Kisspeptin and Seasonality of Reproduction - Kisspeptin Signaling in Reproductive Biology - page 405

reproduction by various brain systems, subserving the infl uence of diet, stress,
mood, etc. For example, forebrain glutamatergic cells and inhibitory cells utilizing
gamma amino butyric acid (GABA) as a neurotransmitter are also important in the
regulation of GnRH secretion [ 41 , 46 - 48 ].

Kisspeptin Cells Transmit the Negative Feedback Effect
of Sex Steroids to GnRH Cells

As mentioned above, GnRH cells do not express estrogen ER , but it is clear that sex

steroids regulate the secretion of GnRH. Unlike GnRH cells, ARC kisspeptin cells
express ER

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and progesterone receptors [ 20 ]. Also, in ewes, upregulation of expres-
sion of the kisspeptin gene, Kiss1 , is seen in the ARC following ovariectomy [ 49 ], and
increased numbers of kisspeptin cells are also seen by immunohistochemistry [ 50 ].
Thus, estrogen exerts a tonic restraint on ARC kisspeptin cells in ewes [ 36 ]. Virtually
all kisspeptin cells in the ovine ARC co-express dynorphin (DYN) and NKB [ 27 ].
This has led to the naming of these cells as KNDy (K-kisspeptin; N-neurokinin B;
Dy-dynorphin) cells [ 51 ]. In sheep, there is good evidence that DYN plays a role in
mediating the negative feedback effects of progesterone [ 52 , 53 ]. NKB most likely
stimulates the reproductive axis in sheep, since intracerebroventricular injection of the
agonist senktide increases plasma LH levels, and implant studies suggest that this is
due to action on the cognate receptors for NKB in the retrochiasmatic area [ 54 ].
Another possible role of NKB is positive autoregulation of kisspeptin cells, since the
ARC kisspeptin cells express NKB receptors [ 55 ], and there is evidence that NKB is
required for the function of kisspeptin cells [ 56 ]. There is little currently known about
how NKB expression in kisspeptin cells relates to seasonality.
Effects of castration and sex steroid replacement on kisspeptin cells have also
been studied in hamsters. Castration of male Syrian hamsters during long days
(i.e., the breeding season) increased Kiss1 gene expression in the ARC and reduced
Kiss1 expression in the AVPV. In females, under long days, ovariectomy increased
Kiss1 - expressing cell numbers in the ARC, with no change in the AVPV [ 57 ]. This
indicates a clear sex difference in the AVPV in the response to photoperiod, in this
species at least. Increased Kiss1 gene expression in the ARC following gonadec-
tomy is consistent with the general fi nding across species that negative feedback of
gonadal hormones is exerted in this region. Under short days (i.e., the nonbreeding
season for hamsters), Kiss1 -expressing cells in the ARC of castrate males were not
changed by chronic testosterone treatment, but there was an increase in Kiss1 cell
number in the AVPV. In female hamsters, chronic treatment with estrogen during
short days reduced Kiss1 expression in the ARC and increased expression in the
AVPV [ 57 ]. Again, sex differences were observed, particularly at the level of ARC,
and this should be taken into account when attempting to decipher the seasonal
changes that occur in the hypothalamus of the hamster.
In another study, effects of castration, photoperiod, and testosterone replacement on
kisspeptin-ir cell numbers were measured in the brains of male Siberian hamsters [ 58 ].

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