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RP3V or ARC populations but not both: the lateral septum receives input from RP3V
but not ARC kisspeptin cells, while the lateral preoptic region and lateral hypothalamic
area contain projections from KNDy cells but not the RP3V [
108
].
There are two signifi cant caveats to these observations on the origin of kisspeptin
fi bers. First, co-localization of kisspeptin and other neuropeptides in individual
fi bers and boutons does not exclude the possibility that these are fi bers of passage
en route to another target. Second, as noted above, caution must be used when
evaluating projections based on co-localization of KNDy peptides, since the ability
to detect these markers is clearly dependent on gonadal hormonal status as well as
the dynamics of peptide storage/release at the axon terminal. The recent generation
of several strains of
Kiss1
-Cre mice [
110
] may soon provide another approach that
has the potential to circumvent these limitations. Specifi cally,
Kiss1
-Cre mice can
be crossed with transgenic strains bearing Cre-inducible markers such as TdTomato
or mCherry to provide complete anterograde fi lling of axons arising specifi cally
from kisspeptin cells. To achieve selective anterograde labeling of individual
Kiss1
cell populations (e.g., ARC, RP3V, amygdala), Cre-inducible virus lines expressing
these markers could be injected into these regions in
Kiss1
-Cre mice. Alternatively,
markers for other neuropeptides co-expressed in kisspeptin cells (see sec-
tion
Distribution of Kisspeptin and
Kiss1
in the Adult Brain
) could be incorporated
into this strategy (e.g., crossing NKB-FLP mice with FLP-inducible Kiss-Cre). In
addition, markers could be linked to synaptophysin or other synaptic terminal pro-
teins to allow for identifi cation of boutons at a light microscopic level that represent
bona fi de synaptic terminals rather than fi bers of passage. The use of transgenic/
viral vector approaches for neuroanatomical studies of the kisspeptin system holds
much promise, and should provide critical information on the anatomy and function
of
Kiss1
cells and their connections.
Afferent Inputs
The array of synaptic inputs received by kisspeptin cells has only recently begun to
be systematically studied, so there is little data to compare among species or differ-
ent kisspeptin cell populations. The best-studied kisspeptin cell population with
respect to afferents is the ARC subset. One of the major conserved anatomical fea-
tures of KNDy cells are the reciprocal connections that exist between them, and that
have been demonstrated at a light microscopic level using confocal microscopy
[
105
,
111
] as well as at an electron microscopic level [
112
]. These so-called
“KNDy-KNDy” connections have been hypothesized to serve as a structural basis
for synchronization of activity among KNDy cells, underlying their proposed role
as a component of the GnRH pulse generator [
38
,
60
,
62
,
63
]. It should be noted that
it is not known whether these reciprocal connections represent axon collaterals
within a single neuron (e.g., autosynapses), connections from neighboring KNDy
cells, or inputs from a segregated subset of KNDy cells. Finally, in addition to
KNDy-KNDy connections, evidence from tracing studies indicates that there are
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