KNDy neurons as the GnRH pulse generator: Recent studies in ruminants

Abstract

This review considers three aspects of recent work on the role of KNDy neurons in GnRH pulse generation in ruminants. First, work on basic mechanisms of pulse generation includes several tests of this hypothesis, all of which support it, and evidence that Kiss1r-containing neurons form a positive feedback circuit with the KNDy neural network that strengthen the activity of this network. The second section on pathways mediating external inputs focuses on the influence of nutrition and photoperiod, and describes the evidence supporting roles for proopiomelanocortin (POMC) and agouti-related peptide (AgRP) afferents to KNDy cells in each of these. Finally, we review studies exploring the potential applications of manipulating signaling by kisspeptin, and the other KNDy peptides, to control reproductive function in domestic animals and conclude that, although these approaches show some promise, they do not have major advantages over current practices at this time.

Keywords: Agouti-related peptide; Kiss1r; Kisspeptin; Kisspeptin analogs; Nutrition; Proopiomelanocortin.

Figure 1.

The current KNDy model for pulse generation. It proposes that NKB (purple) acts within the KNDy network to initiate each pulse, and after a few minutes dynorphin (red) is released onto KNDy neurons to terminate the pulse. In this model, the only role for kisspeptin (green) is as a stimulatory signal to GnRH neurons.

Figure 2.

Kiss-10 resets the next LH pulse. Panel A. Test of whether kisspeptin acts to reset the next pulse: If B2 (the time between kisspeptin injection and the next pulse is shorter than before (A) and after (C ) the injection (top) then no reset occurred, but if B2 is the same as A and C, then it has been reset (from Chen et al.,35). Panel B. Injection of Kiss-10 (arrow) into the ARC of an acutely castrated ram (top) or ewe (bottom) only resets the next LH pulse in the ram (^ indicates peak of a LH pulse). Panel C. Effect of Kiss-10 injection (red, blue lines) or vehicle (dotted black line) on A, B1 (time between peak response to Kiss-10 and previous pulse), B2, and C in males (top) and females (bottom).

Figure 3.

Effect of lesioning ARC NK3R-or Kiss1r-containing cells on LH pulses. Panels depict episodic LH secretion before (left panels), and 2 and 3 weeks after (middle and right panels, respectively) injections of Blank-SAP (top panels), NK3-SAP (middle panels), and Kiss-SAP (bottom panels). ^Peak of a LH pulse.

Figure 4.

Proposed role of ARC Kiss1r neurons in GnRH pulse generation. Kisspeptin released from KNDy neurons during a pulse stimulates Kiss1r cells, which in turn increase the activity of the KNDy neural network to increase pulse amplitude and the regular occurrence of the pulses.

Figure 5.

Current working model for the central control of KNDy neurons during undernutrition and with photoperiod. Melanocortin receptors (MR) in KNDy neurons are poised to relay afferent input from proopiomelanocortin (POMC) and agouti-related peptide (AgRP) neurons. While direct leptin receptor (ObRB) and insulin receptor (IR-β) signaling within KNDy neurons remains to be determined in ruminants, growing evidence supports a role for AgRP action in suppression of GnRH/LH secretion during undernutrition and during anestrus.

Figure 6.

AgRP input to ARC kisspeptin neurons increases during anestrus. Photomicrographs of AgRP-close contacts (green) onto kisspeptin neurons (red) in ovine ARC during breeding season (A) and anestrus (B). (C) Bar graph illustrates the percentage of ARC kisspeptin neurons that receive two or more AgRP close contacts during breeding season (BRS; n=5) and anestrus (ANS; n=3). Arrows indicate AgRP close contacts. Images taken using a 63x objective. Scale bars: 10μm.