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Finally, it is worth mentioning that the NKB system may be susceptible to the
organizing effects of sex steroids during the critical period of sexual differentiation
of the brain, i.e., perinatally. Under a physiologic sex steroid environment, the popu-
lation of NKB neurons in the ARC is larger in females than in males [
28
,
55
,
67
,
72
]; however, supraphysiological doses of E
2
or T in both sexes during this critical
period leads to a signifi cant reduction in the number of NKB neurons in the ARC
that persists throughout the animal's life span [
55
,
67
]. Given the exceedingly high
hormone doses used in these studies, it remains unclear if normal physiological
levels of perinatal sex steroids similarly modulate NKB neuron development.
On the whole, such a modulation of the NKB/NK3R system by sex steroids from
early developmental stages to adulthood further unveils a potential role for this sys-
tem in the central control of the reproductive axis.
Identifi cation of the Hypothalamic KNDy Neuron
The emerging interest to decipher the role of NKB in the central control of repro-
duction arose, as mentioned above, in 2009 when human genetic studies docu-
mented hypogonadotropic hypogonadism in patients bearing loss-of-function
mutations in
TAC3
and
TAC3R
genes [
6
]. Admittedly, however, the potential role
of NKB as modulator of GnRH release had been previously recognized in
humans, primates, rodents, and sheep [
25
-
27
,
29
,
32
,
52
,
53
,
55
,
57
,
58
,
60
,
61
,
63
,
73
-
75
]. Nonetheless, the concept of NKB as a regulator of reproductive
function has recently advanced to now being considered part of an intricate net-
work of central factors that govern the acquisition and maintenance of reproduc-
tive function. In this vein, despite the fact that NKB (transcript and protein) has
been described in the hypothalamus for decades, the manner in which NKB
interacts with other hypothalamic factors is only starting to be deciphered. Initial
studies in sheep and rats documented, by immunohistochemistry, a high degree
of co-localization of NKB with the endogenous opioid peptide, dynorphin A
(Dyn), in the ARC [
25
,
27
]. These fi ndings paved the way for a seminal study by
Goodman and collaborators who showed that NKB/Dyn neurons in the ARC of
ewes are also kisspeptin neurons [
32
]. Thereafter, the co-expression of these
three neuropeptides was confi rmed in mice, goats, and monkeys at the levels of
mRNA by
in situ
hybridization and protein by immunohistochemistry (Fig.
15.3
)
[
31
,
56
,
76
], suggesting high physiological relevance for this phenomenon,
which, otherwise, would not have been maintained throughout evolution. This
conserved co-expression has spurred the scientifi c community to rename this
population of neurons as KNDy neurons [
77
]. In addition, of great signifi cance
for the role of NKB in reproductive biology is the fact that virtually all KNDy
neurons also co-express NK3R [
25
,
29
,
42
,
43
,
56
]. Interestingly, studies in mice
and sheep have revealed that the unambiguous co-expression of kisspeptin with
NKB, dynorphin, and NK3R is exclusive to the population of
Kiss1
neurons in
the ARC, while the other major population of
Kiss1
neurons located in the AVPV
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