The kisspeptin system of the human hypothalamus: sexual dimorphism and relationship with gonadotropin‐releasing hormone and neurokinin B neurons

Abstract

Kisspeptin signaling via the kisspeptin receptor G-protein-coupled receptor-54 plays a fundamental role in the onset of puberty and the regulation of mammalian reproduction. In this immunocytochemical study we addressed the (i) topography, (ii) sexual dimorphism, (iii) relationship to gonadotropin-releasing hormone (GnRH) neurons and (iv) neurokinin B content of kisspeptin-immunoreactive hypothalamic neurons in human autopsy samples. In females, kisspeptin-immunoreactive axons formed a dense periventricular plexus and profusely innervated capillary vessels in the infundibular stalk. Most immunolabeled somata occurred in the infundibular nucleus. Many cells were also embedded in the periventricular fiber plexus. Rostrally, they formed a prominent periventricular cell mass (magnocellular paraventricular nucleus). Robust sex differences were noticed in that fibers and somata were significantly less numerous in male individuals. In dual-immunolabeled specimens, fine kisspeptin-immunoreactive axon varicosities formed axo-somatic, axo-dendritic and axo-axonal contacts with GnRH neurons. Dual-immunofluorescent studies established that 77% of kisspeptin-immunoreactive cells in the infundibular nucleus synthesize the tachykinin peptide neurokinin B, which is known to play crucial role in human fertility; 56 and 17% of kisspeptin fibers in the infundibular and periventricular nuclei, respectively, contained neurokinin B immunoreactivity. Site-specific co-localization patterns implied that kisspeptin neurons in the infundibular nucleus and elsewhere contributed differentially to these plexuses. This study describes the distribution and robust sexual dimorphism of kisspeptin-immunoreactive elements in human hypothalami, reveals neuronal contacts between kisspeptin-immunoreactive fibers and GnRH cells, and demonstrates co-synthesis of kisspeptins and neurokinin B in the infundibular nucleus. The neuroanatomical information will contribute to our understanding of central mechanisms whereby kisspeptins regulate human fertility.

Kisspeptin-GPR54 Signaling in Mouse NO-Synthesizing Neurons Participates in the Hypothalamic Control of Ovulation

“…However, by showing both that kisspeptin fails to modulate nNOS phosphorylation in the tuberal region of the hypothalamus and, in agreement with a previous study (Herbison et al, 2010), that nNOS neurons of the ARH do not express any detectable GPR54 promoter activity, our data clearly suggest that this population of nNOS neurons is unable to respond directly to kisspeptin. Yet the possibility remains that the kisspeptin neurons intimately associated with nNOS neurons in the ARH communicate through other signaling pathways, such as those involving dynorphin and neurokinin B, two transmitters coexpressed with kisspeptin (Ciofi et al, 2006Goodman et al, 2007;Hrabovszky et al, 2010) and that have been postulated to drive short feedback loops within the tuberal region of the hypothalamus to control the rhythmic discharge of kisspeptin and induce the release of GnRH from fibers in the median eminence Wakabayashi et al, 2010).…”

Rola sygnalizacji kisspeptyny w osi podwzgórze–przysadka–nadnercza — aktualna perspektywa

“…The studies performed on human autopsy samples recently have confirmed that kisspeptin neurons in humans are mainly located in the infundibular (arcuate in other species) and rostral preoptic area (POA) of the hypothalamus [24,29]. Studies have also indicated direct participation of kisspeptin in GnRH secretion [30], as evidenced by kisspeptin receptor mRNA expression by GnRH neurons [31,32], and close connections found between kisspeptin and GnRH neurons [22,24,26], although in humans not all GnRH neurons showed close connection with kisspeptin neurons [22,24,26,33].…”

“…Later it was discovered that kisspeptin neurons located in the infundibular region in humans/arcuate nucleus in rodents co-express other neuropeptides, named neurokinin-B and dynorphin, and were collectively called KNDy neurons [24,29,34], but neurons in POA did not express any of these neuropeptides [1]. It has been suggested that these distinctive populations of kisspeptin neurons also differ in physiological function [35,36].…”

“…Several studies have localised kisspeptin neurons in the infundibular/arcuate nuclei across all species, including humans, and have suggested that the rostral portion of the hypothalamus is species specific [22][23][24][25][26] (Fig. 1) [27,28].…”

Role of Kisspeptine in Regulation of Reproductive Function

“…Кисспептиновые нейроны в ARC коэкспрессируют нейропептиды ней-рокинин В (НКВ) и динорфины, породив тер-мин «KNDY-нейроны» (кисспептин-нейрокинин В-ди норфин) [90][91][92]. Были также выявлены мутации, связанные с потерей функции, в ге-нах, кодирующих нейрокинин В (TAC3) и его рецептор (TACR3), у пациентов с нормосомным изолированным ИГГ и отсутствием полового созревания [93].…”