Sex Steroid Regulation of Kisspeptin Circuits - Kisspeptin Signaling in Reproductive Biology - page 271

aspect of the lateral septum and the hypothalamus, running in periventricular and
ventral retrochiasmatic pathways [ 24 ], with a similar distribution in sheep [ 28 ] and
monkeys [ 29 ]. Kisspeptin fi bers make connections and close appositions to GnRH
neurons in mice [ 12 ], rats [ 13 ], sheep [ 14 ], and monkeys [ 29 ]. Despite this, the ana-
tomical origins of kisspeptinergic inputs to GnRH neurons are yet to be fully deter-
mined in any species. In mice, evidence suggests that direct input to GnRH cell
bodies is from AVPV kisspeptin cells, but unlikely to be from kisspeptin cells origi-
nating in the ARC [ 31 ]. However, more recent studies from this group indicate ARC
kisspeptin cells do project to the POA [ 32 ], and a small percentage (<20%) do appose
GnRH neurons [ 33 ]. A similar phenomenon may exist in sheep, because ARC kiss-
peptin cells do not provide substantial input to GnRH cells in the ventromedial POA,
whereas POA kisspeptin cells do [ 34 ]. It was suggested (at least in sheep) that kiss-
peptin cells in the POA could form an interneuronal bridge linking ARC kisspeptin
cells to GnRH cell bodies; this may be particularly relevant in terms of estrogen posi-
tive feedback regulation, but now appears unlikely because no kisspeptin neurons
express Kiss1r [ 15 ]. Alternatively, it is now proposed that the majority of ARC kiss-
peptin neurons fi nd their way to GnRH neurons through terminal-to-terminal com-
munication at the median eminence. Evidence for this stems from in vitro cultures of
mediobasal hypothalamic explants challenged with kisspeptin [ 35 ]. Similar data also
show direct stimulation of GnRH release from the isolated ovine median eminence
[ 15 ]. Kisspeptin fi bers are abundant in the external zone of the median eminence of
sheep [ 36 ] and monkeys [ 29 ] where they appear to appose GnRH terminals. However,
the distribution of kisspeptin fi bers in the median eminence of mice (12, 24) and rats
(12, 24, 25) appears to be less abundant. Whether these kisspeptin terminals are
apposed to GnRH terminals remains to be determined.
Kisspeptin, the “Missing Link” in Sex Steroid Control
of GnRH Secretion
In rodent species, sex steroid-sensitive neurons projecting from the ARC have been
implicated in the negative feedback control of GnRH secretion by estrogen [ 37 - 41 ].
Alternatively, the rodent AVPV/PEN region is a sexually dimorphic nucleus and is
recognized to play an important role in mediating positive feedback effects of estro-
gen to induce the preovulatory surge of GnRH and LH [ 31 , 42 - 44 ]. Kisspeptin cells
in the ARC and AVPV are ideally placed in rodents to mediate these feedback
effects. Moreover, like the LH surge itself, Kiss1 mRNA expression in the AVPV is
sexually dimorphic, with the female AVPV harboring far more Kiss1 -positive cells
than the male [ 12 , 20 ].
In sheep, key differences are apparent in feedback regulation of GnRH compared
to rodents. Estrogen-sensitive cells in the ARC appear central for both the negative
feedback regulation of GnRH and the positive feedback response to estradiol that
causes the preovulatory GnRH/LH surge [ 45 , 46 ]. Again, kisspeptin cells located in