Kisspeptin and Seasonality of Reproduction - Kisspeptin Signaling in Reproductive Biology - page 408

season [ 70 , 71 ]. Although these A15 dopaminergic cells are activated by estrogen
during the nonbreeding season, they do not express ER [ 72 ]. Estrogen regulation

may be via afferents to these cells, such as glutamatergic cells of the POA [ 73 ].
Neither do the A14/A15 dopaminergic cells project directly to GnRH cell bodies [ 74 ],
so the question arises as to how there might be any involvement in the regulation of
reproduction. The answer may be found in anterograde tracing experiments, which
show projections from the A14/A15 region to the caudal ARC and the median emi-
nence [ 69 ]; it is possible that these dopaminergic cells regulate kisspeptin cells at this
level, but further work is required before this is established as a bona fi de pathway.
A working model was provided by Goodman et al. for the sheep [ 69 ], which is that
estrogen feedback to the ventromedial hypothalamus and the retrochiasmatic nucleus
is relayed to the A15 dopaminergic elements that then project to kisspeptin neurons in
the ARC to regulate kisspeptin control of the GnRH neurons. The mechanism by
which melatonin, and hence, photoperiod, might regulate this pathway is not known.

α

Role of Melatonin in the Photoperiodic Control
of Kisspeptin Neurons

Evidence for seasonal changes in kisspeptin cell activity being controlled by melatonin
has been provided by work in hamsters, because the decline in Kiss1 expression that is
seen in Syrian hamsters under short-days is lost if the animals are pinealectomized
[ 63 ]. This outcome was recapitulated in a later study, such that the number of Kiss1 -
expressing cells in the ARC of male and female Syrian hamsters held in short days was
increased following pinealectomy (i.e., removal of endogenous melatonin), with no
change in the AVPV population [ 57 ]. Furthermore, pinealectomy of hamsters in long
days prevents Kiss1 downregulation upon subsequent transfer to short-day photope-
riod [ 63 ]. Because it is accepted that melatonin acts at the level of the mediobasal
hypothalamus [ 75 , 76 ] in sheep at least, this observation is consistent with some mech-
anism at this level—perhaps the ARC—to control reproductive function. Moreover,
these Syrian hamster data suggest that Kiss1 expression in the AVPV and ARC is
downregulated in short days via different mechanisms: in the ARC, short days inhibit
Kiss1 via a direct melatonin effect on the hypothalamus, whereas in the AVPV, the
short-day decrease in Kiss1 expression appears to be secondary to the melatonin-
driven reduction of sex steroid feedback levels.
Under long days (active reproductive photoperiod), male Syrian hamsters treated
with melatonin for 8 weeks showed a reduction in both paired testis weight and plasma
testosterone levels [ 57 ]. This was accompanied by a fall in the number of Kiss1 -
expressing cells in both the AVPV and the ARC, consistent with the effect of simulated
transfer from long-day to short-day photoperiod. In the absence of testes, melatonin
caused a reduction in cell number in the ARC within 1 week (with no change in AVPV
cell number), leading to the suggestion that testosterone may potentiate the effect of
melatonin [ 57 ]. This work in Syrian hamsters supports the notion that melatonin drives
the photoperiodic control of reproduction, through a mechanism upstream of the kiss-
peptin cells. It has not been established that kisspeptin cells express melatonin receptors