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but not endocrine, rhythms [
41
-
43
]. Restoration of locomotor and other behavioral
rhythms occurs in the absence of neural outgrowth from the grafted SCN, suggest-
ing that intact neural connections are required for endocrine rhythms, whereas
behavioral rhythms can be supported by a diffusible signal. Perhaps the best evi-
dence indicating that the SCN communicates via neural connections to the GnRH
system to initiate the LH surge comes from studies using hamsters with “split”
activity rhythms [
44
]. When housed in constant light, some hamsters exhibit a split-
ting in behavior, with two daily activity bouts separated by 12 h, each refl ecting an
antiphase oscillation of the left and right sides of the bilateral SCN [
44
-
46
]. Under
these circumstances, ovariectomized (OVX) hamsters treated with estradiol exhibit
two LH surges in a 24-h period, each phase-locked to an individual activity bout
[
47
]. Because the SCN communicates principally ipsilaterally [
48
-
51
], the authors
hypothesized that, if a neural output signal from the SCN initiates the GnRH/LH
surge, then one hemispheric set of GnRH neurons should be activated, ipsilateral to
the activated SCN, with each locomotor activity bout. Conversely, if controlled by a
diffusible signal, then the GnRH system should be activated concurrently on both
sides of the brain, twice daily, 12 h apart [
52
]. Under these split conditions, the
former possibility manifested, confi rming the importance of neural SCN commu-
nication to the GnRH system in ovulatory control. As described below, more recent
studies by this group and others establish that SCN communication to kisspeptin
cells in the AVPV underlies, in part, this neural signaling cascade initiating the
GnRH/LH surge [
53
-
56
].
Direct SCN Signaling to the GnRH System
The SCN communicates both monosynaptically and multisynaptically to the GnRH
system. Whereas much progress has been made in understanding both modes of
communication, most studies to date have investigated the contribution of individual
pathways in isolation, making it diffi cult to ascertain the signifi cance of interactions
between these pathways. One SCN neuropeptide that has received considerable
attention as a modulator of ovulation is vasoactive intestinal polypeptide (VIP).
Neurons synthesizing VIP are located in the retinorecipient, ventrolateral SCN
“core” [
57
-
59
], and project monsynaptically to GnRH neurons [
49
,
60
] that express
the VIP receptor VPAC
2
[
61
]. SCN-derived VIP input to GnRH neurons is sexually
dimorphic, with female rats exhibiting higher VIPergic innervation [
60
], suggesting
a critical role in female reproductive functioning. Likewise, the number of VIP-
GnRH contacts increases during the post-pubertal transition to reproductive compe-
tence [
62
], a time when estradiol positive feedback is fi rst established. VIP-innervated
GnRH neurons exhibit lower activation levels in middle-aged female rats, suggest-
ing that the degradation of this signaling cascade participates in the transition to
reproductive senescence in female rodents [
63
]. In reproductively competent
females, GnRH neurons receiving VIPergic input preferentially express the neural
activation marker, FOS, at the time of the LH surge [
64
]. In vivo antisense antagonism
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