Hypophysiotropic Gonadotropin-Releasing Hormone Projections Are Exposed to Dense Plexuses of Kisspeptin, Neurokinin B and Substance P Immunoreactive Fibers in the Human: A Study on Tissues from Postmenopausal Women

Abstract

Neuronal populations that synthesize kisspeptin (KP), neurokinin B (NKB) and substance P (SP) in the hypothalamic infundibular nucleus of humans are partly overlapping. These cells are important upstream regulators of gonadotropin-releasing hormone (GnRH) neurosecretion. Homologous neurons in laboratory animals are thought to modulate episodic GnRH secretion primarily via influencing KP receptors on the hypophysiotropic fiber projections of GnRH neurons. To explore the structural basis of this putative axo-axonal communication in humans, we analyzed the anatomical relationship of KP-immunoreactive (IR), NKB-IR and SP-IR axon plexuses with hypophysiotropic GnRH fiber projections. Immunohistochemical studies were carried out on histological samples from postmenopausal women. The neuropeptide-IR axons innervated densely the portal capillary network in the postinfundibular eminence. Subsets of the fibers formed descending tracts in the infundibular stalk, some reaching the neurohypophysis. KP-IR, NKB-IR and SP-IR plexuses intermingled, and established occasional contacts, with hypophysiotropic GnRH fibers in the postinfundibular eminence and through their lengthy course while descending within the infundibular stalk. Triple-immunofluorescent studies also revealed considerable overlap between the KP, NKB and SP signals in individual fibers, providing evidence that these peptidergic projections arise from neurons of the mediobasal hypothalamus. These neuroanatomical observations indicate that the hypophysiotropic projections of human GnRH neurons in the postinfundibular eminence and the descending GnRH tract coursing through the infundibular stalk to the neurohypophysis are exposed to neurotransmitters/neuropeptides released by dense KP-IR, NKB-IR and SP-IR fiber plexuses. Localization and characterization of axonal neuropeptide receptors will be required to clarify the putative autocrine and paracrine interactions in these anatomical regions.

Expanding the role of tachykinins in the neuroendocrine control of reproduction

“…www.reproduction-online.org and the ventromedial nucleus (VMN), in keeping with previous reports of SP immunoreactivity in rats, monkeys and humans (Ronnekleiv et al 1984, Yamano et al 1986, Harlan et al 1989, Rance & Young 1991, Tsuruo et al 1991, Rance & Bruce 1994, Borsay et al 2014. Studies using immunohistochemical detection of SP also report a plethora of fibers that innervate the entire length of the ARC and the median eminence (ME) (Hrabovszky et al 2013, Kalil et al 2015, Fergani et al 2016, which appear to surround the capillaries of the hypophyseal portal system indicating that SP may have the ability to act directly on the anterior pituitary (Kalil et al 2015).…”

“…Studies using immunohistochemical detection of SP also report a plethora of fibers that innervate the entire length of the ARC and the median eminence (ME) (Hrabovszky et al 2013, Kalil et al 2015, Fergani et al 2016, which appear to surround the capillaries of the hypophyseal portal system indicating that SP may have the ability to act directly on the anterior pituitary (Kalil et al 2015). Interestingly, even though the Tac2 (gene encoding NKB; Table 1) is known to be coexpressed within Kiss1 in the ARC of various species, including humans (Goodman et al 2007, Navarro et al 2009, Hrabovszky 2014, the Tac1-positive neurons did not colocalize with Kiss1-positive neurons in the mouse Fig. 1).…”

Association of genetic variation in the tachykinin receptor 3 locus with hot flashes and night sweats in the Women's Health Initiative Study

“…First, colocalization studies support physiologic interaction between the NKB pathway and gonadotropin pathways. For example, NKB and estrogen receptor alpha messenger RNA are co-expressed in the human infundibular nucleus 23 and the descending gonadotropin-releasing hormone tract that courses through the infundibular stalk to the neurohypophysis is exposed to dense NKB fiber plexuses 51 . In rats, monkeys, and sheep, NKB fibers project from the arcuate nucleus (the area corresponding to the human infundibular nucleus) to the median eminence, a site with dense gonadotropin-releasing hormone terminals 23 .…”

Altered Gene Expression Profiles of the Hypothalamic Arcuate Nucleus of Male Mice Suggest Profound Developmental Changes in Peptidergic Signaling

“…CGRP immunoreactivity in the ARC is sexually dimorphic, with higher cell numbers in males [71]. The functional significance of the developmental decrease in ARC Calca expression, and the phenotype(s) of the neurons expressing Calca , need to be determined.…”