KNDy Cells Revisited

Abstract

In the past decade since kisspeptin/neurokinin B/dynorphin (KNDy) cells were first identified in the mammalian hypothalamus, a plethora of new research has emerged adding insights into the role of this neuronal population in reproductive neuroendocrine function, including the basis for GnRH pulse generation and the mechanisms underlying the steroid feedback control of GnRH secretion. In this mini-review, we provide an update of evidence regarding the roles of KNDy peptides and their postsynaptic receptors in producing episodic GnRH release and assess the relative contribution of KNDy neurons to the "GnRH pulse generator." In addition, we examine recent work investigating the role of KNDy neurons as mediators of steroid hormone negative feedback and review evidence for their involvement in the preovulatory GnRH/LH surge, taking into account species differences that exist among rodents, ruminants, and primates. Finally, we summarize emerging roles of KNDy neurons in other aspects of reproductive function and in nonreproductive functions and discuss critical unresolved questions in our understanding of KNDy neurobiology.

Figure 1.

In situ hybridization using RNAscope technology permits three-plex detection of ARC cells colocalizing kisspeptin (Kp), NKB, and dynorphin (Dyn) mRNA. (A) Confocal image (1-µm optical section, ×60 magnification) of kisspeptin (blue), NKB (green), and Dyn (red) mRNA transcripts within ARC cell bodies in the ovariectomized, estradiol-treated ewe. Kp, NKB, and Dyn mRNA is expressed above background threshold levels within all cell bodies except the cell marked with an arrow, which only expresses NKB. (B) High-magnification example image of (i) Kp, (ii) NKB, and (iii) Dyn transcripts expressed in a single cell body (iv, merged image).

Figure 2.

Proposed model for the control of KNDy neuron activity to drive episodic GnRH/LH secretion. Each GnRH pulse is initiated by NKB (green) acting upon reciprocally-connected KNDy neurons to stimulate kisspeptin (blue) release. Kisspeptin drives GnRH (gray) secretion and activates unidentified GPR54/Kiss1R containing ARC neurons (orange) that reinforces the stimulatory actions of NKB on KNDy neurons. GnRH release is then terminated by the release of dynorphin (red) from KNDy neurons acting directly on KNDy neurons, GnRH neurons, and/or unidentified KOR-containing neurons. The color in each terminal indicates the biologically active transmitter (potentially due to selective expression of postsynaptic receptor) and does not reflect selective transport of that peptide to the terminal. Dashed oval represents the ARC. R_Dyn, KOR; R_Kp, GPR54/Kiss1R; R_NKB, NK3R.