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the pituitary, in addition to GnRH cells, in mammalian species requires further inves-
tigation to clarify discrepant fi ndings across studies and species [
127
-
131
].
We fi rst examined the possibility that GnIH participates in mediating the
negative-feedback effects of estradiol. Treatment of female rats with GnIH results
in marked inhibition of GnRH neuronal activity at the time of the LH surge, provid-
ing support for this possibility [
132
]. In Syrian hamsters, we found that GnIH-ir
cells express ER
and respond to acute estradiol treatment with increased
FOS expression, suggesting activation by gonadal steroids [
123
]. Contrasting results
were observed in one recent report, with treatment of mice with estrogen for 4 days
leading to a decrease in GnIH mRNA expression [
133
]. The discrepancy in the
impact of estrogen in mice and hamster may result from the timing at which the
brains were collected for analysis and the dose/duration of estrogen treatment. Both
of these possibilities represent interesting areas of investigation that will help to
clarify the specifi c role of this neuropeptide in female reproductive axis regulation.
We next explored whether GnIH neurons might be a locus of integration for
steroidal and circadian signals, providing a mechanism to coordinate the removal of
estradiol negative feedback with SCN-mediated stimulation of the GnRH/LH surge.
First, we examined the pattern of GnIH cellular activity, uncovering a daily pattern
with trough activity at the time of the LH surge, suggesting the removal of negative
feedback at this time [
127
]. Additionally, using anterograde tract tracing, we found
that the SCN projects to a large proportion of GnIH cells, providing a mechanism for
timing removal of negative drive on the GnRH system (Fig.
18.7
). Finally, by exploit-
ing the “splitting” phenomenon seen in hamsters house in LL described previously,
we found that activation of the GnIH system is asymmetrical. Importantly, this asym-
metry is opposite to that seen for the GnRH system, suggesting that the SCN con-
comitantly activates ipsilateral GnRH cells at the same time as removing the
suppressive infl uence of GnIH on the same side of the brain (Fig.
18.7
) [
127
]. Whether
or not removal of negative feedback is required for the LH surge requires further
empirical investigation. A recent series of studies by Pineda et al. using a selective
antagonist (RF9) of GnIH provides converging evidence for a role of GnIH in the LH
surge, with injections of RF9 increasing LH throughout the ovulatory cycle [
134
].
These fi ndings are consistent with a role for GnIH in maintaining low LH concentra-
tion throughout the ovulatory cycle. Together, these fi ndings and those for kisspeptin,
point to an important role for these neuropeptides in the integration of positive and
negative effects of estradiol with circadian signaling in the generation of the GnRH/
LH surge.
α
Circadian Implications for Reproductive Aging
Age-related decline in reproductive axis function is common across species, with
initiation of this decline typically occurring midway through life. In female rodents,
this waning in reproductive function occurs, at least in part, from a reduction in the
ability of the SCN to stimulate the neural circuits underlying ovulatory functioning.
In middle-aged hamsters, for example, the peak level of LH is delayed and exhibits
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