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bilateral connections between KNDy cells on either side of the hypothalamus [
109
],
as well as reciprocal connection between the POA/RP3V and KNDy populations
[
108
]. Thus the anatomical substrate exists for communication, not just among the
ARC KNDy cells, but also between the two major hypothalamic kisspeptin popula-
tions, as well as between kisspeptin cells on both sides of the brain.
As noted earlier, a majority of KNDy cells are glutamatergic (Table
3.3
), and not
surprisingly, KNDy terminals in contact with other KNDy cells also contain gluta-
matergic markers [
68
]; in addition, KNDy cells receive input from non-KNDy glu-
tamatergic fi bers presumably arising from other regions. Preliminary observations
in the sheep suggest that KNDy cells also receive GABAergic inputs, although
whether these derive in part from neighboring KNDy cells is not known.
Transgenic mice in which the leptin receptor (LepR) drives expression of the
anterograde transneuronal tracer, wheat germ agglutinin (WGA), have been used to
demonstrate that KNDy cells receive synaptic input from LepR-containing cells
[
113
], consistent with evidence that KNDy cells play a functional role in conveying
the infl uence of leptin on the reproductive axis [
114
]. Dual-label ICC studies have
also shown close contacts between NPY and POMC fi bers and KNDy cells in the
sheep ARC [
115
], suggesting that afferents from these metabolic control neurons
may be part of the pathways by which leptin modulates the activity of kisspeptin
neurons and their control of GnRH [
114
]. Such input may be particularly important
in sheep since KNDy neurons in this species appear to lack LepR [
113
].
Less is known about the specifi c afferents that contact RP3V or preoptic
kisspeptin cells. In the mouse, there is clear evidence that RP3V cells of the AVPV
receive direct input from vasopressin (VP) and vasoactive-intestinal polypeptide
(VIP) cells of the suprachiasmatic nucleus (SCN), the site of a central circadian
clock that synchronizes the phase of clock cells in other regions of the brain [
116
].
This input is likely to function as part of the circadian gate regulating the timing of
the GnRH/LH surge in rodents [
117
], and may differ in species in which the surge
is not under circadian control [
45
]. Finally, while there is little anatomical data on
other inputs to RP3V neurons, recent electrophysiological studies of mouse AVPV
kisspeptin neurons in slice preparations [
118
] have provided evidence that these
cells like KNDy neurons are under the presynaptic infl uence of glutamate and
GABA, as well as the inhibitory RFamide peptide, RFRP-3, the mammalian ortho-
log of avian gonadotropin-inhibiting hormone [
119
].
Reciprocal Connections with GnRH Neurons
There is now clear evidence that kisspeptin cells provide direct synaptic input to
GnRH neurons (Fig.
3.2
), from both light and electron microscopic (EM) studies in
rodents, goats, and sheep. Using confocal ICC, kisspeptin-positive close contacts
have been observed upon GnRH cell bodies and dendrites in mice [
11
], sheep [
34
],
horses [
46
], monkeys [
39
], and humans [
44
]. In sheep, these contacts have been co-
localized with synaptophysin, providing further evidence as to their identity as bona
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