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induces cFos in KNDy neurons [
59
,
94
], it is likely that a population of KNDy
neurons in the ARC is at least one of the sites of NKB's stimulatory action.
Indeed, recent electrophysiological studies using
Kiss1 - CreGFP
transgenic mice
demonstrated that NKB elicits trains of action potentials in
Kiss1
neurons in the
ARC via NK3R [
58
].
MUA studies in goats also uncovered an important aspect in the pulse-generating
mechanism. Since the activation of NK3R by either a bolus administration of NKB
or continuous infusion of senktide resulted in intermittent MUA volleys, rather than
a single sustained rise in the MUA, it is hypothesized that the stimulatory action of
NKB/NK3R signaling on MUA fi ring is counteracted by some endogenous inhibi-
tory drive, which operates immediately after the induction of the MUA volley and
gradually reduces its inhibitory tone thereafter.
Dyn/KOR Signaling
It has been shown that administration of naloxone, a nonselective opioid receptor
antagonist, increases the frequency of LH pulses [
94
] and bursts of the GnRH pulse
generator [
34
,
43
]. Moreover, a series of elegant studies in sheep indicated that the
inhibitory effect of P on pulsatile GnRH/LH secretion is mediated by endogenous
opioid peptides, namely, Dyn [
95
-
97
]. In support of this, icv administration of Dyn
in goats suppresses the occurrence of the MUA volleys in the ARC region, resulting
in a marked increase in the intervolley interval after the treatment (Fig.
14.5a
). On
the other hand, the blockade of Dyn/KOR signaling by icv administration of nor-
binaltorphimine (nor-BNI, a selective KOR antagonist) reduced the intervolley
interval and increased the volley duration (Fig.
14.5b, c
) [
53
], indicating that the
GnRH pulse generator activity is under a tonic suppression by endogenous Dyn.
In vasopressin neurons of the supraoptic nucleus, Dyn/KOR signaling has been
suggested to participate in termination of the phasic fi ring and the release of vaso-
pressin by an autosynaptic loop [
98
,
99
]. With an analogy to vasopressin neurons, it
is proposed that Dyn/KOR signaling plays a role in extinguishing the bursts of
KNDy neurons in the ARC and regulating the duration of nadir between each bout
of bursts.
Kisspeptin/Kiss1r Signaling
Peripheral injection of kisspeptin-10 [
39
,
54
], or central administration of the full-
length kisspeptin (Wakabayashi et al., unpublished data), which elicits a robust
release of LH, has no effect on either amplitude or frequency of the MUA volley. In
a preliminary experiment, we observed in goats that the blockade of kisspeptin/
Kiss1r signaling by a continuous activation of Kiss1r resulted in a complete sup-
pression of LH secretion and no detectable LH pulses in plasma, as demonstrated in
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