Kisspeptin and GnRH Pulse Generation - Kisspeptin Signaling in Reproductive Biology - page 306

Putative Mechanism for the Action of Pheromones
on the GnRH Pulse Generator
In goats and sheep, exposure of seasonally anestrous females to the male phero-
mone results in an out-of-seasonal ovulation [ 136 , 137 ]. Because the initial endo-
crine event following the reception of the pheromone is the stimulation of pulsatile
GnRH/LH secretion, it is suggested that the central target of the pheromone signal
is the GnRH pulse generator [ 45 ]. We examined whether the KNDy neuronal net-
work was involved in the pheromone action in OVX goats using MUA recording
with the electrode aimed at KNDy neurons. Exposure to the male pheromone,
between two successive MUA volleys, immediately induced an MUA volley and an
accompanying LH pulse [ 138 ]. This pheromone effect on the MUA volley and LH
secretion was abrogated by the treatment with an NK3R antagonist (Sakamoto
et al., unpublished data). Further, the pheromone evoked the MUA volley but not
LH pulses when kisspeptin/KOR signaling was blocked (Sakamoto et al., unpub-
lished data). Therefore, it seems conceivable that the action of the male pheromone
is indeed mediated by the KNDy neuronal network [ 139 ]. Interestingly, the effect
of the pheromone was time dependent, i.e., the pheromone was not able to induce
the MUA volley immediately after the preceding MUA volley, and the ability of
the pheromone in inducing the MUA volley increased towards the occurrence of the
next MUA volley [ 138 ]. This suggests that pheromone action may be counteracted
by the inhibitory tone of Dyn/KOR signaling, which we propose would gradually
decrease from the maximum to the basal level during the refractory period
(Fig. 14.6b). These pheromone studies also reveal a note of caution that should be
taken into account when observing the GnRH/LH response to an experimental
stimulation of KNDy neurons. If a stimulus acts at the level of Kiss1r (e.g., kiss-
peptin), one would be able to expect a consistent result. However, if the stimulus
acts at the levels of NK3R (e.g., senktide), it is possible that the GnRH/LH response
to the treatment is variable depending on the timing of the treatment between two
spontaneously occurring bursts of KNDy neurons.
Perspective on the Application
GnRH neurons are charged with the role of maintaining the ever-present basal levels
of circulating gonadotropins for the normal functioning of the gonads. Because con-
tinuous exposure of the gonadotrophs to GnRH results in the abolishment of gonad-
otropin secretion, a pulsatile mode of GnRH discharge is obligatory to produce
sustained gonadotropin secretion [ 3 ]. In this context, it is of interest that continuous
infusion of NKB (Fig. 14.4b ) or nor-BNI (Fig. 14.5b ) induced frequent MUA vol-
leys rather than a sustained raise in the MUA. Our hypothesis envisages that the
frequency of periodic bursts in KNDy neurons can be increased by continuously
raising the stimulatory tone of NKB/NK3R signaling by NK3R agonists (Fig. 14.6c)