulaires de tanycytes de rats en presence de doses croissantes d’AMH afin d’evaluer leur morphologie. Puis, nous avons etudie la modification de la plasticite neuro-structurale de l’hypothalamus en microscopie electronique. Nous avons compare la distance entre les terminaisons des neurones a GnRH et l’espace peri-capillaire entre des eminences medianes issues de rats femelles en diestrus (au moment ou ces terminaisons sont normalement enfouies par les tanycytes) traitees par de l’AMH et des controles. Resultats Nous avons confirme que les tanycytes exprimaient le recepteur specifique pour l’AMH (proteine et transcrit). En culture cellulaire, nous avons observe une retraction significative des tanycytes en presence d’AMH a la concentration de 50 ng/mL par rapport aux controles (p Conclusions Nos resultats suggerent que l’AMH pourrait etre responsable d’une retraction des pieds tanycytaires au niveau de l’eminence mediane. Cette retraction autoriserait la germination des terminaisons des neurones a GnRH vers l’espace pericapillaire et pourrait expliquer l’augmentation des secretions de GnRH/LH rencontrees dans le SOPK.

Reproduction is controlled in the brain by a neural network that drives the secretion of gonadotropin-releasing hormone (GnRH). Various permissive homeostatic signals must be integrated to achieve ovulation in mammals. However, the neural events controlling the timely activation of GnRH neurons are not completely understood. Here we show that kisspeptin, a potent activator of GnRH neuronal activity, directly communicates with neurons that synthesize the gaseous transmitter nitric oxide (NO) in the preoptic region to coordinate the progression of the ovarian cycle. Using a transgenicGpr54-null IRES-LacZ knock-in mouse model, we demonstrate that neurons containing neuronal NO synthase (nNOS), which are morphologically associated with kisspeptin fibers, express the kisspeptin receptor GPR54 in the preoptic region, but not in the tuberal region of the hypothalamus. The activation of kisspeptin signaling in preoptic neurons promotes the activation of nNOS through its phosphorylation on serine 1412 via the AKT pathway and mimics the positive feedback effects of estrogens. Finally, we show that while NO release restrains the reproductive axis at stages of the ovarian cycle during which estrogens exert their inhibitory feedback, it is required for the kisspeptin-dependent preovulatory activation of GnRH neurons. Thus, interactions between kisspeptin and nNOS neurons may play a central role in regulating the hypothalamic–pituitary–gonadal axisin vivo.