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GnRH output from the various GnRH cells. However, there is no experimental
evidence yet to support the last possibility.
The discovery of kisspeptin might help to settle the controversy over the loca-
tion of the GnRH pulse generator and synchronization of GnRH release. However,
there are still diffi culties we must overcome in order to unravel the mechanism of
GnRH pulse generation. In the rest of this chapter, we will discuss the possibility
that kisspeptin neurons play a major role in generating GnRH pulses in multiple
mammalian species.
MUA Recording of the GnRH Pulse Generator Activity
at Close Vicinity of Kisspeptin Neurons in the Arcuate Nucleus
The Knobil laboratory was the fi rst to identify changes in the multiple-unit activity
(MUA) corresponding to changes in LH pulses [
29
]. By recording electrical activity
in the MBH, the neural activity of the putative GnRH pulse generator was success-
fully represented as periodic bursts of MUA (termed MUA volleys) in monkeys
[
29
-
35
], rats [
36
-
40
], and goats [
41
-
46
]. Those studies unambiguously demon-
strated that the pulsatile discharge of GnRH into the portal vessels is governed by
neural substrates in the MBH that fi re a high-frequency volley of action potentials.
However, none of the aforementioned studies successfully identifi ed a specifi c neu-
ronal population within the MBH that was responsible for the generation of the
MUA volley.
The MUA volley was observed in the MBH in all animals, regardless of the differ-
ence in the distribution of GnRH neurons between species; GnRH cells are relatively
abundant in the MBH of monkeys [
47
,
48
], moderately so in goats [
49
], and few, if
any, in rats [
50
,
51
]. Moreover, during the LH surge, when the activity of GnRH neu-
rons was extremely enhanced, the basal MUA activity did not change and the MUA
volley frequency decreased rather than increased [
30
,
31
,
42
,
44
]. These fi ndings
strongly suggest that the MUA volley originates outside of the GnRH neuronal net-
work. It was proposed that the observed bursts of MUA in the MBH might refl ect the
pulsatile activation of GnRH fi bers as they traverse en passant to the ME; in this case,
the GnRH pulse would be triggered by another unidentifi ed group of oscillators.
Thus, the neural substrate of the GnRH pulse generator was still to be determined.
When MUA is measured in goats through an electrode targeted to the posterior
ARC (which is part of the MBH), in which a number of kisspeptin neurons are con-
centrated (Fig.
14.1a
), rhythmic MUA volleys are found at regular intervals and are
temporally associated with LH pulses (Fig.
14.1b
) in both gonadectomized males [
52
]
and females [
53
]. Furthermore, treatment of OVX goats with estradiol (E2) increases
the intervolley interval (i.e., decreases the MUA frequency), while the duration of
the volley is decreased (Fig.
14.2a-c
). The frequency of the MUA volley in goats is
also profoundly decreased by progesterone (P) (Fig.
14.2d
) [
53
]. These results are
likely to refl ect the negative feedback actions of gonadal sex steroids. Because these
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