The Development of Kisspeptin Circuits in the Mammalian Brain - Kisspeptin Signaling in Reproductive Biology - page 217

IHC studies, some kisspeptin antibodies were not very specifi c, as they were shown
to cross react with other RFamide family members [ 13 ]. The recent use of more
specifi c kisspeptin antibodies has allowed for more precise detection of kisspeptin
immunoreactivity in the brain [ 14 - 19 ]. Utilizing these various methods, many stud-
ies have confi rmed that in adult rodents, Kiss1 (or kisspeptin) is expressed in just a
few discrete brain regions, including a small population in the medial amygdala
(MeA) [ 20 ] and two larger hypothalamic populations in the anteroventral periven-
tricular nucleus and neighboring periventricular nucleus (AVPV/PeN) and the arcu-
ate nucleus (ARC) [ 21 - 23 ]. In non-rodent species, such as sheep and non-human
primates, Kiss1 gene expression and kisspeptin immunoreactivity have, for the most
part, a similar distribution as in rodents, with expression localized to the pre-optic
area (POA) and the ARC/infundibular nucleus (INF) [ 19 , 24 - 27 ]. Expression of
Kiss1 or kisspeptin in the MeA of non-rodent species has not yet been examined.
In contrast to Kiss1 /kisspeptin cell bodies, which are found in just a few discrete
brain regions, kisspeptin-immunoreactive (ir) fi bers are scattered throughout the
brain (discussed in detail in Chap. 3 ) . In adult rodents and sheep, terminals of kiss-
peptin fi bers are found within the POA (and regions containing GnRH neurons), the
ARC and medial basal hypothalamus, the paraventricular nucleus, and the median
eminence (perhaps targeting GnRH axons/terminals) [ 14 , 15 , 28 ]. In mice, addi-
tional regions have been identifi ed containing kisspeptin fi bers, including the lateral
septum, dorsal-medial nucleus of the hypothalamus, bed nucleus of the stria termi-
nalis (BNST), and the MeA [ 14 ]. It also appears that ARC and AVPV/PeN Kiss1
neurons send a number of projections to one another, perhaps allowing these two
populations to directly communicate [ 29 ], although currently there is no evidence
that Kiss1 neurons themselves express Kiss1r [ 30 ].
In adult rodents, the AVPV/PeN region displays sex differences in various mor-
phological parameters [ 31 , 32 ] and is considered the main anatomical site that drives
the sexually dimorphic preovulatory luteinizing hormone (LH) surge that occurs in
adult females [ 33 ]. Mounting evidence supports a critical involvement of AVPV/
PeN kisspeptin neurons in the sexually differentiated LH surge. For example,
Estradiol (E 2 ) dramatically stimulates Kiss1 expression in the AVPV/PeN, and Kiss1
neurons in this region co-express sex steroid receptors, including ER [ 34 ].

Moreover, Kiss1 neuronal activity (as measured by cfos induction) in the AVPV/PeN
is upregulated in a circadian pattern in complete synchrony with the circadian timing
of the LH surge [ 35 ]. Additionally, as will be discussed in more detail later, the
AVPV/PeN Kiss1 population itself is sexually differentiated, just like the preovula-
tory LH surge, with females expressing greater Kiss1 and kisspeptin expression in
this region than males [ 36 ]. It is also worth noting that the AVPV/PeN region con-
tains several other sexually dimorphic subpopulations that have been implicated in
regulating reproduction, such as dopaminergic neurons, which express the tyrosine
hydroxylase (TH) enzyme [ 37 , 38 ], and cells expressing both GABA and glutamate
[ 39 ]. Interestingly, most Kiss1 neurons in the AVPV/PeN co-express TH [ 40 , 41 ],
though the functional signifi cance of such co-expression has yet to be determined.
Kisspeptin neurons in the ARC comprise the largest kisspeptin population in the
brain [ 15 , 24 , 25 , 34 , 36 , 42 , 43 ]. In contrast to the AVPV/PeN population, Kiss1

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