The Development of Kisspeptin Circuits in the Mammalian Brain - Kisspeptin Signaling in Reproductive Biology - page 221

Although activational effects of sex steroids play a role in transiently increasing
AVPV/PeN Kiss1 expression levels in adulthood [ 22 ], the adult sex steroid milieu does
not account for the observed sex differences in AVPV/PeN Kiss1 expression [ 36 ].
This is evidenced by the fact that male and female rats that are gonadectomized as
adults and treated with identical E 2 levels still display sexually dimorphic Kiss1
expression in the AVPV/PeN [ 36 , 42 ]. In fact, the AVPV/PeN Kiss1 sex difference
appears to be permanently organized by sex steroid signaling early in postnatal
development. In the postnatal “critical period,” which is typically the fi rst week of
postnatal life in rodents, males normally secrete elevated gonadal T, whereas females
secrete little sex steroids at this time. Experiments manipulating the postnatal sex
steroid milieu of rodents support the model that the presence of elevated levels of
postnatal sex steroids determines whether many sexually dimorphic traits develop to
be male-like in adulthood. Thus, in newborn males, elevated sex steroids act to orga-
nize neural circuits to permanently develop a male-like phenotype [ 68 ]. In contrast,
newborn females are not exposed to suffi cient levels of sex steroids, and therefore
their brains permanently develop to be female-like [ 32 , 37 ]. Supporting this “orga-
nizational” model of sexual differentiation, castration of newborn males, to remove
high postnatal T, results in the permanent development of feminized neural popula-
tions. Conversely, sex steroid treatment to newborn females, mimicking elevated T
secretion in postnatal males, results in the permanent development of masculinized
brain circuitry (reviewed in ref. [ 6 ]).
A number of studies have determined that the AVPV/PeN Kiss1 system is orga-
nized postnatally by sex steroids. For example, castrating male rats at birth causes a
permanent feminization of the developing AVPV/PeN Kiss1 system (Fig. 11.3 ) [ 66 ].
Conversely, neonatal female rats treated once with T or E 2 exhibit a permanent
reduction of Kiss1- or kisspeptin-expressing cells in the AVPV/PeN in adulthood,
similar to what is exhibited in normal males (Figs. 11.2 and 11.3 ) [ 36 , 66 , 69 ]. The
fact that postnatal E 2 treatment can, like T, permanently alter the development of the
AVPV/PeN Kiss1 system suggests that postnatal masculinization of this system is
likely mediated via aromatization of T to E 2 . In rats, the effects of postnatal E 2 on
Kiss1 sexual differentiation are likely mediated by ER α and not ER β , because neo-

natal treatment with the ER agonist, PPT, caused a reduction in female AVPV/PeN

kisspeptin levels [ 70 ], while neonatal administration of the ER

α

agonist, DPN, had
no signifi cant effect on adulthood Kiss1 levels [ 71 ]. In these experiments, however,
males and females were not compared, and further studies are needed to determine
if PPT can completely masculinize the female Kiss1 AVPV/PeN population to male
levels. Additionally, the reduction of AVPV/PeN Kiss1 expression in female rats
that were treated neonatally with sex steroids correlates with the inability of these
females to generate an E 2 -mediated LH surge as adults [ 66 ], linking the sexually
dimorphic AVPV/PeN Kiss1 system and the sexually dimorphic LH surge event.
As discussed earlier, Kiss1 mRNA is expressed in the AVPV/PeN as early as
PND 10 in mice of both sexes. However, there are no sex differences in AVPV/PeN
Kiss1 neuron number or Kiss1 mRNA levels/neuron at this age, even though both of
these parameters are well-established sex differences in adulthood [ 40 ]. The sex dif-
ference in Kiss1 cell number, however, is evident by PND 12 and becomes even

β