Stress Regulation of Kisspeptin in the Modulation of Reproductive Function - Kisspeptin Signaling in Reproductive Biology - page 424

A variety of stressors that suppress GnRH pulse generator frequency, including
LPS, downregulate hypothalamic Kiss1 and Kiss1r expression in adult rats [ 35 , 36 ].
Although the neural inputs to the mPOA and ARC that mediate the stress-induced
suppression of Kiss1 and Kiss1r expression within these loci remain to be deter-
mined, CRF is a prime candidate, not only because of its pivotal role in stress-
induced suppression of the GnRH pulse generator [ 37 - 41 ], but also with respect to
data showing that intracerebroventricular (icv) administration of CRF profoundly
decreased Kiss1 and Kiss1r mRNA levels in both the mPOA and ARC [ 35 ].
Moreover, we have shown that icv administration of CRF or CRF antagonist delays
or advances puberty, respectively, without altering the circulating levels of CORT,
suggestive of CRF regulation of kisspeptin at puberty in the female rat [ 42 ]. Indeed,
the delay in puberty consequent to administration of CRF was associated with a
marked reduction in Kiss1 mRNA expression in the mPOA, but not the ARC [ 42 ].
Interestingly, we have shown a reduction in CRF , CRF receptor type 1 ( CRF - R1 ),
and CRF receptor type 2 ( CRF - R2 ) mRNA expression in the PVN, the core regulatory
component of the HPA axis, across pubertal transition in female rats (Fig. 20.2 ) [ 42 ].
Since bilateral lesions of the PVN do not alter the response of the HPG axis to stress
in adult rats [ 43 ], the site and mechanism of action of the endogenous CRF tone that
plays a critical role in the timing of puberty remain elusive. In the Japanese quail,
genetic selection for high or low HPA axis stress responsivity delays or advances
puberty, respectively [ 44 ]. A decrease in CRF and CRF - R1 expression was observed
also in the mPOA, with no change in the ARC, across the pubertal transition in the
rat (Fig. 20.2 ) [ 42 ]. However, possible interaction between CRF and kisspeptin sig-
naling systems in the mPOA remains to be examined.
The importance of the limbic brain, in particular the amygdaloid complex, in
the control of reproductive function and stress responsivity is well recognized
[ 8 , 45 ]. Overexpression of CRF in the central nucleus of the amygdala (CeA)
disrupts estrous cyclicity and reduces GnRH expression [ 46 ]. Further, there is
upregulation of CRF in the CeA with delayed puberty in neonatally LPS-treated
female rats (Li XF and O'Byrne KT; unpublished observation). The MeA is also
a major regulator of the HPG and HPA axes [ 47 ], and there are extensive recip-
rocal connections between the MeA and CeA [ 48 , 49 ]. Stimulation and ablation
studies in prepubertal rats have revealed a critical role for the MeA in the timing
of puberty, with lesions advancing puberty [ 50 ] and stimulation delaying
puberty [ 51 ]. Moreover, we have shown that intra-MeA administration of CRF
delays puberty in female rats (Li XF and O'Byrne KT; unpublished observa-
tion). Although extensive projections from the MeA to the mPOA [ 49 ] provide
an anatomical substrate for a potential interaction with kisspeptin signaling sys-
tems that may mediate this inhibitory effect on pubertal timing, their neuro-
chemical phenotype and modus operandi remain unknown.
Recent studies have shown that kisspeptin neurons project to many brain loc.,
including the PVN, which are not considered components of the HPG axis [ 6 ].
Although kisspeptin administration did not alter glucocorticoid secretion in vivo in
monkeys [ 52 ] and rats [ 53 ], it did decrease CRF mRNA expression in a PVN neural
cell line, thus raising the possibility of a novel mechanism for the regulation of the