Colocalization of cocaine- and amphetamine-regulated transcript with kisspeptin and neurokinin B in the human infundibular region.

Katalin Skrapits,Erik Hrabovszky,Philippe Ciofi,Beáta Á Borsay,Mohammad A Ghatei,Stephen R Bloom,László Herczeg,Waljit S Dhillo,Zsolt Liposits,Andrew Wolfe

doi:10.1371/journal.pone.0103977

Abstract

Kisspeptin (KP)- and neurokinin B (NKB)- synthesizing neurons of the hypothalamic arcuate nucleus play a pivotal role in the regulation of pulsatile gonadotropin-releasing hormone (GnRH) secretion. Unlike in rodents and sheep, the homologous KP and NKB neurons in the human infundibular region rarely express dynorphin- but often exhibit Substance P (SP) immunoreactivity, indicating remarkable species differences in the neurochemical phenotype of these neurons. In search for additional neuropeptides in human KP and NKB neurons, we carried out immunofluorescent studies on hypothalamic sections obtained from five postmenopausal women. Colocalization experiments provided evidence for the presence of cocaine- and amphetamine-regulated transcript (CART) in 47.9±6.6% of KP-immunoreactive (IR) and 30.0±4.9% of NKB-IR perikarya and in 17.0±2.3% of KP-IR and 6.2±2.0% of NKB-IR axon varicosities. All three neuropeptides were present in 33.3±4.9% of KP-IR and 28.2±4.6% of NKB-IR somata, respectively, whereas triple-labeling showed lower incidences in KP-IR (14.3±1.8%) and NKB-IR (5.9±2.0%) axon varicosities. CART-IR KP and NKB neurons established contacts with other peptidergic cells, including GnRH-IR neurons and also sent projections to the infundibular stalk. KP and NKB fibers with CART often contained SP as well, while being distinct from CART fibers co-containing the orexigenic peptide agouti-related protein. Presence of CART in human, but not rodent, KP and NKB neurons represents a new example of species differences in the neuropeptide repertoire of mediobasal hypothalamic KP and NKB neurons. Target cells, receptor sites and physiological significance of CART in the efferent communication of KP and NKB neurons in primates require clarification.

Highlights

Peptidergic neurons co-synthesizing kisspeptin (KP), neurokinin B (NKB) and dynorphin in the hypothalamic arcuate nucleus (ARC) [1,2,3] (‘KNDy neurons’ [4]) play a pivotal role in negative sex steroid feedback to the hypophysiotropic gonadotropinreleasing hormone (GnRH) neurons [1,5,6]; in rats, neurotoxic ablation of these cells prevents the rise in serum LH and attenuates the rise in serum FSH following ovariectomy [7]
cocaine- and amphetamine-regulated transcript (CART)-IR neuronal cell bodies were often detectable in subregions of the infundibular (arcuate) nucleus (Inf) that were populated by KP-IR and NKB-IR neurons (Fig. 1A)
This study provides morphological evidence for the presence of CART neuropeptide in 47.966.6% of the KP-IR and 30.064.9% of the NKB-IR perikarya and in 17.062.3% of the KP-IR and 6.262.0% of the NKB-IR axon varicosities in the Inf of postmenopausal women

Summary

Introduction

Peptidergic neurons co-synthesizing kisspeptin (KP), neurokinin B (NKB) and dynorphin in the hypothalamic arcuate nucleus (ARC) [1,2,3] (‘KNDy neurons’ [4]) play a pivotal role in negative sex steroid feedback to the hypophysiotropic gonadotropinreleasing hormone (GnRH) neurons [1,5,6]; in rats, neurotoxic ablation of these cells prevents the rise in serum LH and attenuates the rise in serum FSH following ovariectomy [7]. NKB and dynorphin, derived at least partly from intrinsic sources, can act on KNDy neurons via autoreceptors. Such autoreceptors include the NK3 [2,9,10], NK1 [11] and NK2 [11] tachykinin receptors through which NKB can excite [11,12,13], and the k-opioid autoreceptor through which dynorphin and selective kappa-opioid receptor agonists can inhibit [11,13] KNDy neuronal activity. In contrast with NKB and dynorphin, intrinsic KP does not seem to influence the electric activity of KNDy neurons [11], but rather, plays an important role in the neuronal transmission from KNDy to GnRH neurons, the latter expressing KISS1R [14,15,16]. The pulsatile KP output into the median eminence of the female rhesus monkey is temporally correlated with GnRH neurosecretory pulses [17]

Methods

Results

Conclusion