Minireview: kisspeptin/neurokinin B/dynorphin (KNDy) cells of the arcuate nucleus: a central node in the control of gonadotropin-releasing hormone secretion

Abstract

Recently, a subset of neurons was identified in the arcuate nucleus of the hypothalamus that colocalize three neuropeptides, kisspeptin, neurokinin B, and dynorphin, each of which has been shown to play a critical role in the central control of reproduction. Growing evidence suggests that these neurons, abbreviated as the KNDy subpopulation, are strongly conserved across a range of species from rodents to humans and play a key role in the physiological regulation of GnRH neurons. KNDy cells are a major target for steroid hormones, form a reciprocally interconnected network, and have direct projections to GnRH cell bodies and terminals, features that position them well to convey steroid feedback control to GnRH neurons and potentially serve as a component of the GnRH pulse generator. In addition, recent work suggests that alterations in KNDy cell peptides may underlie neuroendocrine defects seen in clinical reproductive disorders such as polycystic ovarian syndrome. Taken together, this evidence suggests a key role for the KNDy subpopulation as a focal point in the control of reproductive function in health and disease.

Figure 1

Fluorescent images showing immunocytochemical colocalization of kisspeptin (Kiss) and DYN, kisspeptin and NKB, and DYN and NKB in KNDy cells of the ovine ARC. Bar, 20 μm. (Modified from Refs. and .)

Figure 2

Evidence that KNDy cells directly contact GnRH cell bodies (A and B) and terminals in the median eminence (C and D) in the sheep. A and B, Confocal images (1-μm optical sections) of triple-labeled sections through the ovine MBH showing DYN/NKB-positive (A) and DYN/Kiss-positive (B) axon terminals in close contact with a GnRH soma (A) and dendrite (B), respectively. Note, in A, the presence of a DYN/NKB-positive KNDy cell body nearby. Bars in A and B, 10 μm. C and D, Light microscopic (C) and electron microscopic (D) evidence of direct contacts between DYN and GnRH-positive terminals in the median eminence of a luteal-phase ewe. The section shown in C was processed for dual-label immunoperoxidase detection of DYN (blue-black) and GnRH (brown) and shows close associations (arrows) between DYN and GnRH fibers. D is an electron micrograph of dual-labeled DYN/GnRH section through the median eminence, generated using a preembedding dual-immunoperoxidase technique (110). A terminal containing DYN-positive dense-core vesicles (arrowheads) is seen in direct contact to a GnRH terminal that contains large neurosecretory granules. pt, Pars tuberalis; ze, zona externa of the median eminence. Bars in C and D, 10 μm (C) and 2 μm (D).

Figure 3

A, Schematic diagram showing potential regulatory signals conveyed by KNDy cells to GnRH neurons and the KNDy peptides (kisspeptin, green; NKB, magenta; DYN, red) currently implicated in each action. Note that in some cases (e.g. positive feedback actions of E₂ and stress), two colors indicate that more than one KNDy peptide may be involved. In addition to direct contacts onto GnRH neurons in the POA and MBH, the potential for indirect influence via interneurons (gray cell) is also shown. MB, Mammillary bodies; me, median eminence; oc, optic chiasm; Prog, progesterone. B. Hypothetical model by which synchronous activity among KNDy cells may regulate GnRH pulse frequency (see text for details). GnRH pulse data was redrawn from Moenter et al. (85). Prog, Progesterone.