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administration potently induces LH release as well as upregulates FOS expression in
GnRH neurons [ 93 , 99 - 102 ]. One recent study used genetic ablation strategies to
explore the importance of kisspeptin in puberty and adult reproductive functioning.
Genetic ablation of kisspeptin cells or cells expressing GPR54 throughout develop-
ment does not impact female puberty onset or fertility in adult animals, although loss
of GPR54-expressing cells results in blunted LH, reduced ovarian weights, and
irregular estrous cycling [ 103 ]. In adult animals, acute ablation of kisspeptin neurons
markedly disrupts fertility and estrous cyclicity, whereas removal of ~93% of
GPR54-expressing GnRH cells results in more mild reductions in LH, fertility, and
estrous cycling [ 103 ]. Together, these fi ndings suggest that kisspeptin signaling is
required for adult female reproductive functioning and compensatory mechanisms
can overcome the necessity for kisspeptin when this gene is inactivated throughout
development. However, given that as few as three GnRH neurons are suffi cient to
support activity of the HPG axis [ 104 , 105 ], it is unclear whether GPR54-expressing
GnRH neurons can be dispensed with in LH surge control if a few GPR54-expressing
cell remain following the ablation.
The observation across rodent species that the SCN projects to the AVPV, and
that this brain region is essential for production of the LH surge, combined with the
knowledge that AVPV kisspeptin cells respond positively to estradiol, made these
cells an attractive target of exploration in the initiation of GnRH/LH surge. An early
study showing that Kiss1 cells in the AVPV express FOS at the time of the LH surge
in naturally cycling, OVX, estradiol-treated rats [ 106 , 107 ], provided strong support
for this possibility. To explore the circadian control of this activation pattern,
Kauffman and colleagues maintained mice in constant conditions and examined
Kiss1 mRNA and the percentage of Kiss1 cells expressing the c - fos gene (Fig. 18.2 ).
The maintenance of a circadian pattern in the absence of environmental cues would
suggest endogenous rhythmic control through a circadian mechanism rather than a
rhythm driven by environmental time cues. The authors established that the circa-
dian pattern of Kiss1 expression and the percentage of Kiss1 / c - fos cells persist in
constant darkness [ 56 ], with peak expression of both measures coordinated with the
LH surge, suggesting endogenous circadian regulation of this cell population rather
than reliance on external temporal cues. This daily pattern of Kiss1 expression, and
Kiss1 cells expressing c - fos , is abolished by ovariectomy, and reinstated following
steady-state estradiol replacement [ 56 ], indicating a permissive role for estradiol in
the circadian control of Kiss1 in this species.
These results point to either an endogenous, self-sustained rhythm in kisspeptin
neurons, circadian control through upstream projections from the SCN, or a combi-
nation of both mechanisms of control. We examined these possibilities in Syrian
hamsters. Consistent with fi ndings in mice, FOS expression in kisspeptin immuno-
reactive (ir) cells expressed a daily rhythm in OVX, estradiol-treated hamsters, with
peak coexpression concomitant with the timing of the LH surge. In contrast to
results observed in mice, ovariectomy results in a blunted rhythm of kisspeptin-FOS
coexpression, but not its abolition [ 54 ]. These latter fi ndings point to potential spe-
cies differences in the role that estrogen plays in AVPV kisspeptin regulation and/or
posttranscriptional modifi cation of the Kiss1 gene, resulting in differences in cells
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