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of VIP production in the SCN abolishes GnRH/FOS activation in female rats,
providing further support for the necessity of VIP output in surge generation [ 65 ,
66 ]. Finally, blocking the VPAC 2 receptor attenuates GnRH neuronal cell fi ring dur-
ing the afternoon surge in female, estradiol-treated mice [ 67 ]. Together, these lines
of evidence suggest that direct VIP projections from the SCN to the GnRH system
positively drive the GnRH/LH surge. The potential means by which this pathway
synergizes with multisynaptic projections from the SCN to the reproductive axis is
discussed further below.
Indirect SCN Signaling to the GnRH System
Historically, it was thought that estradiol positive feedback occurred through the
convergence of estrogenic and circadian signaling at the level of GnRH neurons.
The observation that GnRH neurons do not express estrogen receptor
), the
estrogen receptor subtype mediating the positive feedback effects of estradiol
[ 68 - 70 ], motivated the search for additional neural loci at which stimulatory circa-
dian and estrogenic signals converge. The AVPV emerged as a likely site as neurons
in this brain region send monosynaptic projections to GnRH cells, express FOS
coincident with the LH surge, and lesions of the AVPV eliminate estrous cyclicity
in both intact and OVX, estradiol-treated rats [ 8 , 71 - 74 ]. Moreover, the SCN sends
pronounced monosynaptic projections to cells in the AVPV that express ER
α
(ER
α
α
[ 68 , 75 - 77 ], leading to the search for the SCN neurochemical cell phenotypes sending
projections to the AVPV.
Vasopressinergic (AVPergic) cells in the dorsomedial SCN target ER
expressing cells in the AVPV [ 50 , 75 , 76 , 78 - 80 ], and AVP injections produce
surge-like LH levels in SCN-lesioned, OVX, estradiol-treated rats [ 81 ]. Likewise,
cells in this brain region express the vasopressin receptor, V1 a [ 82 , 83 ]. Antiestrogens
targeting the AVPV inhibit the LH surge in OVX, estradiol-treated rats [ 84 ], con-
fi rming the importance of estrogen signaling in ovulation. Vasopressin gene tran-
scription in the SCN is directly controlled by the molecular clockwork at the cellular
level [ 85 - 87 ] and is released in a circadian manner [ 88 ], with a peak coinciding
with the onset of the LH surge [ 89 , 90 ]. AVP release is synchronous with GnRH
secretion in cocultures of medial preoptic area (mPOA) and SCN brains slices [ 91 ].
By contrast, central AVP receptor antagonists attenuate the LH surge in proestrous
rats [ 92 ]. Finally, the inability of clock mutant mice to generate an LH surge is asso-
ciated with diminished AV P mRNA expression in the SCN, a phenotype that can be
restored via central injections of AVP, further linking this peptide to the circadian
control of ovulation [ 6 ].
In rodents, Kiss1 mRNA expressing cells in the AVPV and arcuate (ARC) nuclei
exhibit robust ER
α
labeling [ 93 - 97 ]. The effects of estradiol on kisspeptin activity,
however, varies by nucleus, with ovariectomy decreasing Kiss1 mRNA in the AVPV
and increasing Kiss1 expression in the ARC, pointing to a role for kisspeptin in estra-
diol positive and negative feedback, respectively [ 94 , 98 ]. Exogenous kisspeptin
α
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