Modelling KNDy neurons and gonadotropin-releasing hormone pulse generation

Abstract

The pulsatile release of gonadotropin-releasing hormone (GnRH) and its frequency are crucial for healthy reproductive function. To understand what drives GnRH pulses, a combination of experimental and mathematical modelling approaches has been used. Early work focussed on the possibility that GnRH pulse generation is an intrinsic feature of GnRH neurons, with autocrine feedback generating pulsatility. However, there is now ample evidence suggesting that a network of upstream neurons secreting kisspeptin, neurokinin-B and dynorphin are the source of this GnRH pulse generator. The interplay of slow positive and negative feedback via neurokinin-B and dynorphin, respectively, allows the network to act as a relaxation oscillator, driving pulsatile secretion of kisspeptin, and consequently, of GnRH and LH. Here, we review the mathematical modelling approaches exploring both scenarios and suggest that with pulsatile GnRH secretion driven by the KNDy pulse generator, autocrine feedback still has the potential to modulate GnRH output.

Figure 1

(a) Diagram of the GnRH pulse generator driven by the KNDy neuronal population and showing the stimulation of gonadotropes by GnRH in the anterior pituitary. (b) Diagram showing the KNDy pulse generator hypothesis. The positive feedback from NKB moves the system into a pulsatile regime. Dynorphin builds up slower, meaning after a period of pulsatility dynorphin builds up enough to inhibit the release of NKB. This causes a decrease in NKB signalling, which moves the system out of the area of pulsatile dynamics in the parameter space.

Figure 2

Effect of perturbations in network excitability and NKB signalling on the position of the solution within the parameter space, and therefore the pulsatile dynamics of the KNDy network model. At position 1, the described increase in either of these two parameters allows the system to retain pulsatility while impacting the pulse frequency and shape (Voliotis et al., 2021). While at point 2, a similar increase would cause the system to cease pulsing and become quiescent.