Population bursts in a modular neural network as a mechanism for synchronized activity in KNDy neurons.

The pulsatile activity of gonadotropin-releasing hormone neurons (GnRH neurons) is a key factor in the regulation of reproductive hormones. This pulsatility is orchestrated by a network of neurons that release the neurotransmitters kisspeptin, neurokinin B, and dynorphin (KNDy neurons), and produce episodic bursts of activity driving the GnRH neurons. We show in this computational study that the features of coordinated KNDy neuron activity can be explained by a neural network in which connectivity among neurons is modular. That is, a network structure consisting of clusters of highly-connected neurons with sparse coupling among the clusters. This modular structure, with distinct parameters for intracluster and intercluster coupling, also yields predictions for the differential effects on synchronization of changes in the coupling strength within clusters versus between clusters.

The role of KNDy neurons in human reproductive health.

In the early 2000s, metastin, an endogenous ligand for G protein-coupled receptor 54 (GPR54), was discovered in human placental extracts. In 2003, GPR54 receptor mutations were found in a family with congenital hypogonadotropic hypogonadism. Metastin was subsequently renamed kisspeptin after its coding gene, Kiss1. Since then, studies in mice and other animals have revealed that kisspeptin is located at the apex of the hypothalamic-pituitary-gonadal axis and regulates reproductive functions by modulating gonadotropin-releasing hormone (GnRH). In rodents, kisspeptin (Kiss1) neurons localize to two regions, the hypothalamic arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV). ARC Kiss1 neurons co-express neurokinin B (NKB) and dynorphin and are thus termed KNDy neurons. Kiss1 neurons in humans are concentrated in the infundibular nucleus (equivalent to the ARC), with few Kiss1 neurons localized to the preoptic area (equivalent to the AVPV), and the mechanisms underlying GnRH surge secretion in humans are poorly understood. However, peripheral administration of kisspeptin to humans promotes gonadotropin secretion, and administration of kisspeptin to patients with hypothalamic amenorrhea or congenital hypogonadotropic hypogonadism restores the pulsatile secretion of GnRH/luteinizing hormone. Thus, kisspeptin undoubtedly plays an important role in reproductive function in humans. Studies are currently underway to develop kisspeptin receptor agonists or antagonists for clinical application. Modification of KNDy neurons by NKB agonists/antagonists is also being attempted to develop therapeutic agents for various menstrual abnormalities, including polycystic ovary syndrome and menopausal hot flashes. Here, we review the role of kisspeptin in humans and its clinical applications.

How to pause fertility.

Prolactin suppresses the ovarian cycles of lactating mice by directly repressing the activity of a cell population known as kisspeptin neurons.

Kisspeptinas y pubertad / No disponible

Las kisspeptinas fueron inicialmente identificadas como un grupo de péptidos estructuralmente relacionados, codificados por el gen KiSS-1, con capacidad de inhibir la metástasis de ciertos tumores mediante la activación del receptor acoplado a proteínas G, GPR54. No obstante, a finales de 2003, sendas publicaciones demostraron que mutaciones inactivantes del gen GPR54 se asocian a ausencia de pubertad e hipogonadismo hipogonadotropico, tanto en humanos como en roedores, lo que puso de manifiesto el papel clave del sistema ligando-receptor KiSS-1/GPR54 en el control del eje reproductor en general, y de los mecanismos de activación de la pubertad en particular. Estas observaciones iniciales se han visto sustanciadas en los últimos 3 años a través de numerosos estudios experimentales en diversas especies (desde roedores hasta humanos), que han permitido establecer el papel absolutamente crucial de las kisspeptinas y su receptor en la regulación de diversas facetas de la función reproductora. En este trabajo revisaremos los aspectos más sobresalientes del papel del sistema KiSS-1/GPR54 en el control del eje gonadotrópico, con especial atención a la descripción de la implicación de las kisspeptinas en la activación puberal del sistema reproductor y su modulación por factores relevantes, tales como el estado energético y metabólico del organismo (AU)

Kisspeptins were first identified as a family of structurally-related peptides, encoded by the KiSS-1 gene, with ability to inhibit tumor metastasis through binding to the G protein-coupled receptor GPR54. However, in late 2003, two independent publications demonstrated the presence of inactivating mutations of GPR54 gene in patients suffering lack of puberty onset and hypogonadotropic hypogonadism; a phenotype which was also observed in mice with genetic inactivation of GPR54. These observations disclosed the essential roles of the ligand/receptor system KiSS-1/ GPR54 in the control of reproductive function in general, and in the regulation of puberty onset in particular. These contentions have been fully substantiated during the last three years, by a number of experimental studies in different species (from Mouse and rats to humans), which have defined the indispensable role of kisspeptins and their receptor in the regulation of different aspects of reproduction. In the present article, we will review the most salient facets of the KiSS-1/GPR54 system in the control of the gonadotropic axis, with special emphasis on the potential involvement of kisspeptins in the pubertal activation of the reproductive system and its modulation by key regulatory factors, such as energy balance and the metabolic status of the organism (AU)

La regulación neuroendocrina de la pubertad normal y precoz: nuevos genes y nuevos conceptos / No disponible

No disponible