Biology Reference
In-Depth Information
Historically, given the fundamental role of the SCN in maintaining rhythmicity,
it was believed that only cells in this nucleus are capable of intrinsic rhythm
generation. However, this view was challenged in a seminal study establishing that
cultured rat fi broblasts exhibit oscillations in core clock genes when presented with
a serum shock [
29
]. Over the next decade, it became clear that oscillations are a
pervasive property of cells throughout the CNS and periphery. However, in the
SCN, individual oscillators are coupled to form a coherent network where the phase
relationship of individual oscillators is coordinated. In other central and peripheral
systems, whereas individual cells are competent oscillators, without SCN commu-
nication, the phase relationship among populations of oscillators is lost, leading to
an abolition of tissue-level rhythmicity [
30
]. Thus, it is now more appropriate to
conceptualize the “circadian system” as an assembly comprised not only of a master
clock, but also a series of subordinate clocks whose phase and activity is coordi-
nated by the SCN. As described further below, this hierarchy of circadian control
has important implications for understanding the means by which kisspeptin initi-
ates the LH surge and ovulation.
Circadian Control of the Preovulatory LH Surge and Ovulation
Discovery of Ovulatory Circadian Control
The neural mechanisms regulating ovulation are under circadian control in many
spontaneously ovulating species, ensuring that the timing of maximal fertility is
concomitant with the period of highest sexual motivation [
31
,
32
]. Superimposed
upon this circadian control is a dependence of the reproductive cycle on estradiol to
ensure proper maturation of the oocyte at the time of ovulation. The notion that
rodent ovulation is under circadian control was fi rst proposed based on data from a
classic study by Everett and Sawyer [
33
]. In this seminal paper, Everett and Sawyer
sought to determine if ovulation required “neurogenic” activation of the reproduc-
tive axis. To explore this possibility, rats were injected with barbiturate to inhibit
neural communication at the time of ovulation. Through a series of studies, they
determined that a single barbiturate injection delayed ovulation by 24 h, despite the
fact that the impact of the drug was short-lived. Based on this observation, the
authors proposed that a 24 h neural signal initiates ovulation.
Over two decades following the work of Everett and Sawyer, Zucker and col-
leagues performed an elegant series of studies providing further evidence for a 24 h
clock in ovulation and associated sexual motivation in Syrian hamsters (
Mesocricetus
auratus
). When held in a light:dark (LD) cycle, ovulation and the onset of behav-
ioral receptivity occur precisely every 96 h in this species [
34
]. This rhythm in
reproductive activity is endogenously generated and persists in constant conditions
with a period four times their free-running circadian period. Exposing hamsters
housed in constant darkness (DD) to deuterium oxide (a treatment that results in a
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